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1. Prognostic value of HPV circulating tumor DNA detection and quantification in locally advanced cervical cancer

Author: Ludivine Beaussire-Trouvay, Orianne Duhamel, Anne Perdrix, Emilie Lévêque, Roman Vion, Anne Rovelet-Lecrux, Nasrin Sarafan-Vasseur, Frédéric Di Fiore, Agathe Crouzet, Marianne Leheurteur, and Florian Clatot
Subjects: locally advanced, cervical cancer, HPV, circulating DNA, SCC-A and digital PCR, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract: BackgroundCervical cancers are mainly caused by an oncogenic HPV. For locally advanced stages, the standard treatment is radio-chemotherapy (RTCT) followed by brachytherapy. Nevertheless, the prognosis remains highly heterogeneous between patients.ObjectiveWe investigated the prognostic value of HPV circulating tumor DNA (ctDNA) in locally advanced cervical cancers alongside that of Squamous Cell Carcinoma Antigen (SCC-A).MethodsThis single-center retrospective study included patients treated in curative intent for an IB3 to IVA squamous cell cervical cancer. Quantification of HPV ctDNA in serum collected at diagnosis was performed using a multiplex digital PCR assay for the simultaneous detection of 8 HPV genotypes.ResultsAmong the 97 patients included, 76 patients (78.4%) were treated by RTCT, followed by brachytherapy for 57 patients (60%). HPV ctDNA was detected in 59/97 patients at diagnosis (60.8%). This detection was associated with lymph node invasion (p=0.04) but not with tumor stage. A high level of SCC-A at diagnosis was associated with tumor stage (p=0.008) and lymph node invasion (p=0.012). In univariate analysis, better disease-free survival (DFS) was associated with optimal RTCT regimen (p=0.002), exposure to brachytherapy (p=0.0001) and a low SCC-A at diagnosis (continuous analysis, p=0.002). Exploratory analysis revealed that 3/3 patients (100%) whose HPV ctDNA was still detectable at the end of treatment relapsed, while 6/22 patients (27.3%) whose HPV ctDNA was negative at the end of treatment relapsed.ConclusionHPV ctDNA detection at diagnosis of locally advanced cervical squamous cell carcinomas is frequent and related to node invasion, but not to DFS. The prognostic value of HPV ctDNA detection after treatment warrants specific studies.
Published: 2024
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2. Phenotype and imaging features associated with APP duplications

Author: Lou Grangeon, Camille Charbonnier, Aline Zarea, Stephane Rousseau, Anne Rovelet-Lecrux, David Bendetowicz, Marion Lemaitre, Cécile Malrain, Muriel Quillard-Muraine, Kevin Cassinari, David Maltete, Jeremie Pariente, Olivier Moreaud, Eloi Magnin, Benjamin Cretin, Marie-Anne Mackowiak, Adeline Rollin Sillaire, Martine Vercelletto, Elsa Dionet, Olivier Felician, Pauline Rod-Olivieri, Catherine Thomas-Antérion, Gaelle Godeneche, Mathilde Sauvée, Leslie Cartz-Piver, Isabelle Le Ber, Valérie Chauvire, Therèse Jonveaux, Anna-Chloé Balageas, Annie Laquerriere, Charles Duyckaerts, Anne Vital, Andre Maues de Paula, David Meyronet, Lucie Guyant-Marechal, Didier Hannequin, Elisabeth Tournier-Lasserve, Dominique Campion, CNR-MAJ collaborators, Gaël Nicolas, and David Wallon
Subjects: Cerebral amyloid angiopathy, Alzheimer disease, APP duplication, Cerebral MRI, Autosomal dominant, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Background APP duplication is a rare genetic cause of Alzheimer disease and cerebral amyloid angiopathy (CAA). We aimed to evaluate the phenotypes of APP duplications carriers. Methods Clinical, radiological, and neuropathological features of 43 APP duplication carriers from 24 French families were retrospectively analyzed, and MRI features and cerebrospinal fluid (CSF) biomarkers were compared to 40 APP-negative CAA controls. Results Major neurocognitive disorders were found in 90.2% symptomatic APP duplication carriers, with prominent behavioral impairment in 9.7%. Symptomatic intracerebral hemorrhages were reported in 29.2% and seizures in 51.2%. CSF Aβ42 levels were abnormal in 18/19 patients and 14/19 patients fulfilled MRI radiological criteria for CAA, while only 5 displayed no hemorrhagic features. We found no correlation between CAA radiological signs and duplication size. Compared to CAA controls, APP duplication carriers showed less disseminated cortical superficial siderosis (0% vs 37.5%, p = 0.004 adjusted for the delay between symptoms onset and MRI). Deep microbleeds were found in two APP duplication carriers. In addition to neurofibrillary tangles and senile plaques, CAA was diffuse and severe with thickening of leptomeningeal vessels in all 9 autopsies. Lewy bodies were found in substantia nigra, locus coeruleus, and cortical structures of 2/9 patients, and one presented vascular amyloid deposits in basal ganglia. Discussion Phenotypes associated with APP duplications were heterogeneous with different clinical presentations including dementia, hemorrhage, and seizure and different radiological presentations, even within families. No apparent correlation with duplication size was found. Amyloid burden was severe and widely extended to cerebral vessels as suggested by hemorrhagic features on MRI and neuropathological data, making APP duplication an interesting model of CAA.
Published: 2023
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3. A postzygotic de novo NCDN mutation identified in a sporadic FTLD patient results in neurochondrin haploinsufficiency and altered FUS granule dynamics

Author: Gaël Nicolas, Myriam Sévigny, François Lecoquierre, Florent Marguet, Andréanne Deschênes, Maria Carment del Pelaez, Sébastien Feuillette, Anaïs Audebrand, Magalie Lecourtois, Stéphane Rousseau, Anne-Claire Richard, Kévin Cassinari, Vincent Deramecourt, Charles Duyckaerts, Anne Boland, Jean-François Deleuze, Vincent Meyer, Jordi Clarimon Echavarria, Ellen Gelpi, Haruhiko Akiyama, Masato Hasegawa, Ito Kawakami, Tsz H. Wong, Jeroen G. J. Van Rooij, John C. Van Swieten, Dominique Campion, Paul A. Dutchak, David Wallon, Flavie Lavoie-Cardinal, Annie Laquerrière, Anne Rovelet-Lecrux, and Chantelle F. Sephton
Subjects: FUS (fused in sarcoma), Frontotemporal dementia (FTD), NCDN (neurochondrin), Norbin, Genetic variant, De novo mutation, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Frontotemporal dementia (FTD) is a heterogeneous clinical disorder characterized by progressive abnormalities in behavior, executive functions, personality, language and/or motricity. A neuropathological subtype of FTD, frontotemporal lobar degeneration (FTLD)-FET, is characterized by protein aggregates consisting of the RNA-binding protein fused in sarcoma (FUS). The cause of FTLD-FET is not well understood and there is a lack of genetic evidence to aid in the investigation of mechanisms of the disease. The goal of this study was to identify genetic variants contributing to FTLD-FET and to investigate their effects on FUS pathology. We performed whole-exome sequencing on a 50-year-old FTLD patient with ubiquitin and FUS-positive neuronal inclusions and unaffected parents, and identified a de novo postzygotic nonsense variant in the NCDN gene encoding Neurochondrin (NCDN), NM_014284.3:c.1206G > A, p.(Trp402*). The variant was associated with a ~ 31% reduction in full-length protein levels in the patient’s brain, suggesting that this mutation leads to NCDN haploinsufficiency. We examined the effects of NCDN haploinsufficiency on FUS and found that depleting primary cortical neurons of NCDN causes a reduction in the total number of FUS-positive cytoplasmic granules. Moreover, we found that these granules were significantly larger and more highly enriched with FUS. We then examined the effects of a loss of FUS function on NCDN in neurons and found that depleting cells of FUS leads to a decrease in NCDN protein and mRNA levels. Our study identifies the NCDN protein as a likely contributor of FTLD-FET pathophysiology. Moreover, we provide evidence for a negative feedback loop of toxicity between NCDN and FUS, where loss of NCDN alters FUS cytoplasmic dynamics, which in turn has an impact on NCDN expression.
Published: 2022
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4. Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease

Author: Anne Rovelet-Lecrux, Sebastien Feuillette, Laetitia Miguel, Catherine Schramm, Ségolène Pernet, Olivier Quenez, Isabelle Ségalas-Milazzo, Laure Guilhaudis, Stéphane Rousseau, Gaëtan Riou, Thierry Frébourg, Dominique Campion, Gaël Nicolas, and Magalie Lecourtois
Subjects: SorLA, iPSC, Alzheimer’s disease, Maturation defects, Trafficking, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract The SorLA protein, encoded by the SORL1 gene, is a major player in Alzheimer’s disease (AD) pathophysiology. Functional and genetic studies demonstrated that SorLA deficiency results in increased production of Aβ peptides, and thus a higher risk of AD. A large number of SORL1 missense variants have been identified in AD patients, but their functional consequences remain largely undefined. Here, we identified a new pathophysiological mechanism, by which rare SORL1 missense variants identified in AD patients result in altered maturation and trafficking of the SorLA protein. An initial screening, based on the overexpression of 70 SorLA variants in HEK293 cells, revealed that 15 of them (S114R, R332W, G543E, S564G, S577P, R654W, R729W, D806N, Y934C, D1535N, D1545E, P1654L, Y1816C, W1862C, P1914S) induced a maturation and trafficking-deficient phenotype. Three of these variants (R332W, S577P, and R654W) and two maturation-competent variants (S124R and N371T) were further studied in details in CRISPR/Cas9-modified hiPSCs. When expressed at endogenous levels, the R332W, S577P, and R654W SorLA variants also showed a maturation defective profile. We further demonstrated that these variants were largely retained in the endoplasmic reticulum, resulting in a reduction in the delivery of SorLA mature protein to the plasma membrane and to the endosomal system. Importantly, expression of the R332W and R654W variants in hiPSCs was associated with a clear increase of Aβ secretion, demonstrating a loss-of-function effect of these SorLA variants regarding this ultimate readout, and a direct link with AD pathophysiology. Furthermore, structural analysis of the impact of missense variants on SorLA protein suggested that impaired cellular trafficking of SorLA protein could be due to subtle variations of the protein 3D structure resulting from changes in the interatomic interactions.
Published: 2021
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5. Generation of 17q21.31 duplication iPSC-derived neurons as a model for primary tauopathies

Author: Laetitia Miguel, Anne Rovelet-Lecrux, Pascal Chambon, Géraldine Joly-Helas, Stéphane Rousseau, David Wallon, Stéphane Epelbaum, Thierry Frébourg, Dominique Campion, Gaël Nicolas, and Magalie Lecourtois
Subjects: Tauopathies, iPSC-induced neurons, MAPT, 17q21.31, Tau, Biology (General), QH301-705.5
Abstract: Tau proteins belong to the microtubule associated protein family and are mainly expressed in neurons. Tau accumulates in patients’ brain in several neurodegenerative diseases, including Fronto-temporal dementia and Alzheimer’s disease. Recently, we described a 17q21.31 duplication in patients presenting different cognitive or motor symptoms and characterized by the accumulation of different Tau isoforms. This duplication involves four genes, including the MAPT gene that encodes the Tau protein. The main pathophysiological consequence associated with this duplication was a 1.6–1.9-fold increase in the MAPT messenger RNA as measured in blood samples of duplication carriers. However, the pathophysiological consequences of this duplication in a cell type relevant for neurodegenerative diseases have never been explored so far. In this study, we developed the first model of primary tauopathy linked to a 17q21.31 duplication in iPSC-induced neurons from 2 unrelated carriers. As in patients’ blood, we demonstrated that this duplication was associated with an increase in MAPT mRNA resulting in elevated Tau protein levels in iPSC-derived cortical neurons. We believe that these iPSC lines will be a pertinent tool to elucidate how a same genetic cause could lead to distinct types of tauopathies and the pathophysiological mechanisms associated with Tau-mediated neurodegeneration in the 17q21.31 duplication context.
Published: 2022
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6. Description of Joint Alterations Observed in a Family Carrying p.Asn453Ser COMP Variant: Clinical Phenotypes, In Silico Prediction of Functional Impact on COMP Protein and Stability, and Review of the Literature

Author: Quitterie Rochoux, Jana Sopkova-de Oliveira Santos, Christian Marcelli, Anne Rovelet-Lecrux, Virginie Chevallier, Jean-Jacques Dutheil, Sylvain Leclercq, Karim Boumédiene, Catherine Baugé, and Juliette Aury-Landas
Subjects: mutation, genetics, arthritis, osteoarthritis, COMP, dysplasia, Microbiology, QR1-502
Abstract: The role of genetics in the development of osteoarthritis is well established but the molecular bases are not fully understood. Here, we describe a family carrying a germline mutation in COMP (Cartilage Oligomeric Matrix Protein) associated with three distinct phenotypes. The index case was enrolled for a familial form of idiopathic early-onset osteoarthritis. By screening potential causal genes for osteoarthritis, we identified a heterozygous missense mutation of COMP (c.1358C>T, p.Asn453Ser), absent from genome databases, located on a highly conserved residue and predicted to be deleterious. Molecular dynamics simulation suggests that the mutation destabilizes the overall COMP protein structure and consequently the calcium releases from neighboring calcium binding sites. This mutation was once reported in the literature as causal for severe multiple epiphyseal dysplasia (MED). However, no sign of dysplasia was present in the index case. The mutation was also identified in one of her brothers diagnosed with MED and secondary osteoarthritis, and in her sister affected by an atypical syndrome including peripheral inflammatory arthritis of unknown cause, without osteoarthritis nor dysplasia. This article suggests that this mutation of COMP is not only causal for idiopathic early-onset osteoarthritis or severe MED, but can also be associated to a broad phenotypic variability with always joint alterations.
Published: 2021
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7. Deletion of exons 9 and 10 of the Presenilin 1 gene in a patient with Early-onset Alzheimer Disease generates longer amyloid seeds

Author: Kilan Le Guennec, Sarah Veugelen, Olivier Quenez, Maria Szaruga, Stéphane Rousseau, Gaël Nicolas, David Wallon, Frédérique Fluchere, Thierry Frébourg, Bart De Strooper, Dominique Campion, Lucía Chávez-Gutiérrez, and Anne Rovelet-Lecrux
Subjects: Alzheimer Disease, Early-onset, PSEN1, Hydrophilic loop, Aβ43, Amyloid, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Presenilin 1 (PSEN1) mutations are the main cause of autosomal dominant Early-onset Alzheimer Disease (EOAD). Among them, deletions of exon 9 have been reported to be associated with a phenotype of spastic paraparesis.Using exome data from a large sample of 522 EOAD cases and 584 controls to search for genomic copy-number variations (CNVs), we report here a novel partial, in-frame deletion of PSEN1, removing both exons 9 and 10. The patient presented with memory impairment associated with spastic paraparesis, both starting from the age of 56 years. He presented a positive family history of EOAD. We performed functional analysis to elucidate the impact of this novel deletion on PSEN1 activity as part of the γ-secretase complex. The deletion does not affect the assembly of a mature protease complex but has an extreme impact on its global endopeptidase activity. The mutant carboxypeptidase-like activity is also strongly impaired and the deleterious mutant effect leads to an incomplete digestion of long Aβ peptides and enhances the production of Aβ43, which has been shown to be potently amyloidogenic and neurotoxic in vivo.
Published: 2017
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8. Detection of all adult Tau isoforms in a 3D culture model of iPSC-derived neurons

Author: Laetitia Miguel, Anne Rovelet-Lecrux, Maxime Feyeux, Thierry Frebourg, Pierre Nassoy, Dominique Campion, and Magalie Lecourtois
Subjects: Biology (General), QH301-705.5
Abstract: Tauopathies are a class of neurodegenerative diseases characterized by the presence of pathological intracellular deposits of Tau proteins. Six isoforms of Tau are expressed in the adult human brain, resulting from alternative splicing of the MAPT gene. Tau splicing is developmentally regulated such that only the smallest Tau isoform is expressed in fetal brain, contrary to the adult brain showing the expression of all 6 isoforms. Induced Pluripotent Stem Cell (iPSC) technology has opened up new perspectives in human disease modeling, including tauopathies. However, a major challenge to in vitro recapitulation of Tau pathology in iPSC-derived neurons is their relative immaturity. In this study, we examined the switch in Tau splicing from fetal-only to all adult Tau isoforms during the differentiation of iPSC-derived neurons in a new 3D culture system. First, we showed that iPSC-induced neurons inside Matrigel-coated alginate capsules were able to differentiate into cortical neurons. Then, using a new assay that allowed both the qualitative and the quantitative analysis of all adult MAPT mRNA isoforms individually, we demonstrated that BrainPhys-maintained neurons expressed the 6 adult MAPT mRNA transcripts from 25 weeks of maturation, making this model highly suitable for modeling Tau pathology and therapeutic purposes. Keywords: Tau, iPSC-derived neurons, 3D culture
Published: 2019
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9. APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases.

Author: Hélène-Marie Lanoiselée, Gaël Nicolas, David Wallon, Anne Rovelet-Lecrux, Morgane Lacour, Stéphane Rousseau, Anne-Claire Richard, Florence Pasquier, Adeline Rollin-Sillaire, Olivier Martinaud, Muriel Quillard-Muraine, Vincent de la Sayette, Claire Boutoleau-Bretonniere, Frédérique Etcharry-Bouyx, Valérie Chauviré, Marie Sarazin, Isabelle le Ber, Stéphane Epelbaum, Thérèse Jonveaux, Olivier Rouaud, Mathieu Ceccaldi, Olivier Félician, Olivier Godefroy, Maite Formaglio, Bernard Croisile, Sophie Auriacombe, Ludivine Chamard, Jean-Louis Vincent, Mathilde Sauvée, Cecilia Marelli-Tosi, Audrey Gabelle, Canan Ozsancak, Jérémie Pariente, Claire Paquet, Didier Hannequin, Dominique Campion, and collaborators of the CNR-MAJ project
Subjects: Medicine
Abstract: BackgroundAmyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series.Methods and findingsWe report here a novel update (2012-2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers-total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42-in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification.ConclusionsOur findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.
Published: 2017
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10. Deletion of the progranulin gene in patients with frontotemporal lobar degeneration or Parkinson disease

Author: Anne Rovelet-Lecrux, Vincent Deramecourt, Solenn Legallic, Claude-Alain Maurage, Isabelle Le Ber, Alexis Brice, Jean-Charles Lambert, Thierry Frébourg, Didier Hannequin, Florence Pasquier, and Dominique Campion
Subjects: Progranulin, Deletion, Frontotemporal lobar degeneration, Parkinson disease, Neurosciences. Biological psychiatry. Neuropsychiatry, RC321-571
Abstract: Progranulin gene (PGRN) mutations cause ubiquitin-positive frontotemporal lobar degeneration linked to chromosome 17 (FTLDU-17). The spectrum of known mutations strongly suggests that neurodegeneration results from a partial loss of PGRN function and leads to the hypothesis that PGRN gene deletions could be present in a subset of patients. We analysed 63 unrelated French patients with frontotemporal lobar degeneration (FTLD) for PGRN gene dosage alteration by quantitative multiplex PCR of short fluorescent fragments (QMPSF). We identified in one patient with typical PGRN neuropathology a near complete deletion, removing exons 1–11, of the PGRN gene. This deletion, which resulted from a nonhomologous recombination event, was equally present in one affected sister presenting with Parkinson disease (PD). This observation provides a final argument that PGRN mutations exert their pathogenic effect through haploinsufficiency and underlines the diversity of clinical presentations associated with these PGRN alterations.
Published: 2008
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11. uORF-introducing variants in the 5'UTR of the NIPBL gene as a cause of Cornelia de Lange syndrome

Author: Juliette Coursimault, Anne Rovelet‐Lecrux, Kévin Cassinari, Elise Brischoux‐Boucher, Pascale Saugier‐Veber, Alice Goldenberg, François Lecoquierre, Nathalie Drouot, Anne‐Claire Richard, Gabriella Vera, Sophie Coutant, Olivier Quenez, Marion Rolain, Céline Bonnet, Myriam Bronner, Magalie Lecourtois, and Gaël Nicolas
Subjects: Male, Open Reading Frames, Phenotype, Adolescent, De Lange Syndrome, Genetics, Humans, Cell Cycle Proteins, RNA, Messenger, 5' Untranslated Regions, Genetics (clinical)
Abstract: Cornelia de Lange syndrome (CdLS) is a clinically-recognizable rare developmental disorder. About 70% of patients carry a missense or loss-of-function pathogenic variant in the NIPBL gene. We hypothesized that some variants in the 5'-untranslated region (UTR) of NIPBL may create an upstream open reading frame (uORF), putatively leading to a loss of function. We searched for NIPBL 5'-UTR variants potentially introducing uORF by (i) reannotating NGS data of 102 unsolved CdLS patients and (ii) literature and variant databases search. We set up a green fluorescent protein (GFP) reporter assay and studied NIPBL expression in a lymphoblastoid cell line (LCL). We identified two variants introducing a novel ATG codon sequence in the 5'-UTR of NIPBL, both predicted to introduce uORF: a novel c.-457_-456delinsAT de novo mutation in a 15-year-old male with classic CdLS, and a c.-94CT variant in a published family. Our reporter assay showed a significant decrease of GFP levels in both mutant contexts, with similar levels of messenger RNA (mRNA) as compared to wt constructs. Assessment of LCL of one patient showed consistent results with decreased NIPBL protein and unchanged mRNA levels. 5'-UTR uORF-introducing NIPBL variants may represent a rare source of pathogenic variants in unsolved CdLS patients.
Published: 2022

12. Detection of copy-number variations from NGS data using read depth information: a diagnostic performance evaluation

Author: Anne-Claire Richard, Anne Rovelet-Lecrux, Dominique Campion, Sophie Coutant, Kilan Le Guennec, Jean-François Deleuze, Gaëlle Bougeard, Mathieu Castelain, Nathalie Drouot, Pascal Chambon, Stéphanie Vasseur, Thierry Frebourg, Jacqueline Bou, François Lecoquierre, Anne Boland, Géraldine Joly-Helas, Kévin Cassinari, Gaël Nicolas, Stéphane Rousseau, Steeve Fourneaux, Gwendoline Lienard, Edwige Kasper, Myriam Vezain, Pascale Saugier-Veber, Isabelle Tournier, Nathalie Le Meur, Olivier Quenez, Françoise Charbonnier, Emilie Bouvignies, Virginie N'Guyen-Viet, Stéphanie Baert-Desurmont, Sandrine Manase, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre Hospitalier du Rouvray, PORCHET, Nathalie, Université de Rouen Normandie (UNIROUEN), and Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: DNA Copy Number Variations, Computer science, [SDV]Life Sciences [q-bio], Read depth, Computational biology, Sensitivity and Specificity, Article, Workflow, 03 medical and health sciences, 0302 clinical medicine, Gene panel, Exome Sequencing, Multiplex polymerase chain reaction, Genetics, Humans, Genetic Testing, Copy-number variation, Exome, Genetics (clinical), 030304 developmental biology, Comparative Genomic Hybridization, 0303 health sciences, High-Throughput Nucleotide Sequencing, Predictive value, [SDV] Life Sciences [q-bio], Multiplex Polymerase Chain Reaction, 030217 neurology & neurosurgery, Comparative genomic hybridization
Abstract: International audience; The detection of copy-number variations (CNVs) from NGS data is underexploited as chip-based or targeted techniques are still commonly used. We assessed the performances of a workflow centered on CANOES, a bioinformatics tool based on read depth information. We applied our workflow to gene panel (GP) and whole-exome sequencing (WES) data, and compared CNV calls to quantitative multiplex PCR of short fluorescent fragments (QMSPF) or array comparative genomic hybridization (aCGH) results. From GP data of 3776 samples, we reached an overall positive predictive value (PPV) of 87.8%. This dataset included a complete comprehensive QMPSF comparison of four genes (60 exons) on which we obtained 100% sensitivity and specificity. From WES data, we first compared 137 samples with aCGH and filtered comparable events (exonic CNVs encompassing enough aCGH probes) and obtained an 87.25% sensitivity. The overall PPV was 86.4% following the targeted confirmation of candidate CNVs from 1056 additional WES. In addition, our CANOES-centered workflow on WES data allowed the detection of CNVs with a resolution of single exons, allowing the detection of CNVs that were missed by aCGH. Overall, switching to an NGS-only approach should be cost-effective as it allows a reduction in overall costs together with likely stable diagnostic yields. Our bioinformatics pipeline is available at: https://gitlab.bioinfo-diag.fr/nc4gpm/canoes-centered-workflow.
Published: 2020

13. Haploinsufficiency of the Primary Familial Brain Calcification Gene <scp> SLC20A2 </scp> Mediated by Disruption of a Regulatory Element

Author: Christel Thauvin-Robinet, Benoit Delpont, Anne Boland, Robert Olaso, Thierry Frebourg, François Lecoquierre, Pascal Chambon, Anne-Claire Richard, Jean-Luc Battini, Gaël Nicolas, Anne Rovelet-Lecrux, Kévin Cassinari, Dominique Campion, Camille Charbonnier, Olivier Quenez, Jean-François Deleuze, Sandrine Tury, Dorothée Pouliquen, and Jean-François Besancenot
Subjects: 0301 basic medicine, Brain Diseases, DNA Copy Number Variations, Sodium-Phosphate Cotransporter Proteins, Type III, HEK 293 cells, Brain, Haploinsufficiency, Biology, Molecular biology, Reverse transcriptase, 03 medical and health sciences, HEK293 Cells, 030104 developmental biology, 0302 clinical medicine, Neurology, Mutation, Humans, Neurology (clinical), Copy-number variation, Allele, Enhancer, Gene, 030217 neurology & neurosurgery, Exome sequencing
Abstract: OBJECTIVE Primary familial brain calcification (PFBC) is a rare cerebral microvascular calcifying disorder with diverse neuropsychiatric expression. Five genes were reported as PFBC causative when carrying pathogenic variants. Haploinsufficiency of SLC20A2, which encodes an inorganic phosphate importer, is a major cause of autosomal-dominant PFBC. However, PFBC remains genetically unexplained in a proportion of patients, suggesting the existence of additional genes or cryptic mutations. We analyzed exome sequencing data of 71 unrelated, genetically unexplained PFBC patients with the aim to detect copy number variations that may disrupt the expression of core PFBC-causing genes. METHODS After the identification of a deletion upstream of SLC20A2, we assessed its consequences on gene function by reverse transcriptase droplet digital polymerase chain reaction (RT-ddPCR), an ex vivo inorganic phosphate uptake assay, and introduced the deletion of a putative SLC20A2 enhancer mapping to this region in human embryonic kidney 293 (HEK293) cells by clustered regularly interspaced short palindromic repeats (CRISPR) - CRISPR-associated protein 9 (Cas9). RESULTS The 8p11.21 deletion, segregating with PFBC in a family, mapped 35 kb upstream of SLC20A2. The deletion carriers/normal controls ratio of relative SLC20A2 mRNA levels was 60.2% (P
Published: 2020

14. Impaired SorLA maturation and trafficking as a new mechanism for SORL1 missense variants in Alzheimer disease

Author: Sébastien Feuillette, Segalas-Milazzo I, Catherine Schramm, Dominique Campion, Anne Rovelet-Lecrux, Laetitia Miguel, Magalie Lecourtois, Pernet S, Gaëtan Riou, Gaël Nicolas, Thierry Frebourg, Stéphane Rousseau, Guilhaudis L, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Rouen, Normandie Université (NU), Chimie Organique et Bioorganique : Réactivité et Analyse (COBRA), Institut Normand de Chimie Moléculaire Médicinale et Macromoléculaire (INC3M), Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Université Le Havre Normandie (ULH), Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie Organique Fine (IRCOF), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Physiopathologie, Autoimmunité, maladies Neuromusculaires et THErapies Régénératrices (PANTHER)
Subjects: 0303 health sciences, iPSC, Endosome, Endoplasmic reticulum, [SDV]Life Sciences [q-bio], HEK 293 cells, SORL1, maturation defects, Biology, medicine.disease, Phenotype, Cell biology, 03 medical and health sciences, SorLA, 0302 clinical medicine, trafficking, medicine, Missense mutation, Secretion, Alzheimer's disease, Alzheimer’s disease, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: The SorLA protein, encoded by the SORL1 gene, is a major player in Alzheimer’s disease (AD) pathophysiology. Functional and genetic studies demonstrated that SorLA deficiency results in increased production of Aβ peptides, and thus a higher risk of AD. A large number of SORL1 missense variants have been identified in AD patients, but their functional consequences remain largely undefined. Here, we identified a new pathophysiological mechanism, by which rare SORL1 missense variants identified in AD patients result in altered maturation and trafficking of the SorLA protein. An initial screening, based on the overexpression of 71 SorLA variants in HEK293 cells, revealed that 15 of them (S114R, R332W, G543E, S564G, S577P, R654W, R729W, D806N, Y934C, D1535N, D1545E, P1654L, Y1816C, W1862C, P1914S) induced a maturation and trafficking-deficient phenotype. Three of these variations (R332W, S577P, and R654W) and two maturation-competent variations (S124R and N371T) were further studied in details in CRISPR/Cas9-modified hiPSCs. When expressed at endogenous levels, the R332W, S577P, and R654W SorLA variants also showed a maturation defective profile. We further demonstrated that these variants were largely retained in the endoplasmic reticulum, resulting in a reduction in the delivery of SorLA mature protein to the plasma membrane and to the endosomal system. Importantly, expression of the R332W and R654W variants in hiPSCs was associated with a clear increase of Aβ secretion, demonstrating a loss-of-function effect of these SorLA variants regarding this ultimate readout, and a direct link with AD pathophysiology. Furthermore, structural analysis of the impact of missense variations on SorLA protein indicated that impaired cellular trafficking of SorLA protein could be due to subtle variations of the protein 3D structure resulting from changes in the interatomic interactions.
Published: 2021

15. Generation of 17q21.31 duplication iPSC-derived neurons as a model for primary tauopathies

Author: Laetitia Miguel, Anne Rovelet-Lecrux, Pascal Chambon, Géraldine Joly-Helas, Stéphane Rousseau, David Wallon, Stéphane Epelbaum, Thierry Frébourg, Dominique Campion, Gaël Nicolas, and Magalie Lecourtois
Subjects: Neurons, Tauopathies, Induced Pluripotent Stem Cells, Humans, Neurodegenerative Diseases, tau Proteins, Cell Biology, General Medicine, Developmental Biology
Abstract: Tau proteins belong to the microtubule associated protein family and are mainly expressed in neurons. Tau accumulates in patients' brain in several neurodegenerative diseases, including Fronto-temporal dementia and Alzheimer's disease. Recently, we described a 17q21.31 duplication in patients presenting different cognitive or motor symptoms and characterized by the accumulation of different Tau isoforms. This duplication involves four genes, including the MAPT gene that encodes the Tau protein. The main pathophysiological consequence associated with this duplication was a 1.6-1.9-fold increase in the MAPT messenger RNA as measured in blood samples of duplication carriers. However, the pathophysiological consequences of this duplication in a cell type relevant for neurodegenerative diseases have never been explored so far. In this study, we developed the first model of primary tauopathy linked to a 17q21.31 duplication in iPSC-induced neurons from 2 unrelated carriers. As in patients' blood, we demonstrated that this duplication was associated with an increase in MAPT mRNA resulting in elevated Tau protein levels in iPSC-derived cortical neurons. We believe that these iPSC lines will be a pertinent tool to elucidate how a same genetic cause could lead to distinct types of tauopathies and the pathophysiological mechanisms associated with Tau-mediated neurodegeneration in the 17q21.31 duplication context.
Published: 2021

16. Clinical and neuropathological diversity of tauopathy in MAPT duplication carriers

Author: Isabelle Le Ber, Marie Sarazin, Olivier Quenez, Florence Clavaguera, Catherine Schramm, Anne Rovelet-Lecrux, Camille Heitz, Mathieu Mula, Stéphane Epelbaum, Susana Boluda, Charles Duyckaerts, Manon Thierry, Didier Hannequin, Magalie Lecourtois, Serge Marty, Michel Bottlaender, Julien Lagarde, David Wallon, Natsuko Nakamura, François Sellal, Antoine Bonnevalle, Laetitia Miguel, Gaël Nicolas, Stéphane Rousseau, Dominique Campion, Thérèse Rivasseau Jonveaux, Aline Zarea, Eloi Magnin, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Neurologie de la mémoire et du langage [CHU Ste Anne], Université Paris Descartes - Paris 5 (UPD5), Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), LaBoratoire d'Imagerie biOmédicale MultimodAle Paris-Saclay (BIOMAPS), Service Hospitalier Frédéric Joliot (SHFJ), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité BioMaps (BIOMAPS), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Proband, Adult, Male, Pathology, medicine.medical_specialty, Heterozygote, [SDV]Life Sciences [q-bio], Tau protein, tau Proteins, Pathology and Forensic Medicine, Progressive supranuclear palsy, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Extrapyramidal symptoms, Alzheimer Disease, Basal ganglia, medicine, Humans, Cognitive Dysfunction, Age of Onset, ComputingMilieux_MISCELLANEOUS, Inclusion Bodies, biology, business.industry, Brain, Middle Aged, medicine.disease, 030104 developmental biology, Tauopathies, Chromosomal region, biology.protein, Female, Neurology (clinical), Tauopathy, Alzheimer's disease, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract: Microduplications of the 17q21.31 chromosomal region encompassing the MAPT gene, which encodes the Tau protein, were identified in patients with a progressive disorder initially characterized by severe memory impairment with or without behavioral changes that can clinically mimic Alzheimer disease. The unique neuropathological report showed a primary tauopathy, which could not be unanimously classified in a given known subtype, showing both 4R- and 3R-tau inclusions, mainly within temporal cortical subregions and basal ganglia, without amyloid deposits. Recently, two subjects harboring the same duplication were reported with an atypical extrapyramidal syndrome and gait disorder. To decipher the phenotypic spectrum associated with MAPT duplications, we studied ten carriers from nine families, including two novel unrelated probands, gathering clinical (n = 10), cerebrospinal fluid (n = 6), MRI (n = 8), dopamine transporter scan (n = 4), functional (n = 5), amyloid (n = 3) and Tau-tracer (n = 2) PET imaging data as well as neuropathological examination (n = 4). Ages at onset ranged from 37 to 57 years, with prominent episodic memory impairment in 8/10 patients, associated with behavioral changes in four, while two patients showed atypical extrapyramidal syndrome with gait disorder at presentation, including one with associated cognitive deficits. Amyloid imaging was negative but Tau imaging showed significant deposits mainly in both mesiotemporal cortex. Dopaminergic denervation was found in 4/4 patients, including three without extrapyramidal symptoms. Neuropathological examination exclusively showed Tau-immunoreactive lesions. Distribution, aspect and 4R/3R tau aggregates composition suggested a spectrum from predominantly 3R, mainly cortical deposits well correlating with cognitive and behavioral changes, to predominantly 4R deposits, mainly in the basal ganglia and midbrain, in patients with prominent extrapyramidal syndrome. Finally, we performed in vitro seeding experiments in HEK-biosensor cells. Morphological features of aggregates induced by homogenates of three MAPT duplication carriers showed dense/granular ratios graduating between those induced by homogenates of a Pick disease and a progressive supranuclear palsy cases. These results suggest that MAPT duplication causes a primary tauopathy associated with diverse clinical and neuropathological features.
Published: 2021

17. Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene dose-sensitive AD suppressor in human brain

Author: Jia Nee Foo, Andre Strydom, Xiaowei Shao, David Koschut, Goran Šimić, Željka Krsnik, Sarah Hamburg, Ivan Alić, Steven Havlicek, Hlin Kvartsberg, Jürgen Groet, Paul T. Francis, Yee Jie Yeap, Pollyanna Goh, Hilkka Soininen, Rosalyn Hithersay, John Hardy, Niamh L. O'Brien, Margaret Phillips, David Laurence Becker, N. Ray Dunn, Gunnar Brinkmalm, David Wallon, Gillian Gough, Henrik Zetterberg, Erik Portelius, Mark Turmaine, Aoife Murray, Jorge Ghiso, Kaj Blennow, Eleni Gkanatsiou, Agueda Rostagno, Carla M. Startin, Ivica Kostović, Konstantin Pervushin, Emanuela V. Volpi, Dean Nižetić, Joanne E. Martin, Dinko Mitrečić, Reinhard Brunmeir, Kin Y. Mok, and Anne Rovelet-Lecrux
Subjects: 0301 basic medicine, Pathology, Diseases, Trisomy, cerebral organoid, 0302 clinical medicine, β-secretase, Aspartic Acid Endopeptidases, Genes, Suppressor, education.field_of_study, Human Biology & Physiology, biology, BACE2, Brain, Human brain, trisomy 21, Organoids, Psychiatry and Mental health, medicine.anatomical_structure, Model organisms, Down syndrome, medicine.medical_specialty, Amyloid beta, Population, Immunology, BACE-inhibitor, Alzheimer, cerebral organoids, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Signalling & Oncogenes, Alzheimer Disease, medicine, Organoid, Genetics, Dementia, Humans, education, Molecular Biology, Amyloid beta-Peptides, business.industry, FOS: Clinical medicine, Cell Biology, medicine.disease, 030104 developmental biology, biology.protein, Amyloid Precursor Protein Secretases, Down Syndrome, business, Chromosome 21, 030217 neurology & neurosurgery, Neuroscience, Developmental Biology
Abstract: A population of more than six million people worldwide at high risk of Alzheimer’s disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grown in vitro from non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss. Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome 21 gene BACE2, but prevented by combined chemical β and γ-secretase inhibition. We found that T21 organoids secrete increased proportions of Aβ-preventing (Aβ1–19) and Aβ-degradation products (Aβ1–20 and Aβ1–34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1 inhibitors. Combined, our data prove the physiological role of BACE2 as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ~30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.
Published: 2021

18. Atypical astroglial pTDP-43 pathology in astroglial predominant tauopathy

Author: Estrella Morenas, Roser Ribosa, Anne Rovelet-Lecrux, Raquel Sánchez-Valle, Teresa Ximelis, Anna Antonell, Sergi Borrego, Pilar Mercadel‐Fañanas, Pol Andrés-Benito, Maria Teresa Abellan-Vidal, Beatriz Gómez-Ansón, Laura Molina-Porcel, Ellen Gelpi, Sigrid Klotz, Dolores Lopez-Villegas, Iban Aldecoa, Isidre Ferrer, and Juan Fortea
Subjects: Pathology, medicine.medical_specialty, Histology, TDP-43, Biology, medicine.disease, Pathology and Forensic Medicine, Neurology, astroglial tauopathy, glia limitans/perivascular glia, Physiology (medical), pTDP-43, medicine, FTLD-Tau, Neurology (clinical), Tauopathy, Glia limitans/perivascular glia, Astroglial tauopathy
Abstract: We observed atypical astrocytic pTDP-43 pathology in astroglial predominant tauopathy.
Published: 2021

19. Assessment of SORL1 rare variants segregation in Alzheimer disease families and in vitro models suggests diverse penetrance and oligogenic inheritance

Author: Laetitia Miguel, Magalie Lecourtois, Anne Rovelet-Lecrux, Aline Zarea, Dominique Campion, Camille Charbonnier, Catherine Schramm, Gaël Nicolas, Stéphane Rousseau, David Wallon, and Morgane Lacour
Subjects: Genetics, Epidemiology, Health Policy, SORL1, Oligogenic Inheritance, Disease, Biology, medicine.disease, Penetrance, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, medicine, Neurology (clinical), Geriatrics and Gerontology, Alzheimer's disease
Published: 2020

20. Alzheimer‐like pathology in trisomy 21 cerebral organoids amenable to pharmacological inhibition reveals BACE2 as a gene‐dose‐sensitive AD‐suppressor in human brain

Author: John Hardy, Aoife Murray, David Wallon, Dean Nizetic, Agueda Rostagno, Ivan Alić, Pollyanna Goh, Gillian Gough, Jorge Ghiso, Andre Strydom, Henrik Zetterberg, Erik Portelius, Eleni Gkanatsiou, Anne Rovelet-Lecrux, and Paul T. Francis
Subjects: Pathology, medicine.medical_specialty, Epidemiology, Health Policy, Human brain, Biology, medicine.disease, law.invention, Psychiatry and Mental health, Cellular and Molecular Neuroscience, medicine.anatomical_structure, Developmental Neuroscience, law, medicine, Organoid, Suppressor, Neurology (clinical), Geriatrics and Gerontology, Trisomy, Gene
Published: 2020

21. Phenotypes associated with MAPT duplications

Author: Stéphane Epelbaum, Muriel Quillard-Muraine, David Wallon, Dominique Campion, François Sellal, Antoine Bonnevalle, Gaël Nicolas, Michel Bottlaender, Susana Boluda, Marie Sarazin, Camille Heitz, Isabelle Le Ber, Didier Hannequin, Thérèse Rivasseau Jonveaux, Anne-Claire Richard, Anne Rovelet-Lecrux, Stéphane Rousseau, Charles Duyckaerts, Julien Lagarde, Olivier Quenez, Camille Charbonnier, Eloi Magnin, and Mathieu Chastan
Subjects: Genetics, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Epidemiology, Health Policy, Neurology (clinical), Geriatrics and Gerontology, Biology, Phenotype
Published: 2020

22. 'Patient-specific Alzheimer-like pathology in trisomy 21 cerebral organoids reveals BACE2 as a gene-dose-sensitive AD-suppressor in human brain'

Author: Jorge Ghiso, Agueda Rostagno, Steven Havlicek, Sarah Hamburg, Ivan Alić, Carla M. Startin, Rosalyn Hithersay, Eleni Gkanatsiou, David Koschut, Hlin Kvartsberg, Hilkka Soininen, Emanuela V. Volpi, Xiaowei Shao, Goran Šimić, Željka Krsnik, Dean Nižetić, Mark Turmaine, Joanne E. Martin, Jürgen Groet, Aoife Murray, Erik Portelius, Pollyanna Goh, Jia Nee Foo, Niamh L. O'Brien, Henrik Zetterberg, Andre Strydom, Yee Jie Yeap, David Wallon, Gillian Gough, John Hardy, Margaret Phillips, N. Ray Dunn, Dinko Mitrečić, Gunnar Brinkmalm, Reinhard Brunmeir, Kin Y. Mok, Anne Rovelet-Lecrux, Kaj Blennow, Ivica Kostović, Konstantin Pervushin, Paul T. Francis, and David Laurence Becker
Subjects: education.field_of_study, Down syndrome, Pathology, medicine.medical_specialty, business.industry, Population, Human brain, Disease, medicine.disease, Cerebrospinal fluid, medicine.anatomical_structure, medicine, Organoid, Dementia, education, Trisomy, business
Abstract: A population of >6 million people worldwide at high risk of Alzheimer’s disease (AD) are those with Down Syndrome (DS, caused by trisomy 21 (T21)), 70% of whom develop dementia during lifetime, caused by an extra copy of β-amyloid-(Aβ)-precursor-protein gene. We report AD-like pathology in cerebral organoids grownin vitrofrom non-invasively sampled strands of hair from 71% of DS donors. The pathology consisted of extracellular diffuse and fibrillar Aβ deposits, hyperphosphorylated/pathologically conformed Tau, and premature neuronal loss.Presence/absence of AD-like pathology was donor-specific (reproducible between individual organoids/iPSC lines/experiments). Pathology could be triggered in pathology-negative T21 organoids by CRISPR/Cas9-mediated elimination of the third copy of chromosome-21-geneBACE2, but prevented by combined chemical β and γ-secretase inhibition. We found that T21-organoids secrete increased proportions of Aβ-preventing (Aβ1-19) and Aβ-degradation products (Aβ1-20 and Aβ1-34). We show these profiles mirror in cerebrospinal fluid of people with DS. We demonstrate that this protective mechanism is mediated by BACE2-trisomy and cross-inhibited by clinically trialled BACE1-inhibitors. Combined, our data prove the physiological role ofBACE2as a dose-sensitive AD-suppressor gene, potentially explaining the dementia delay in ∼30% of people with DS. We also show that DS cerebral organoids could be explored as pre-morbid AD-risk population detector and a system for hypothesis-free drug screens as well as identification of natural suppressor genes for neurodegenerative diseases.
Published: 2020
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23. Early-Onset Cerebral Amyloid Angiopathy and Alzheimer Disease Related to an APP Locus Triplication

Author: Manuele Mine, Eva Pipiras, Anne Rovelet-Lecrux, Lou Grangeon, Bernard Croisile, Nathalie Le Meur, Olivier Moreaud, Thibault Coste, Kévin Cassinari, Jean Boutonnat, Elisabeth Tournier-Lasserve, Stéphane Rousseau, David Wallon, Gaël Nicolas, Dominique Campion, and Maïté Formaglio
Subjects: Proband, Pathology, medicine.medical_specialty, Amyloid, biology, Locus (genetics), medicine.disease, Article, mental disorders, Gene duplication, medicine, Amyloid precursor protein, biology.protein, Neurology (clinical), Cerebral amyloid angiopathy, Alzheimer's disease, Genetics (clinical), Comparative genomic hybridization
Abstract: Background and ObjectiveTo report a triplication of the amyloid-β precursor protein (APP) locus along with relative messenger RNA (mRNA) expression in a family with autosomal dominant early-onset cerebral amyloid angiopathy (CAA) and Alzheimer disease (AD).MethodsFour copies of the APP gene were identified by quantitative multiplex PCR of short fluorescent fragments, fluorescent in situ hybridization (FISH), and array comparative genomic hybridization. APP mRNA levels were assessed using reverse-transcription–digital droplet PCR in the proband's whole blood and compared with 10 controls and 9 APP duplication carriers.ResultsBeginning at age 39 years, the proband developed severe episodic memory deficits with a CSF biomarker profile typical of AD and multiple lobar microbleeds in the posterior regions on brain MRI. His father had seizures and recurrent cerebral hemorrhage since the age of 37 years. His cerebral biopsy showed abundant perivascular amyloid deposits, leading to a diagnosis of CAA. In the proband, we identified 4 copies of a 506-kb region located on chromosome 21q21.3 and encompassing the whole APP gene without any other gene. FISH suggested that the genotype of the proband was 3 copies/1 copy corresponding to an APP locus triplication, which was consistent with the presence of 2 APP copies in the healthy mother and with the paternal medical history. Analysis of the APP mRNA level showed a 2-fold increase in the proband and a 1.8 fold increase in APP duplication carriers compared with controls.DiscussionIncreased copy number of APP is sufficient to cause AD and CAA, with likely earlier onset in case of triplication compared with duplication.
Published: 2021

24. Detection of copy number variations from NGS data using read depth information: a diagnostic performance evaluation

Author: Olivier Quenez, Kevin Cassinari, Sophie Coutant, Francois Lecoquierre, Kilan Le Guennec, Stéphane Rousseau, Anne-Claire Richard, Stéphanie Vasseur, Emilie Bouvignies, Jacqueline Bou, Gwendoline Lienard, Sandrine Manase, Steeve Fourneaux, Nathalie Drouot, Virginie Nguyen-Viet, Myriam Vezain, Pascal Chambon, Géraldine Joly Helas, Nathalie Le Meur, Mathieu Castelain, Anne Boland, Jean-François Deleuze, Isabelle Tournier, Francoise Charbonnier, Edwige Kasper, Gaëlle Bougeard, Thierry Frebourg, Pascale Saugier-Veber, Stephanie Baert-Desurmont, Dominique Campion, Anne Rovelet-Lecrux, Gaël Nicolas, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National en Génomique Humaine, Institut de Génomique, CEA, Evry, France, Department of Research, Centre hospitalier du Rouvray, Sotteville-lès-Rouen, France, and Quenez, Olivier
Subjects: [SDV.BIBS] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Sensitivity, CANOES, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Bioinformatics, Read-depth information, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Panel, Exome, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], CNVs detection
Published: 2019

25. Causative Mutations and Genetic Risk Factors in Sporadic Early Onset Alzheimer’s Disease Before 51 Years

Author: Aline Zarea, Eloi Magnin, Stéphane Epelbaum, Claire Paquet, Valérie Chauviré, Florence Pasquier, Anne Boland, Marie Sarazin, David Wallon, Bruno Salomon, Dominique Campion, Olivier Godefroy, Olivier Martinaud, Mathilde Sauvée, Sophie Auriacombe, Cecilia Marelli, Frédérique Etcharry-Bouyx, Gaël Nicolas, Jean-François Deleuze, Anne-Claire Richard, Vincent de la Sayette, Audrey Gabelle, Thérèse Rivasseau Jonveaux, Stéphane Rousseau, Jérémie Pariente, Mathieu Ceccaldi, Maïté Formaglio, Anne Rovelet-Lecrux, Didier Hannequin, Adeline Rollin-Sillaire, Bernard Croisile, Isabelle Le Ber, Morgane Lacour, Olivier Quenez, Olivier Rouaud, Muriel Quillard-Muraine, Claire Boutoleau-Bretonnière, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Normandie Université (NU)-Normandie Université (NU), CHU Rouen, Normandie Université (NU), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de neurologie [Rouen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Centre Hospitalier Sainte Anne [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de neurologie et de neuropsychologie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Laboratoire de Neurosciences Fonctionnelles et Pathologies (LNFP), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [Lyon], CHU Lyon, Hospices Civils de Lyon (HCL), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre Hospitalier Universitaire [Grenoble] (CHU), CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut National de la Santé et de la Recherche Médicale (INSERM), Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Male, MESH: Mutation, 03 medical and health sciences, Amyloid beta-Protein Precursor, 0302 clinical medicine, MESH: Whole Exome Sequencing, Alzheimer Disease, Risk Factors, MESH: Risk Factors, MESH: Amyloid beta-Protein Precursor, PSEN2, Genotype, Genetic variation, Presenilin-2, Exome Sequencing, medicine, PSEN1, Presenilin-1, Humans, Early-onset Alzheimer's disease, Genetic Predisposition to Disease, Risk factor, Allele, Exome sequencing, Genetics, MESH: Humans, MESH: Middle Aged, business.industry, General Neuroscience, MESH: Genetic Predisposition to Disease, General Medicine, Middle Aged, medicine.disease, MESH: Presenilin-1, MESH: Male, 3. Good health, MESH: Presenilin-2, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Female, Geriatrics and Gerontology, business, MESH: Female, 030217 neurology & neurosurgery, MESH: Alzheimer Disease
Abstract: International audience; Background:Pathogenic variants in the autosomal dominant genes PSEN1, PSEN2, or APP, APOE4 alleles, and rare variants within TREM2, SORL1, and ABCA7 contribute to early-onset Alzheimer’s disease (EOAD). However, sporadic EOAD patients have been insufficiently studied to define the probability of being a carrier of one of these variants.Objective:To describe the proportion of each genetic variation among patients with very young-onset sporadic AD. Methods:We first screened PSEN1, PSEN2, and APP in 154 EOAD patients with an onset before 51 years and a negative family history. Among 99 patients with no mutation (NMC), whole exome sequencing (WES) was performed. We analyzed the APOE genotype and rare protein-truncating or missense predicted damaging variants of TREM2, SORL1, and ABCA7. Neurological examination and cerebrospinal fluid (CSF) biomarkers were systematically retrieved. Results:Nineteen (12.3%) mutation carriers (MC) harbored an APP or PSEN1 pathogenic or likely pathogenic variant. Among the NMC, 54/99 carried at least one genetic risk factor, including 9 APOE4/E4 homozygous, 37 APOE4 heterozygous, and 14 with a rare variant in another risk factor gene: 3 SORL1, 4 TREM2, and 9 ABCA7. MC presented an earlier disease onset (p
Published: 2019

26. A Simple, Universal, and Cost-Efficient Digital PCR Method for the Targeted Analysis of Copy Number Variations

Author: Ludivine Beaussire, Nathalie Le Meur, Géraldine Joly-Helas, Anne-Claire Brehin, Anne Boland, Gaël Nicolas, Dominique Campion, Jean-François Deleuze, Pascal Chambon, Anne Rovelet-Lecrux, Kévin Cassinari, Mathieu Castelain, Thierry Frebourg, Nasrin Sarafan-Vasseur, Olivier Quenez, Nicolas Gruchy, Pascale Saugier-Veber, Anne-Marie Guerrot, Alice Goldenberg, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Umea Plant Science Center (UPSC), Department of Forest Genetics and Plant Physiology, Swedish University of Agricultural Sciences (SLU)-Swedish University of Agricultural Sciences (SLU), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Laboratoire de cytogénétique prénatale [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), and The authors are grateful to Matthieu Dujardin, Coralie Tiercin, Stéphane Le Mignot, Donovan Liot, Anne-Claire Richard, Stéphane Rousseau, Françoise Charbonnier, and Myriam Vezain for technical support.
Subjects: Male, 0301 basic medicine, DNA Copy Number Variations, Computer science, Clinical Biochemistry, Oligonucleotides, Computational biology, Polymerase Chain Reaction, Genome, 03 medical and health sciences, 0302 clinical medicine, Humans, Genomic medicine, Digital polymerase chain reaction, Copy-number variation, Locked nucleic acid, Selection (genetic algorithm), [SDV.GEN]Life Sciences [q-bio]/Genetics, Base Sequence, Genome, Human, Hydrolysis, Biochemistry (medical), Reproducibility of Results, DNA, Amplicon, 3. Good health, 030104 developmental biology, Human genome, 030217 neurology & neurosurgery
Abstract: BACKGROUND Rare copy number variations (CNVs) are a major cause of genetic diseases. Simple targeted methods are required for their confirmation and segregation analysis. We developed a simple and universal CNV assay based on digital PCR (dPCR) and universal locked nucleic acid (LNA) hydrolysis probes. METHODS We analyzed the mapping of the 90 LNA hydrolysis probes from the Roche Universal ProbeLibrary (UPL). For each CNV, selection of the optimal primers and LNA probe was almost automated; probes were reused across assays and each dPCR assay included the CNV amplicon and a reference amplicon. We assessed the assay performance on 93 small and large CNVs and performed a comparative cost-efficiency analysis. RESULTS UPL-LNA probes presented nearly 20000000 occurrences on the human genome and were homogeneously distributed with a mean interval of 156 bp. The assay accurately detected all the 93 CNVs, except one ( CONCLUSIONS The universal dPCR CNV assay is simple, robust, and cost-efficient because it combines a straightforward design allowed by universal probes and end point PCR, the advantages of a relative quantification of the target to the reference within the same reaction, and the high flexibility of the LNA hydrolysis probes. This method should be a useful tool for genomic medicine, which requires simple methods for the interpretation and segregation analysis of genomic variations.
Published: 2019

27. Copy Number Variants in miR-138 as a Potential Risk Factor for Early-Onset Alzheimer’s Disease

Author: Anne Boland, Gaël Nicolas, Camille Charbonnier, Sébastien S. Hébert, Annie Laquerrière, Kévin Cassinari, Emmanuelle Boscher, Dominique Campion, Olivier Martinaud, Jean-François Deleuze, Thomas Husson, David Wallon, Olivier Quenez, Mark Lathrop, Anne Rovelet-Lecrux, Florent Marguet, Thierry Frebourg, CHU de Québec–Université Laval, Université Laval [Québec] (ULaval), Faculté de médecine de l'Université Laval [Québec] (ULaval), UNIROUEN - UFR Santé (UNIROUEN UFR Santé), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Normandie Université (NU)-Normandie Université (NU)-CHU Rouen, Normandie Université (NU), Department of Pathology, Rouen University Hospital, Service de neurologie [Rouen], CHU Rouen, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Research, Centre hospitalier du Rouvray, Sotteville-lès-Rouen, France, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), and Département de Pathologie [CHU Rouen]
Subjects: Adult, Male, 0301 basic medicine, DNA Copy Number Variations, [SDV]Life Sciences [q-bio], Blotting, Western, miR-138, Locus (genetics), Biology, Real-Time Polymerase Chain Reaction, Gene dosage, 03 medical and health sciences, 0302 clinical medicine, Alzheimer Disease, Risk Factors, Exome Sequencing, PSEN2, Gene duplication, mental disorders, PSEN1, medicine, Humans, Genetic Predisposition to Disease, Early-onset Alzheimer's disease, Copy-number variation, Age of Onset, Cells, Cultured, Exome sequencing, Aged, Genetics, Copy number variants, microRNA, General Neuroscience, early-onset Alzheimer’s disease, General Medicine, Middle Aged, medicine.disease, 3. Good health, MicroRNAs, Psychiatry and Mental health, Clinical Psychology, 030104 developmental biology, Case-Control Studies, Female, Geriatrics and Gerontology, Multiplex Polymerase Chain Reaction, 030217 neurology & neurosurgery
Abstract: International audience; Early-onset Alzheimer’s disease (EOAD) accounts for 5-10% of all AD cases, with a heritability ranging between 92% to 100%. With the exception of rare mutations in APP, PSEN1, and PSEN2 genes causing autosomal dominant EOAD, little is known about the genetic factors underlying most of the EOAD cases. In this study, we hypothesized that copy number variations (CNVs) in microRNA (miR) genes could contribute to risk for EOAD. miRs are short non-coding RNAs previously implicated in the regulation of AD-related genes and phenotypes. Using whole exome sequencing, we screened a series of 546 EOAD patients negative for autosomal dominant EOAD mutations and 597 controls. We identified 86 CNVs in miR genes of which 31 were exclusive to EOAD cases, including a duplication of the MIR138-2 locus. In functional studies in human cultured cells, we could demonstrate that miR-138 overexpression leads to higher Aβ production as well as tau phosphorylation, both implicated in AD pathophysiology. These changes were mediated in part by GSK-3β and FERMT2, a potential risk factor for AD. Additional disease-related genes were also prone to miR-138 regulation including APP and BACE1. This study suggests that increased gene dosage of MIR138-2 could contribute to risk for EOAD by regulating different biological pathways implicated in amyloid and tau metabolism. Additional studies are now required to better understand the role of miR-CNVs in EOAD.
Published: 2019

28. Generation of induced pluripotent stem cells (iPSCs) IRMBi002-A from an Alzheimer's disease patient carrying a D694N mutation in the APP gene

Author: V. Cacheux, L. Auboyer, C. Monzo, I. Gazagne, David Wallon, Audrey Gabelle, Sylvain Lehmann, Anne Rovelet-Lecrux, Carole Crozet, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: Heterozygote, Cellular differentiation, [SDV]Life Sciences [q-bio], Induced Pluripotent Stem Cells, Germ layer, medicine.disease_cause, 03 medical and health sciences, Amyloid beta-Protein Precursor, 0302 clinical medicine, Alzheimer Disease, Amyloid precursor protein, medicine, Humans, Induced pluripotent stem cell, lcsh:QH301-705.5, Cells, Cultured, 030304 developmental biology, 0303 health sciences, Mutation, biology, Cell Differentiation, Cell Biology, General Medicine, Fibroblasts, Middle Aged, biology.organism_classification, Cellular Reprogramming, Phenotype, Sendai virus, In vitro, 3. Good health, lcsh:Biology (General), Cancer research, biology.protein, Female, 030217 neurology & neurosurgery, Developmental Biology
Abstract: International audience; Induced pluripotent stem cells (iPSC) were generated from skin fibroblasts obtained from a 58 year-old woman suffering from Alzheimer's disease and carrying a D694N mutation on Amyloid precursor protein (APP). Fibroblasts were reprogrammed into iPSC using the integration-free Sendai Virus which allows the expression of the Yamanaka factors. Verification of their pluripotency was achieved by demonstrating the expression of pluripotency markers and their differentiation potential into the three primary germ layers. The cells have the corresponding mutation and present a normal karyotype. The reported APP-D694N iPSC line may be used to model and study human AD pathology in vitro.
Published: 2019

29. Generation of induced pluripotent stem cells (IRMBi001-A) from an Alzheimer's disease patient carrying a G217D mutation in the PSEN1 gene

Author: Sylvain Lehmann, Audrey Gabelle, Anne Rovelet-Lecrux, David Wallon, V. Cacheux, L. Auboyer, Carole Crozet, C. Monzo, I. Gazagne, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Salvy-Córdoba, Nathalie, and Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
Subjects: 0301 basic medicine, Male, Induced Pluripotent Stem Cells, Cell Culture Techniques, Germ layer, Biology, medicine.disease_cause, Presenilin, Cell Line, 03 medical and health sciences, Mice, 0302 clinical medicine, Alzheimer Disease, PSEN1, medicine, Presenilin-1, Animals, Humans, Induced pluripotent stem cell, lcsh:QH301-705.5, Mutation, Base Sequence, MESH: Alzheimer Disease / pathology, Cell Culture Techniques / methods, Induced Pluripotent Stem Cells / pathology, Mutation / genetics, Presinilin-1 / genetics, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Cell Biology, General Medicine, Middle Aged, biology.organism_classification, Sendai virus, 030104 developmental biology, lcsh:Biology (General), Cell culture, Cancer research, Reprogramming, 030217 neurology & neurosurgery, Developmental Biology
Abstract: International audience; Induced pluripotent stem cells (iPSC) were generated from skin fibroblasts obtained from a 50 year-old patient suffering from Alzheimer's disease and carrying a G217D causal mutation on presenilin 1 (PSEN1). iPSCs were obtained following reprogramming using the integration-free Sendai Virus system which allows expression of the Yamanaka factors. Verification of their pluripotency was achieved by demonstrating the expression of pluripotency markers and their differentiation potential into the three primary germ layers. iPS cells carry the patient G217D mutation and present a normal karyotype. The reported PS1-G217D iPSC line may be used to model and study human AD pathology in vitro.
Published: 2019

30. SORL1 rare variants: a major risk factor for familial early-onset Alzheimer’s disease

Author: Didier Hannequin, A-C Richard, Emmanuelle Génin, Anne Boland, Delphine Bacq, Benjamin Grenier-Boley, Céline Bellenguez, Luc Letenneur, Olivier Quenez, Hans Markus Munter, J.F. Deleuze, J-C Lambert, Thierry Frebourg, Camille Charbonnier, Dominique Campion, Stéphane Rousseau, Vincent Meyer, Mark Lathrop, Gaël Nicolas, P. Amouyel, Robert Olaso, Guillaume Bourque, Richard Redon, J. F. Dartigues, J-G Garnier, David Wallon, Anne Rovelet-Lecrux, and K Le Guennec
Subjects: Male, 0301 basic medicine, Oncology, medicine.medical_specialty, SORL1, Bioinformatics, Amyloid beta-Protein Precursor, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Gene Frequency, Alzheimer Disease, Risk Factors, Internal medicine, Odds Ratio, medicine, Humans, Exome, Genetic Predisposition to Disease, Early-onset Alzheimer's disease, Risk factor, Family history, Molecular Biology, Allele frequency, Alleles, LDL-Receptor Related Proteins, Amyloid beta-Peptides, business.industry, Genetic Variation, Membrane Transport Proteins, Odds ratio, Middle Aged, medicine.disease, Minor allele frequency, Psychiatry and Mental health, 030104 developmental biology, Case-Control Studies, Female, France, business, 030217 neurology & neurosurgery
Abstract: The SORL1 protein plays a protective role against the secretion of the amyloid β peptide, a key event in the pathogeny of Alzheimer's disease. We assessed the impact of SORL1 rare variants in early-onset Alzheimer's disease (EOAD) in a case-control setting. We conducted a whole exome analysis among 484 French EOAD patients and 498 ethnically matched controls. After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of disruptive and predicted damaging missense SORL1 variants in cases (odds radio (OR)=5.03, 95% confidence interval (CI)=(2.02-14.99), P=7.49.10(-5)). This enrichment was even stronger when restricting the analysis to the 205 cases with a positive family history (OR=8.86, 95% CI=(3.35-27.31), P=3.82.10(-7)). We conclude that predicted damaging rare SORL1 variants are a strong risk factor for EOAD and that the association signal is mainly driven by cases with positive family history.
Published: 2015

31. 17q21.31 duplication causes prominent tau-related dementia with increased MAPT expression

Author: Emmanuelle Génin, Céline Bellenguez, Vincent Meyer, I. Le Ber, Thérèse Rivasseau Jonveaux, Paola Caroppo, Olivier Quenez, Thierry Frebourg, Luc Letenneur, Robert Olaso, Doris Lechner, D. Wallon, Dominique Campion, Lucie Guyant-Maréchal, Ognian Kalev, Philippe Amouyel, Anne-Claire Richard, Camille Charbonnier, Olivier Martinaud, L. Traykov, Shima Mehrabian, Jean-François Deleuze, Gaël Nicolas, Anne Rovelet-Lecrux, Mark Lathrop, Hans Markus Munter, Gabor G. Kovacs, Florence Pasquier, Stéphane Rousseau, Marie-Thérèse Bihoreau, Adeline Rollin-Sillaire, Stéphane Epelbaum, Guillaume Bourque, Anne Boland, Richard Redon, Jean-François Dartigues, Jean-Charles Lambert, Thomas Ströbel, Didier Hannequin, Peristera Paschou, K Le Guennec, John Alexander, Benjamin Grenier-Boley, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Unité de recherche de l'institut du thorax (ITX-lab)
Subjects: Male, 0301 basic medicine, Pathology, medicine.medical_specialty, DNA Copy Number Variations, Amyloid, [SDV]Life Sciences [q-bio], Gene Dosage, Neuroimaging, tau Proteins, Gene dosage, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Alzheimer Disease, Gene Duplication, Gene duplication, medicine, Humans, Dementia, Copy-number variation, Molecular Biology, Aged, Brain, Neurofibrillary Tangles, Neurofibrillary tangle, Middle Aged, medicine.disease, 3. Good health, Psychiatry and Mental health, 030104 developmental biology, Tauopathies, Case-Control Studies, Biomarker (medicine), Female, Tauopathy, Psychology, Neuroscience, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 17
Abstract: International audience; To assess the role of rare copy number variations in Alzheimer's disease (AD), we conducted a case-control study using whole-exome sequencing data from 522 early-onset cases and 584 controls. The most recurrent rearrangement was a 17q21.31 microduplication, overlapping the CRHR1, MAPT, STH and KANSL1 genes that was found in four cases, including one de novo rearrangement, and was absent in controls. The increased MAPT gene dosage led to a 1.6-1.9-fold expression of the MAPT messenger RNA. Clinical signs, neuroimaging and cerebrospinal fluid biomarker profiles were consistent with an AD diagnosis in MAPT duplication carriers. However, amyloid positon emission tomography (PET) imaging, performed in three patients, was negative. Analysis of an additional case with neuropathological examination confirmed that the MAPT duplication causes a complex tauopathy, including prominent neurofibrillary tangle pathology in the medial temporal lobe without amyloid-β deposits. 17q21.31 duplication is the genetic basis of a novel entity marked by prominent tauopathy, leading to early-onset dementia with an AD clinical phenotype. This entity could account for a proportion of probable AD cases with negative amyloid PET imaging recently identified in large clinical series.
Published: 2017

32. [P3–168]: GENETIC DISSECTION OF SEVERITY AND ONSET MODULATORS FOR ALZHEIMER's PATHOLOGY IN DOWN SYNDROME USING CELLULAR SYSTEMS

Author: Elizabeth M. C. Fisher, Rosalyn Hithersay, Andre Strydom, David Wallon, Jürgen Groet, Frances K. Wiseman, Sarah Hamburg, Hana D'Souza, Yee-Jie Yeap, Annette Karmiloff-Smith, Pollyanna Goh, Kin Y. Mok, John Hardy, Aoife Murray, Anne Rovelet-Lecrux, Alexandra Botté, Carla M. Startin, Dean Nizetic, Victor L. J. Tybulewicz, Jerry Chan, Marie-Claude Potier, George Augustine, and Mahesh Choolani
Subjects: Genetic dissection, Down syndrome, Pathology, medicine.medical_specialty, Epidemiology, business.industry, Health Policy, medicine.disease, Psychiatry and Mental health, Cellular and Molecular Neuroscience, Developmental Neuroscience, Medicine, Neurology (clinical), Geriatrics and Gerontology, business
Published: 2017

33. Deletion of exons 9 and 10 of the Presenilin 1 gene in a patient with Early-onset Alzheimer Disease generates longer amyloid seeds

Author: Stéphane Rousseau, Gaël Nicolas, Olivier Quenez, Maria Szaruga, Kilan Le Guennec, David Wallon, Frédérique Fluchère, Thierry Frebourg, Sarah Veugelen, Anne Rovelet-Lecrux, Dominique Campion, Bart De Strooper, and Lucía Chávez-Gutiérrez
Subjects: 0301 basic medicine, Male, Models, Molecular, Amyloid, Biology, Presenilin, lcsh:RC321-571, 03 medical and health sciences, Exon, 0302 clinical medicine, Endopeptidase activity, Alzheimer Disease, PSEN1, medicine, Presenilin-1, Humans, Exome, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Sequence Deletion, Genetics, Early-onset, Aβ43, Exons, Middle Aged, medicine.disease, Molecular biology, Phenotype, 030104 developmental biology, Neurology, Hydrophilic loop, Paraparesis, Spastic, Alzheimer's disease, Cognition Disorders, 030217 neurology & neurosurgery
Abstract: Presenilin 1 (PSEN1) mutations are the main cause of autosomal dominant Early-onset Alzheimer Disease (EOAD). Among them, deletions of exon 9 have been reported to be associated with a phenotype of spastic paraparesis. Using exome data from a large sample of 522 EOAD cases and 584 controls to search for genomic copy-number variations (CNVs), we report here a novel partial, in-frame deletion of PSEN1, removing both exons 9 and 10. The patient presented with memory impairment associated with spastic paraparesis, both starting from the age of 56years. He presented a positive family history of EOAD. We performed functional analysis to elucidate the impact of this novel deletion on PSEN1 activity as part of the γ-secretase complex. The deletion does not affect the assembly of a mature protease complex but has an extreme impact on its global endopeptidase activity. The mutant carboxypeptidase-like activity is also strongly impaired and the deleterious mutant effect leads to an incomplete digestion of long Aβ peptides and enhances the production of Aβ43, which has been shown to be potently amyloidogenic and neurotoxic in vivo.
Published: 2017

34. TREM2 R47H Variant as a Risk Factor for Early-Onset Alzheimer's Disease

Author: Stéphane Rousseau, Dominique Campion, Thierry Frebourg, David Wallon, Cyril Pottier, Adeline Rollin-Sillaire, Anne-Claire Richard, Didier Hannequin, and Anne Rovelet-Lecrux
Subjects: Adult, Male, Disease, Biology, Exon, Alzheimer Disease, Risk Factors, Genetic variation, medicine, Humans, Early-onset Alzheimer's disease, Receptors, Immunologic, Risk factor, Aged, Genetics, Membrane Glycoproteins, TREM2, General Neuroscience, Genetic Variation, General Medicine, Middle Aged, medicine.disease, Psychiatry and Mental health, Clinical Psychology, Immunology, Female, Geriatrics and Gerontology, Alzheimer's disease, Age of onset
Abstract: The rs75932628-T variant of the gene encoding the triggering receptor expressed on myeloid cells 2 (TREM2) has recently been identified as a rare risk factor for late-onset Alzheimer's disease (AD). In this study we examined the association between TREM2 exon 2 variants and early-onset AD in a sample of Caucasian subjects of French origin including 726 patients with age of onset ≤65 years and 783 controls. Only the rs75932628-T variant (predicted to cause an R47H substitution) conferred a significant risk for early-onset AD (OR, 4.07; 95% CI, 1.3 to 16.9; p = 0.009). These results confirm the association between this variant and AD and underline its involvement in early-onset cases.
Published: 2013

35. Seizures in dominantly inherited Alzheimer disease

Author: Aline, Zarea, Camille, Charbonnier, Anne, Rovelet-Lecrux, Gaël, Nicolas, Stéphane, Rousseau, Alaina, Borden, Jeremie, Pariente, Isabelle, Le Ber, Florence, Pasquier, Maite, Formaglio, Olivier, Martinaud, Adeline, Rollin-Sillaire, Marie, Sarazin, Bernard, Croisile, Claire, Boutoleau-Bretonnière, Mathieu, Ceccaldi, Audrey, Gabelle, Ludivine, Chamard, Frédéric, Blanc, François, Sellal, Claire, Paquet, Dominique, Campion, Didier, Hannequin, David, Wallon, Karl, Mondon, Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre d'investigation clinique de Toulouse (CIC 1436), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Mémoire de Ressources et de Recherche -CMRR [Lille-Bailleul], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro, Hôpital Neurologique Pierre Wertheimer, Service de Neurologie, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de Neurologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Mémoire de Ressources et de Recherche, CHU Marseille, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), CHU Strasbourg, Service de neurologie, Hôpital pasteur [Colmar], Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Lariboisière-François Widal, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Supported by the Hospital Program for Clinical Research (PHRC) ofthe French Ministry of Health (GMAJ, PHRC 2008/067) and sponsoredby the National Reference Center for Young Alzheimer Patients(CNR-MAJ)., CHU Lille, CNRS, Inserm, Université de Lille, Troubles cognitifs dégénératifs et vasculaires - U1171, Troubles cognitifs dégénératifs et vasculaires - U 1171 [TCDV], Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Imagerie cérébrale et handicaps neurologiques, Université Paul Sabatier - Toulouse 3 ( UPS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Troubles cognitifs dégénératifs et vasculaires ( DN2M ), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -INSERM, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -Hôpital Roger Salengro, Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Centre Hospitalier Lyon Sud [CHU - HCL] ( CHLS ), Hospices Civils de Lyon ( HCL ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôpital Nord Laënnec, Institut de Neurosciences des Systèmes ( INS ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Biomarqueurs CArdioNeuroVASCulaires ( BioCANVAS ), Université Paris Diderot - Paris 7 ( UPD7 ) -Université Paris 13 ( UP13 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Nantes ( UN ) -Hôpital Nord Laënnec-Centre hospitalier universitaire de Nantes ( CHU Nantes ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Université Paris 13 ( UP13 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Amiens-Picardie, Laboratoire de Neurosciences Fonctionnelles et Pathologies - UR UPJV 4559 (LNFP), Université de Picardie Jules Verne (UPJV), PHRC GMAJ Collaborators, Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Pôle Santé publique et médecine publique [CHU Toulouse], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Wallon, David
Subjects: 0301 basic medicine, Adult, Male, medicine.medical_specialty, [ SDV.MHEP.PSM ] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, DNA Mutational Analysis, Bioinformatics, Gastroenterology, Statistics, Nonparametric, Cohort Studies, 03 medical and health sciences, Amyloid beta-Protein Precursor, Young Adult, 0302 clinical medicine, Alzheimer Disease, Internal medicine, PSEN2, Gene duplication, Presenilin-2, PSEN1, medicine, Presenilin-1, Humans, Age of Onset, Aged, Epilepsy, business.industry, Proportional hazards model, Hazard ratio, Middle Aged, medicine.disease, Confidence interval, 030104 developmental biology, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Cohort, Mutation, Female, Neurology (clinical), France, Alzheimer's disease, business, 030217 neurology & neurosurgery
Abstract: OBJECTIVE: To assess seizure frequency in a large French cohort of autosomal dominant early-onset Alzheimer disease (ADEOAD) and to determine possible correlations with causative mutations. METHODS: A national multicentric study was performed in patients with ADEOAD harboring a pathogenic mutation within PSEN1, PSEN2, APP, or a duplication of APP, and a minimal follow-up of 5 years. Clinical, EEG, and imaging data were systematically recorded. RESULTS: We included 132 patients from 77 families: 94 PSEN1 mutation carriers (MCs), 16 APP duplication carriers, 15 APP MCs, and 7 PSEN2 MCs. Seizure frequency was 47.7% after a mean follow-up of 8.4 years (range 5-25). After 5-year follow-up and using a Cox model analysis, the percentages of patients with seizures were respectively 19.1% (10.8%-26.7%) for PSEN1, 28.6% (0%-55.3%) for PSEN2, 31.2% (4.3%-50.6%) for APP duplications, and no patient for APP mutation. APP duplication carriers showed a significantly increased seizure risk compared to both APP MCs (hazard ratio [HR] = 5.55 [95% confidence interval 1.87-16.44]) and PSEN1 MCs (HR = 4.46 [2.11-9.44]). Among all PSEN1 mutations, those within the domains of protein hydrophilic I, transmembrane II (TM-II), TM-III, TM-IV, and TM-VII were associated with a significant increase in seizure frequency compared to other domains (HR = 4.53 [1.93-10.65], p = 0.0005). CONCLUSIONS: Seizures are a common feature of ADEOAD. In this population, risk was significantly higher in the APP duplication group than in all other groups. Within PSEN1, 5 specific domains were associated with a higher seizure risk indicating specific correlations between causative mutation and seizures. 87
Published: 2016

36. Identification of partial SLC20A2 deletions in primary brain calcification using whole-exome sequencing

Author: Marc Vérin, Anne-Claire Richard, Olivier Quenez, Anne Rovelet-Lecrux, Dominique Campion, Stéphanie David, João Ricardo Mendes de Oliveira, Joana Ferreira, Gaël Nicolas, Isabelle Le Ber, Anne Boland, Jean-François Deleuze, Thierry Frebourg, Snejana Jurici, Didier Hannequin, Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Service de neurologie [Rennes], Université de Rennes (UR), Comportement et noyaux gris centraux = Behavior and Basal Ganglia [Rennes], Université de Rennes (UR)-Université européenne de Bretagne - European University of Brittany (UEB)-CHU Pontchaillou [Rennes]-Institut des Neurosciences Cliniques de Rennes = Institute of Clinical Neurosciences of Rennes (INCR), Centre Hospitalier Saint Jean de Perpignan, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Universidade Federal de Pernambuco [Recife] (UFPE), DEA20140630628, FRM, Fondation pour la Recherche Médicale, Jonchère, Laurent, Université de Rennes (UR)-Université européenne de Bretagne - European University of Brittany (UEB)-CHU Pontchaillou [Rennes]-Institut des Neurosciences Cliniques de Rennes (INCR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Université européenne de Bretagne - European University of Brittany (UEB)-CHU Pontchaillou [Rennes]-Institut des Neurosciences Cliniques de Rennes (INCR)
Subjects: 0301 basic medicine, Male, Sequence analysis, Short Report, PDGFRB, Biology, 03 medical and health sciences, Exon, 0302 clinical medicine, Genetics, Humans, Exome, Copy-number variation, Genotyping, Genetics (clinical), Exome sequencing, Aged, Brain Diseases, Sodium-Phosphate Cotransporter Proteins, Type III, [SCCO.NEUR]Cognitive science/Neuroscience, [SCCO.NEUR] Cognitive science/Neuroscience, Calcinosis, Sequence Analysis, DNA, Syndrome, Amplicon, Middle Aged, 030104 developmental biology, Female, Xenotropic and Polytropic Retrovirus Receptor, 030217 neurology & neurosurgery, Algorithms, Gene Deletion
Abstract: International audience; Primary brain calcification (PBC) is a dominantly inherited calcifying disorder of the brain. SLC20A2 loss-of-function variants account for the majority of families. Only one genomic deletion encompassing SLC20A2 and six other genes has been reported. We performed whole-exome sequencing (WES) in 24 unrelated French patients with PBC, negatively screened for sequence variant in the known genes SLC20A2, PDGFB, PDGFRB and XPR1. We used the CANOES tool to detect copy number variations (CNVs). We detected two deletions of exon 2 of SLC20A2 in two unrelated patients, which segregated with PBC in one family. We then reanalyzed the same series using a QMPSF assay including one amplicon in each exon of SLC20A2 and detected two supplemental partial deletions in two patients: one deletion of exon 4 and one deletion of exons 4 and 5. These deletions were missed by the first screening step of CANOES but could finally be detected after readjustment of bioinformatic parameters and use of a genotyping step of CANOES. This study reports the first partial deletions of SLC20A2 and strengthens its position as the major PBC-causative gene. It is possible to detect short CNVs from WES data, although the sensitivity of such tools should be evaluated in comparison with other methods. © 2016 Macmillan Publishers Limited, part of Springer Nature.
Published: 2016

37. Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons

Author: Frédéric Blanc, Adeline Rollin-Sillaire, O. Moreaud, Mark Lathrop, Mathieu Ceccaldi, Anne-Claire Richard, Catherine Thomas-Antérion, Olivier Quenez, Camille Charbonnier, Anne Rovelet-Lecrux, Vincent Meyer, Dominique Campion, Didier Hannequin, Bernard Croisile, Robert Olaso, Claire Paquet, Hans Markus Munter, Ludivine Chamard, Mathilde Sauvée, Anne Boland, Marie Sarazin, Lucie Guyant-Maréchal, Sophie Coutant, Florence Pasquier, Kilan Le Guennec, François Sellal, David Wallon, Guillaume Bourque, Claire Boutoleau-Bretonnière, Stéphane Rousseau, Alexandre Montpetit, Delphine Bacq, Jean-François Deleuze, Jérémie Pariente, Audrey Gabelle, Thierry Frebourg, Isabelle Le Ber, Daniel Auld, Jean-Guillaume Garnier, Olivier Martinaud, Gaël Nicolas, Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre Mémoire de Ressources et Recherche - CMRR [Haute-Normandie], Normandie Université (NU)-Normandie Université (NU), Service de neurologie [Rouen], Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes (LITIS), Université Le Havre Normandie (ULH), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), McGill University and Genome Quebec Innovation Centre, Centre d'Innovation (Génome Québec), Génome Québec, Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Mémoire de Ressources et de Recherche -CMRR [Lille-Bailleul], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Neurologique Pierre Wertheimer, Service de Neurologie, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de neurologie [Nantes], Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Hôpital Guillaume-et-René-Laennec [Saint-Herblain], Laboratoire d'Etude des Mécanismes Cognitifs (EMC), Université Lumière - Lyon 2 (UL2), Laboratoire d'Histologie et de Biologie du Vieillissement, Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Biomarqueurs CArdioNeuroVASCulaires (BioCANVAS), Université Paris 13 (UP13)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Mémoire [AP-HP Hôpital Lariboisière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Centre Mémoire de Ressources et de Recherche [Grenoble] (CMRR), Centre Hospitalier Universitaire [Grenoble] (CHU), Laboratoire de Psychologie et NeuroCognition (LPNC ), Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie, Hôpital pasteur [Colmar], Institut de Neurosciences des Systèmes (INS), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie (ICube), École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg (ENGEES)-Université de Strasbourg (UNISTRA)-Institut National des Sciences Appliquées - Strasbourg (INSA Strasbourg), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de Recherche en Informatique et en Automatique (Inria)-Les Hôpitaux Universitaires de Strasbourg (HUS)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et Nanosciences Grand-Est (MNGE), Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Département de Gériatrie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS)-Hôpital de jour St François [Strasbourg], Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de Neurologie [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace (FMNGE), Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA), Imagerie cérébrale et handicaps neurologiques, Institut des sciences du cerveau de Toulouse. (ISCT), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Troubles cognitifs dégénératifs et vasculaires (U1171), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-INSERM, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Saint-Antoine [APHP], Université Lumière - Lyon 2 (UL2)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Laboratoire de Psychologie et NeuroCognition (LPNC), Université Pierre Mendès France - Grenoble 2 (UPMF)-Université Joseph Fourier - Grenoble 1 (UJF)-Université Savoie Mont Blanc (USMB [Université de Savoie] [Université de Chambéry])-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Matériaux et nanosciences d'Alsace, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Réseau nanophotonique et optique, Université de Strasbourg (UNISTRA)-Université de Haute-Alsace (UHA) Mulhouse - Colmar (Université de Haute-Alsace (UHA))-Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), Génétique du cancer et des maladies neuropsychiatriques ( GMFC ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Institute for Research and Innovation in Biomedicine ( IRIB ), Laboratoire d'Informatique, de Traitement de l'Information et des Systèmes ( LITIS ), Université Le Havre Normandie ( ULH ), Normandie Université ( NU ) -Normandie Université ( NU ) -Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Institut national des sciences appliquées Rouen Normandie ( INSA Rouen Normandie ), Normandie Université ( NU ), Centre National de Génotypage ( CNG ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ), Centre National de Séquençage (Genoscope) ( CNS ), Centre d'Innovation ( Génome Québec ), Université Toulouse III - Paul Sabatier ( UPS ), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Troubles cognitifs dégénératifs et vasculaires ( DN2M ), Université de Lille-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -INSERM, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ) -Hôpital Roger Salengro, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Saint-Antoine [APHP], Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Université de Nantes ( UN ) -Centre hospitalier universitaire de Nantes ( CHU Nantes ) -Hôpital Nord Laënnec, Laboratoire d'Etude des Mécanismes Cognitifs ( EMC ), Université Lumière - Lyon 2 ( UL2 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Biomarqueurs CArdioNeuroVASCulaires ( BioCANVAS ), Université Paris 13 ( UP13 ) -Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 ( UPD7 ), Centre Mémoire de Ressources et de Recherche [Grenoble] ( CMRR ), Centre Hospitalier Universitaire [Grenoble] ( CHU ), Laboratoire de Psychologie et NeuroCognition ( LPNC ), Université Pierre Mendès France - Grenoble 2 ( UPMF ) -Université Joseph Fourier - Grenoble 1 ( UJF ) -Université Savoie Mont Blanc ( USMB [Université de Savoie] [Université de Chambéry] ) -Centre National de la Recherche Scientifique ( CNRS ) -Université Grenoble Alpes ( UGA ), Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Institut de Neurosciences des Systèmes ( INS ), Aix Marseille Université ( AMU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre Hospitalier Régional Universitaire [Besançon] ( CHRU Besançon ), Laboratoire des sciences de l'ingénieur, de l'informatique et de l'imagerie ( ICube ), Institut National des Sciences Appliquées - Strasbourg ( INSA Strasbourg ), Institut National des Sciences Appliquées ( INSA ) -Institut National des Sciences Appliquées ( INSA ) -Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ) -École Nationale du Génie de l'Eau et de l'Environnement de Strasbourg ( ENGEES ) -Réseau nanophotonique et optique, Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Centre National de la Recherche Scientifique ( CNRS ) -Matériaux et nanosciences d'Alsace, Université de Strasbourg ( UNISTRA ) -Université de Haute-Alsace (UHA) Mulhouse - Colmar ( Université de Haute-Alsace (UHA) ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
Subjects: 0301 basic medicine, Male, Pediatrics, medicine.medical_specialty, Biology, Bioinformatics, Article, 03 medical and health sciences, Amyloid beta-Protein Precursor, 0302 clinical medicine, Alzheimer Disease, PSEN2, Presenilin-2, Genetics, medicine, PSEN1, Presenilin-1, Dementia, Humans, Exome, Genetic Testing, Family history, Genetics (clinical), Exome sequencing, [SCCO.NEUR]Cognitive science/Neuroscience, Middle Aged, medicine.disease, 3. Good health, Pedigree, 030104 developmental biology, Case-Control Studies, [ SCCO.NEUR ] Cognitive science/Neuroscience, Mutation, Female, Alzheimer's disease, Age of onset, Protein Processing, Post-Translational, 030217 neurology & neurosurgery
Abstract: International audience; Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of late-onset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes.
Published: 2016

38. The 22q11 PRODH/DGCR6 deletion is frequent in hyperprolinemic subjects but is not a strong risk factor for ASD

Author: Peggy S. Eis, Elsa Delaby, Anne Claire Richard, Catalina Betancur, Anne Rovelet-Lecrux, Alexandra Afenjar, Brigitte Gilbert Dussardier, Stephen W. Scherer, Eli Hatchwell, Bhooma Thiruvahindrapuram, Camille Charbonnier, Dominique Campion, Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroscience Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Program in Genetics and Genomic Biology, Hospital for Sick Children-University of Toronto McLaughlin Centre, Population Diagnostics, Inc., Service de Neuropédiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Trousseau [APHP], Service de Génétique, CHU Poitiers, Centre hospitalier universitaire de Poitiers (CHU Poitiers), McLaughlinCentreandDepartmentofMolecularGenetics, University of Toronto, Centre Hospitalier du Rouvray, Betancur, Catalina, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Rouen, Normandie Université (NU)-Normandie Université (NU), and Neurosciences Paris Seine (NPS)
Subjects: 0301 basic medicine, Adult, Male, 22q11.2 deletion, Autism Spectrum Disorder, Chromosomes, Human, Pair 22, autism, [SDV.GEN] Life Sciences [q-bio]/Genetics, Cohort Studies, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Proline dehydrogenase, Risk Factors, medicine, Proline Oxidase, Missense mutation, Humans, Genetic Predisposition to Disease, copy number variant, Copy-number variation, Risk factor, Child, Gene, Amino Acid Metabolism, Inborn Errors, Genetics (clinical), Genetics, Extracellular Matrix Proteins, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Nuclear Proteins, medicine.disease, Psychiatry and Mental health, 030104 developmental biology, Autism spectrum disorder, Child, Preschool, hyperprolinemia, Hyperprolinemia, Autism, Female, proline dehydrogenase, business, 030217 neurology & neurosurgery, Gene Deletion
Abstract: International audience; The proline dehydrogenase (PRODH) gene maps to 22q11.2 in the region deleted in the velo-cardio-facial syndrome (VCFS). A moderate to severe reduction (>50%) in PRODH activity resulting from recessive deletions and/or missense mutations has been shown to cause type 1 hyperprolinemia (HPI). Autistic features have been reported as a common clinical manifestation of HPI. Here we studied the frequency of a recurrent small 22q11.2 deletion encompassing PRODH and the neighboring DGCR6 gene in three case-control studies, one comprising HPI patients (n=83), and the other two comprising autism spectrum disorder (ASD) patients (total of n=2800), analyzed with high-resolution microarrays. We found that the PRODH deletion is a strong risk factor for HPI (OR = 50.7; 95% CI = 7.5-2147) but not for ASD (p=0.4, OR= 0.6-3.3). This result indicates either that the suggested association between ASD and HPI is spurious and results from a bias leading to the preferential inclusion of ASD patients in HPI series, or that HPI is present in only a very small subset of ASD patients. In this latter case, a very large sample size would be required to detect an association between the PRODH deletion and ASD in a case-control study.
Published: 2016

39. Copy number variations involving the microtubule-associated protein tau in human diseases

Author: Dominique Campion and Anne Rovelet-Lecrux
Subjects: Genetics, DNA Copy Number Variations, biology, Tau protein, Neurodegenerative Diseases, tau Proteins, Frontotemporal lobar degeneration, medicine.disease, Biochemistry, Hypotonia, Microtubule, mental disorders, Gene duplication, Schizophrenia, biology.protein, medicine, Humans, Copy-number variation, Tauopathy, medicine.symptom, Microtubule-Associated Proteins, Gene
Abstract: Mutations of the MAPT (microtubule-associated protein tau) gene are associated with FTLD (frontotemporal lobar degeneration) with tau pathology. These mutations result in a decreased ability of tau to bind MTs (microtubules), an increased production of tau with four MT-binding repeats or enhanced tau aggregation. In two FTLD patients, we recently described CNVs (copy number variations) affecting the MAPT gene, consisting of a partial deletion and a complete duplication of the gene. The partial deletion resulted in a truncated protein lacking the first MT-binding domain, which had a dramatic decrease in the binding to MTs but acquired the ability to bind MAP (microtubule-associated protein) 1-B. In this case, tauopathy probably resulted from both a loss of normal function and a gain of function by which truncated tau would sequester another MAP. In the other FTLD patient, the complete duplication might result in the overexpression of tau, which in the mouse model induces axonopathy and tau aggregates reminiscent of FTLD-tau pathology. Interestingly, the same rearrangement was also described in several children with mental retardation, autism spectrum disorders and dysmorphic features, as well as in a schizophrenic patient. Finally, complete deletions of the MAPT gene have been associated with mental retardation, hypotonia and facial dysmorphism.
Published: 2012

40. Amyloid-β Protein Precursor Gene Expression in Alzheimer's Disease and Other Conditions

Author: Anne Rovelet Lecrux, Thierry Frebourg, David Maltête, Stephanie Bombois, Cyril Pottier, Didier Hannequin, David Wallon, Dominique Campion, and Snejana Jurici
Subjects: Adult, Male, medicine.medical_specialty, Down syndrome, BACE1-AS, Amyloid beta-Protein Precursor, Alzheimer Disease, Internal medicine, Presenilin-2, Gene duplication, Gene expression, Presenilin-1, medicine, Amyloid precursor protein, Humans, RNA, Messenger, Age of Onset, Aged, biology, business.industry, General Neuroscience, P3 peptide, General Medicine, Middle Aged, medicine.disease, Biochemistry of Alzheimer's disease, Stroke, Psychiatry and Mental health, Clinical Psychology, Endocrinology, Gene Expression Regulation, Mutation, biology.protein, Female, Down Syndrome, Geriatrics and Gerontology, business, Amyloid precursor protein secretase
Abstract: Several lines of evidence suggest that AβPP gene expression could influence risk for Alzheimer's disease (AD). Using a highly sensitive multiplex fluorescent RT-PCR assay, we compared peripheral blood cells expression of AβPP mRNA among sporadic AD patients (n = 133), autosomal dominant early-onset AD cases (ADEOAD, n = 21), Down syndrome patients (n = 21), AD patients with AβPP duplication (n = 9), patients with recent ischemic stroke (n = 25), and healthy controls (n = 58). Compared to healthy controls (median = 0.98), AβPP expression was not increased in sporadic AD patients (median = 1.01, p = 0.42) nor in ADEOAD patients (median = 0.96, p = 0.26). Down syndrome patients as well as patients with AβPP duplication had significantly increased levels of AβPP mRNA compared to controls (median = 1.48 and median = 1.36, p < 0.0001 and p = 0.0007, respectively). A weaker but significant increase in relative amount of AβPP transcripts in patients who suffered from recent stroke was observed (median = 1.14, p = 0.0007). Our results do not support a pathogenic role of AβPP overexpression in sporadic AD although a small subset of patients displays AβPP overexpression in the same range as Down syndrome patients.
Published: 2012

41. Plasma progranulin levels predict progranulin mutation status in frontotemporal dementia patients and asymptomatic family members

Author: Vincent Deramecourt, Julia E. Crook, Rosa Rademakers, Bradley F. Boeve, Gina Bisceglio, Steven G. Younkin, Nicole A. Finch, Anne Rovelet-Lecrux, Karen M. Kuntz, Rebecca Surtees, Neill R. Graff-Radford, Katie Swanson, Matt Baker, Dennis W. Dickson, Ronald C. Petersen, and Richard Crook
Subjects: Adult, Male, Heterozygote, Progranulin, Granulin, Enzyme-Linked Immunosorbent Assay, Biology, medicine.disease_cause, Sensitivity and Specificity, Cohort Studies, 03 medical and health sciences, 0302 clinical medicine, Degenerative disease, Progranulins, Pick Disease of the Brain, Alzheimer Disease, medicine, Humans, 030304 developmental biology, Aged, Genetics, Family Health, 0303 health sciences, Mutation, Frontotemporal lobar degeneration, Original Articles, Middle Aged, Alzheimer's disease, medicine.disease, 3. Good health, Scientific Commentary, frontotemporal lobar degeneration, Intercellular Signaling Peptides and Proteins, Female, ELISA, Dementia, Neurology (clinical), Human medicine, Haploinsufficiency, Asymptomatic carrier, 030217 neurology & neurosurgery, Biomarkers, Frontotemporal dementia
Abstract: Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD) with ubiquitin and TAR DNA-binding protein 43 (TDP43)-positive pathology. The clinical presentation associated with GRN mutations is heterogeneous and may include clinical probable Alzheimer's disease. All GRN mutations identified thus far cause disease through a uniform disease mechanism, i.e. the loss of functional GRN or haploinsufficiency. To determine if expression of GRN in plasma could predict GRN mutation status and could be used as a biological marker, we optimized a GRN ELISA and studied plasma samples of a consecutive clinical FTLD series of 219 patients, 70 control individuals, 72 early-onset probable Alzheimer's disease patients and nine symptomatic and 18 asymptomatic relatives of GRN mutation families. All FTLD patients with GRN loss-of-function mutations showed significantly reduced levels of GRN in plasma to about one third of the levels observed in non-GRN carriers and control individuals (P < 0.001). No overlap in distributions of GRN levels was observed between the eight GRN loss-of-function mutation carriers (range: 53-94 ng/ml) and 191 non-GRN mutation carriers (range: 115-386 ng/ml). Similar low levels of GRN were identified in asymptomatic GRN mutation carriers. Importantly, ELISA analyses also identified one probable Alzheimer's disease patient (1.4%) carrying a loss-of-function mutation in GRN. Biochemical analyses further showed that the GRN ELISA only detects full-length GRN, no intermediate granulin fragments. This study demonstrates that using a GRN ELISA in plasma, pathogenic GRN mutations can be accurately detected in symptomatic and asymptomatic carriers. The approximately 75% reduction in full-length GRN, suggests an unbalanced GRN metabolism in loss-of-function mutation carriers whereby more GRN is processed into granulins. We propose that plasma GRN levels could be used as a reliable and inexpensive tool to identify all GRN mutation carriers in early-onset dementia populations and asymptomatic at-risk individuals.
Published: 2009

42. Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study

Author: Valérie Hahn-Barma, Bruno Dubois, Jean-Charles Lambert, Dominique Campion, Serge Bakchine, Agnès Camuzat, Christine Van Broeckhoven, Serge Belliard, Michèle Puel, Patrice Verpillat, Eric Guedj, Alexis Brice, Fabienne Clot, Marie-Odile Habert, Isabelle Le Ber, Jacqueline Mikol, Pascal Lejeune, Ftd-Mnd, Julie van der Zee, Mustapha Ghanim, Didier Hannequin, Vincent Deramecourt, Christian Meyrignac, Martine Vercelletto, Anne Rovelet-Lecrux, Florence Pasquier, Lucette Lacomblez, Vincent de La Sayette, Neurologie et thérapeutique expérimentale, Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), Department of Genetics, University Hospital, Département de neurologie[Lille], Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service Central de Biophysique et de Médecine Nucléaire, Hôpital de la Timone [CHU - APHM] (TIMONE), Centre des Maladies Cognitives et Comportementales [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neurodegenerative Brain Diseases Group, Department of Molecular Genetics, Flanders Interuniversity Institute for Biotechnology, Antwerpen, Université de Reims Champagne-Ardenne (URCA), Neurologie générale et maladies inflammatoires du système nerveux [Toulouse], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse], Fédération des Maladies du Système Nerveux, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de pharmacologie médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d′Anatomie et de Cytologie Pathologiques [Lariboisiere], Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Neuroendocrinologie et physiopathologie neuronale, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Centre Hospitalier Intercommunal, Centre Hospitalier Départemental, Laboratoire de Neuropsychologie, Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie [CHU Caen], Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Service de neurologie [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Clinique neurologique, Hôpital Laennec, Service de neurologie, Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Laboratoire d'Imagerie Fonctionnelle (LIF), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-IFR49-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de médecine nucléaire [CHU Pitié-Salpétrière], Neuro-anatomie fonctionnelle du comportement et de ses troubles, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre du Langage et de Neuropsychologie, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ANR-06-MRAR-005-01, ANR, Département de neurologie [Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Normandie Université (NU)-Normandie Université (NU)-École Pratique des Hautes Études (EPHE), Université de Rennes (UR), French research Network on FTD/FTD-MND, and Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)
Subjects: Male, Pathology, Neuropsychological Tests, MESH: Epidemiologic Methods, MESH: Aphasia, Primary Progressive, Apraxia, MESH: Magnetic Resonance Imaging, Primary progressive aphasia, Progranulins, MESH: Aged, 80 and over, 0302 clinical medicine, MESH: Motor Neuron Disease, Corticobasal degeneration, Age of Onset, MESH: Brain Mapping, MESH: Heterozygote, Aged, 80 and over, MESH: Aged, Brain Mapping, 0303 health sciences, MESH: Middle Aged, Parkinsonism, Brain, MESH: Neuropsychological Tests, Middle Aged, Magnetic Resonance Imaging, MESH: Dementia, 3. Good health, Phenotype, Disease Progression, Intercellular Signaling Peptides and Proteins, Female, MESH: Disease Progression, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Psychology, Haploinsufficiency, Frontotemporal dementia, Adult, Heterozygote, medicine.medical_specialty, MESH: Mutation, MESH: Age of Onset, MESH: Phenotype, MESH: Brain, 03 medical and health sciences, medicine, Humans, Dementia, Motor Neuron Disease, MESH: Intercellular Signaling Peptides and Proteins, Aged, 030304 developmental biology, MESH: Humans, Lewy body, MESH: Adult, medicine.disease, MESH: Male, MESH: Cognition Disorders, Aphasia, Primary Progressive, Mutation, Neurology (clinical), Cognition Disorders, Epidemiologic Methods, MESH: Female, 030217 neurology & neurosurgery
Abstract: Frontotemporal dementia (FTD), characterized by behavioural and language disorders, is a clinically, genetically and pathologically heterogeneous group of diseases. The most recently identified of the four known genes is GRN, associated with 17q-linked FTD with ubiquitin-immunoreactive inclusions. GRN was analysed in 502 probands with frontal variant FTD (fvFTD), FTD with motoneuron disease (FTD-MND), primary progressive aphasia (PPA) and corticobasal degeneration syndrome (CBDS). We studied the clinical, neuropsychological and brain perfusion characteristics of mutation carriers. Eighteen mutations, seven novel were found in 24 families including 32 symptomatic mutation carriers. No copy number variation was found. The phenotypes associated with GRN mutations vary greatly: 20/32 (63%) carriers had fvFTD, the other (12/32, 37%) had clinical diagnoses of PPA, CBDS, Lewy body dementia or Alzheimer's disease. Parkinsonism developed in 13/32 (41%), visual hallucinations in 8/32 (25%) and motor apraxia in 5/21 (24%). Constructional disorders were present in 10/21 (48%). Episodic memory disorders were frequent (16/18, 89%), consistent with hippocampal amnestic syndrome in 5/18 (28%). Hypoperfusion was observed in the hippocampus, parietal lobe and posterior cingulate gyrus, as well as the frontotemporal cortices. The frequency of mutations according to phenotype was 5.7% (20/352) in fvFTD, 17.9% (19/106) in familial forms, 4.4% in PPA (3/68), 3.3% in CBDS (1/30). Hallucinations, apraxia and amnestic syndrome may help differentiate GRN mutation carriers from others FTD patients. Variable phenotypes and neuropsychological profiles, as well as brain perfusion profiles associated with GRN mutations may reflect different patterns of neurodegeneration. Since all the mutations cause a progranulin haploinsufficiency, additional factors probably explain the variable clinical presentation of the disease.
Published: 2008

43. Alzheimer disease: modeling an Aβ-centered biological network

Author: Cyril Pottier, Anne Rovelet-Lecrux, K Le Guennec, Dominique Campion, and Gaël Nicolas
Subjects: 0301 basic medicine, Amyloid beta, Gene regulatory network, 03 medical and health sciences, Cellular and Molecular Neuroscience, Amyloid beta-Protein Precursor, 0302 clinical medicine, Missing heritability problem, Alzheimer Disease, medicine, Dementia, Animals, Humans, Gene Regulatory Networks, Molecular Biology, Amyloid beta-Peptides, biology, High-Throughput Nucleotide Sequencing, medicine.disease, Psychiatry and Mental health, 030104 developmental biology, Behavioral medicine, biology.protein, Alzheimer's disease, Psychology, Databases, Nucleic Acid, Neuroscience, 030217 neurology & neurosurgery, Function (biology), Biological network
Abstract: In genetically complex diseases, the search for missing heritability is focusing on rare variants with large effect. Thanks to next generation sequencing technologies, genome-wide characterization of these variants is now feasible in every individual. However, a lesson from current studies is that collapsing rare variants at the gene level is often insufficient to obtain a statistically significant signal in case-control studies, and that network-based analyses are an attractive complement to classical approaches. In Alzheimer disease (AD), according to the prevalent amyloid cascade hypothesis, the pathology is driven by the amyloid beta (Aβ) peptide. In past years, based on experimental studies, several hundreds of proteins have been shown to interfere with Aβ production, clearance, aggregation or toxicity. Thanks to a manual curation of the literature, we identified 335 genes/proteins involved in this biological network and classified them according to their cellular function. The complete list of genes, or its subcomponents, will be of interest in ongoing AD genetic studies.
Published: 2015

44. ABCA7 rare variants and Alzheimer disease risk

Author: Kilan, Le Guennec, Gaël, Nicolas, Olivier, Quenez, Camille, Charbonnier, David, Wallon, Céline, Bellenguez, Benjamin, Grenier-Boley, Stéphane, Rousseau, Anne-Claire, Richard, Anne, Rovelet-Lecrux, Delphine, Bacq, Jean-Guillaume, Garnier, Robert, Olaso, Anne, Boland, Vincent, Meyer, Jean-François, Deleuze, Philippe, Amouyel, Hans Markus, Munter, Guillaume, Bourque, Mark, Lathrop, Thierry, Frebourg, Richard, Redon, Luc, Letenneur, Jean-François, Dartigues, Florence, Pasquier, Adeline, Rollin-Sillaire, Emmanuelle, Génin, Jean-Charles, Lambert, Didier, Hannequin, Dominique, Campion, Karl, Mondon, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)
Subjects: 0301 basic medicine, Oncology, medicine.medical_specialty, [SDV]Life Sciences [q-bio], Article, 03 medical and health sciences, 0302 clinical medicine, Belgium, Gene Frequency, Alzheimer Disease, Internal medicine, Missense mutation, Medicine, Humans, Exome, Genetic Predisposition to Disease, Allele frequency, Genetic Association Studies, Aged, business.industry, Case-control study, Odds ratio, Confidence interval, Minor allele frequency, 030104 developmental biology, Meta-analysis, Case-Control Studies, Mutation, ATP-Binding Cassette Transporters, Neurology (clinical), France, business, 030217 neurology & neurosurgery
Abstract: Objective:To study the association between ABCA7 rare coding variants and Alzheimer disease (AD) in a case-control setting.Methods:We conducted a whole exome analysis among 484 French patients with early-onset AD and 590 ethnically matched controls.Results:After collapsing rare variants (minor allele frequency ≤1%), we detected an enrichment of ABCA7 loss of function (LOF) and predicted damaging missense variants in cases (odds ratio [OR] 3.40, 95% confidence interval [CI] 1.68–7.35, p = 0.0002). Performing a meta-analysis with previously published data, we found that in a combined sample of 1,256 patients and 1,347 controls from France and Belgium, the OR was 2.81 (95% CI 1.89–4.20, p = 3.60 × 10−7).Conclusions:These results confirm that ABCA7 LOF variants are enriched in patients with AD and extend this finding to predicted damaging missense variants.
Published: 2015

45. Mutation in the 3’untranslated region of APP as a genetic determinant of cerebral amyloid angiopathy

Author: Gaël Nicolas, Florence Riant, Thierry Frebourg, Dominique Campion, Pierre-Marie Preux, Claudia Goupil, Cyril Pottier, Bébène Ndamba-Bandzouzi, Pascal M'Belesso, Jean-Charles Lambert, Didier Hannequin, David Wallon, Elisabeth Tournier-Lasserve, Mariana Sarov-Rivière, Véronique Dorval, Dominique Hervé, Sébastien S. Hébert, Philippe Amouyel, Anne Rovelet-Lecrux, Maëlenn Guerchet, Anne Claire Richard, Jean-François Dartigues, Génomique et Médecine Personnalisée du Cancer et des Maladies Neuropsychiatriques (GPMCND), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de neurologie [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU), GeoRessources, Institut national des sciences de l'Univers (INSU - CNRS)-Centre de recherches sur la géologie des matières premières minérales et énergétiques (CREGU)-Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), Université de Lille, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP), Neuroépidémiologie Tropicale (NET), CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM), Epidémiologie et Biostatistique [Bordeaux], Université Bordeaux Segalen - Bordeaux 2-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département Imagerie et Simulation pour le Contrôle (DISC), Laboratoire d'Intégration des Systèmes et des Technologies (LIST (CEA)), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Laboratoire de Recherche en Informatique (LRI), Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biostatistique et d'Informatique Médicale, Université de Limoges (UNILIM), Service de l'Information Médicale et de l'Évaluation [CHU Limoges] (SIME), CHU Limoges, Génétique du cancer et des maladies neuropsychiatriques (GMFC), Laboratoire de cristallographie et sciences des matériaux (CRISMAT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche sur les Matériaux Avancés (IRMA), Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut national des sciences appliquées Rouen Normandie (INSA Rouen Normandie), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université de Rouen Normandie (UNIROUEN), Institut National des Sciences Appliquées (INSA)-Normandie Université (NU)-Institut National des Sciences Appliquées (INSA)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université de Lorraine (UL)-Centre de recherches sur la géologie des matières premières minérales et énergétiques (CREGU)-Institut national des sciences de l'Univers (INSU - CNRS), Institut Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST), Université de Limoges (UNILIM)-Université de Limoges (UNILIM)-CHU Limoges-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Intégration des Systèmes et des Technologies (LIST), CentraleSupélec-Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), École Nationale Supérieure d'Ingénieurs de Caen (ENSICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Université de Caen Normandie (UNICAEN), and Normandie Université (NU)-Institut de Chimie du CNRS (INC)
Subjects: Adult, Male, 0301 basic medicine, Untranslated region, [SDV]Life Sciences [q-bio], Molecular Sequence Data, medicine.disease_cause, Article, Amyloid beta-Protein Precursor, 03 medical and health sciences, 0302 clinical medicine, Gene duplication, mental disorders, Genetics, medicine, Amyloid precursor protein, Humans, Age of Onset, 3' Untranslated Regions, Genetics (clinical), Sequence Deletion, Regulation of gene expression, Mutation, Messenger RNA, Binding Sites, Base Sequence, biology, Three prime untranslated region, Computational Biology, Sequence Analysis, DNA, Middle Aged, medicine.disease, Cerebral Amyloid Angiopathy, MicroRNAs, 030104 developmental biology, Gene Expression Regulation, biology.protein, Nucleic Acid Conformation, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cerebral amyloid angiopathy, 030217 neurology & neurosurgery
Abstract: International audience; Aβ-related cerebral amyloid angiopathy (CAA) is a major cause of primary non-traumatic brain hemorrhage. In families with an early onset of the disease, CAA can be due to amyloid precursor protein (APP) pathogenic variants or duplications. APP duplications lead to a ~1.5-fold increased APP expression, resulting in Aβ overproduction and deposition in the walls of leptomeningeal vessels. We hypothesized that rare variants in the 3’untranslated region (UTR) of APP might lead to APP overexpression in patients with CAA and no APP pathogenic variant or duplication. We performed direct sequencing of the whole APP 3’UTR in 90 patients with CAA and explored the functional consequences of one previously unreported variant. We identified three sequence variants in four patients, of which a two-base pair deletion (c.*331_*332del) was previously unannotated and absent from 175 controls of same ethnicity. This latter variant was associated with increased APP expression in vivo and in vitro. Bioinformatics and functional assays showed that the APP c.*331_*332del variant affected APP messenger RNA (mRNA) structure and binding of two microRNAs (miR-582-3p and miR-892b), providing a mechanism for the observed effects on APP expression. These results identify APP 3’UTR sequence variants as genetic determinants of Aβ-CAA.
Published: 2015

46. De novo deleterious genetic variations target a biological network centered on Aβ peptide in early-onset Alzheimer disease

Author: Didier Hannequin, A-C Richard, Dominique Campion, Anne Boland, Sophia Y. Breusegem, J.F. Deleuze, K Le Guennec, Anne Rovelet-Lecrux, Stéphane Rousseau, Aamir S. Mukadam, Olivier Quenez, David Wallon, Premendu P. Mathur, Pranitha Jenardhanan, Gaël Nicolas, Thierry Frebourg, Matthew N.J. Seaman, Cyril Pottier, Camille Charbonnier, and Sophie Coutant
Subjects: Male, DNA Copy Number Variations, Amyloid beta, Cellular and Molecular Neuroscience, Amyloid beta-Protein Precursor, Alzheimer Disease, Amyloid precursor protein, PSEN1, medicine, Presenilin-1, Missense mutation, Humans, Exome, Gene Regulatory Networks, Copy-number variation, Molecular Biology, Genetics, Comparative Genomic Hybridization, Amyloid beta-Peptides, biology, Genetic heterogeneity, Middle Aged, medicine.disease, Pedigree, Psychiatry and Mental health, biology.protein, Female, Alzheimer's disease, Multiplex Polymerase Chain Reaction
Abstract: We hypothesized that de novo variants (DNV) might participate in the genetic determinism of sporadic early-onset Alzheimer disease (EOAD, onset before 65 years). We investigated 14 sporadic EOAD trios first by array-comparative genomic hybridization. Two patients carried a de novo copy number variation (CNV). We then performed whole-exome sequencing in the 12 remaining trios and identified 12 non-synonymous DNVs in six patients. The two de novo CNVs (an amyloid precursor protein (APP) duplication and a BACE2 intronic deletion) and 3/12 non-synonymous DNVs (in PSEN1, VPS35 and MARK4) targeted genes from a biological network centered on the Amyloid beta (Aβ) peptide. We showed that this a priori-defined genetic network was significantly enriched in amino acid-altering DNV, compared with the rest of the exome. The causality of the APP de novo duplication (which is the first reported one) was obvious. In addition, we provided evidence of the functional impact of the following three non-synonymous DNVs targeting this network: the novel PSEN1 variant resulted in exon 9 skipping in patient's RNA, leading to a pathogenic missense at exons 8-10 junction; the VPS35 missense variant led to partial loss of retromer function, which may impact neuronal APP trafficking and Aβ secretion; and the MARK4 multiple nucleotide variant resulted into increased Tau phosphorylation, which may trigger enhanced Aβ-induced toxicity. Despite the difficulty to recruit Alzheimer disease (AD) trios owing to age structures of the pedigrees and the genetic heterogeneity of the disease, this strategy allowed us to highlight the role of de novo pathogenic events, the putative involvement of new genes in AD genetics and the key role of Aβ network alteration in AD.
Published: 2015

47. Regional distribution of synaptic markers and APP correlate with distinct clinicopathological features in sporadic and familial Alzheimer’s disease

Author: Ronald C. Petersen, Joseph E. Parisi, Neill R. Graff-Radford, Aleksandra Wojtas, Dennis W. Dickson, Guojun Bu, Pritam Das, Matt Baker, Rosa Rademakers, Melissa E. Murray, Shinsuke Fujioka, Anne Rovelet-Lecrux, and Mitsuru Shinohara
Subjects: Apolipoprotein E, Adult, Male, Pathology, medicine.medical_specialty, Nerve Tissue Proteins, tau Proteins, Disease, Presenilin, Amyloid beta-Protein Precursor, Alzheimer Disease, mental disorders, PSEN1, Amyloid precursor protein, Presenilin-1, Medicine, Aspartic Acid Endopeptidases, Humans, Aged, Aged, 80 and over, Amyloid beta-Peptides, biology, business.industry, Brain, Neurofibrillary Tangles, Original Articles, Middle Aged, medicine.disease, Ageing, Postmortem Changes, Synapses, biology.protein, Female, Human medicine, Neurology (clinical), Alzheimer's disease, Amyloid Precursor Protein Secretases, business, Amyloid precursor protein secretase
Abstract: Recent studies suggest that subcortical structures, including striatum, are vulnerable to amyloid-beta accumulation and other neuropathological features in familial Alzheimer's disease due to autosomal dominant mutations. We explored differences between familial and sporadic Alzheimer's disease that might shed light on their respective pathogenic mechanisms. To this end, we analysed 12 brain regions, including neocortical, limbic and subcortical areas, from post-mortem brains of familial Alzheimer's disease (n = 10; age at death: 50.0 +/- 8.6 years) with mutations in amyloid precursor protein (APP) or presenilin 1 (PSEN1), sporadic Alzheimer's disease (n = 19; age at death: 84.7 +/- 7.8 years), neurologically normal elderly without amyloid-beta accumulation (normal ageing; n = 13, age at death: 82.9 +/- 10.8 years) and neurologically normal elderly with extensive cortical amyloid-beta deposits (pathological ageing; n = 15; age at death: 92.7 +/- 5.9 years). The levels of amyloid-beta(40), amyloid-beta(42), APP, apolipoprotein E, the synaptic marker PSD95 (now known as DLG4), the astrocyte marker GFAP, other molecules related to amyloid-beta metabolism, and tau were determined by enzyme-linked immunosorbent assays. We observed that familial Alzheimer's disease had disproportionate amyloid-beta(42) accumulation in subcortical areas compared with sporadic Alzheimer's disease, whereas sporadic Alzheimer's disease had disproportionate amyloid-beta(42) accumulation in cortical areas compared to familial Alzheimer's disease. Compared with normal ageing, the levels of several proteins involved in amyloid-beta metabolism were significantly altered in both sporadic and familial Alzheimer's disease; however, such changes were not present in pathological ageing. Among molecules related to amyloid-beta metabolism, the regional distribution of PSD95 strongly correlated with the regional pattern of amyloid-beta(42) accumulation in sporadic Alzheimer's disease and pathological ageing, whereas the regional distribution of APP as well as beta-C-terminal fragment of APP were strongly associated with the regional pattern of amyloid-beta(42) accumulation in familial Alzheimer's disease. Apolipoprotein E and GFAP showed negative regional association with amyloid-beta (especially amyloid-beta(40)) accumulation in both sporadic and familial Alzheimer's disease. Familial Alzheimer's disease had greater striatal tau pathology than sporadic Alzheimer's disease. In a retrospective medical record review, atypical signs and symptoms were more frequent in familial Alzheimer's disease compared with sporadic Alzheimer's disease. These results suggest that disproportionate amyloid-beta(42) accumulation in cortical areas in sporadic Alzheimer's disease may be mediated by synaptic processes, whereas disproportionate amyloid-beta(42) accumulation in subcortical areas in familial Alzheimer's disease may be driven by APP and its processing. Region-specific amyloid-beta(42) accumulation might account for differences in the relative amounts of tau pathology and clinical symptoms in familial and sporadic Alzheimer's disease.
Published: 2014

48. A de novo nonsense PDGFB mutation causing idiopathic basal ganglia calcification with laryngeal dystonia

Author: Olivier Rouaud, David Wallon, Didier Hannequin, Christian Duvillard, Yannick Béjot, Agnès Jacquin, Christel Thauvin-Robinet, Dominique Campion, Anne Rovelet-Lecrux, Marie-Hélène Aubriot-Lorton, Cyril Pottier, Maurice Giroud, Gaël Nicolas, Stéphane Rousseau, and Thierry Frebourg
Subjects: Proband, Pathology, medicine.medical_specialty, Nonsense mutation, Short Report, Basal ganglia calcification, PDGFRB, Biology, Polymorphism, Single Nucleotide, Basal Ganglia, Laryngeal Diseases, Young Adult, Basal Ganglia Diseases, Genetics, medicine, Humans, Basal ganglia disease, Genetics (clinical), Dystonia, Brain Diseases, PDGFB, Brain, Exons, Proto-Oncogene Proteins c-sis, Ribonucleoprotein, U2 Small Nuclear, medicine.disease, Pedigree, DNA Topoisomerases, Type I, Codon, Nonsense, Female, RNA Splicing Factors, Tomography, X-Ray Computed, Calcification
Abstract: Idiopathic basal ganglia calcification (IBGC) is characterized by brain calcification and a wide variety of neurologic and psychiatric symptoms. In families with autosomal dominant inheritance, three causative genes have been identified: SLC20A2, PDGFRB, and, very recently, PDGFB. Whereas in clinical practice sporadic presentation of IBGC is frequent, well-documented reports of true sporadic occurrence are rare. We report the case of a 20-year-old woman who presented laryngeal dystonia revealing IBGC. Her healthy parents' CT scans were both normal. We identified in the proband a new nonsense mutation in exon 4 of PDGFB, c.439C>T (p.Gln147*), which was absent from the parents' DNA. This mutation may result in a loss-of-function of PDGF-B, which has been shown to cause IBGC in humans and to disrupt the blood-brain barrier in mice, resulting in brain calcification. The c.439C>T mutation is located between two previously reported nonsense mutations, c.433C>T (p.Gln145*) and c.445C>T (p.Arg149*), on a region that could be a hot spot for de novo mutations. We present the first full demonstration of the de novo occurrence of an IBGC-causative mutation in a sporadic case.
Published: 2014

49. PDGFB partial deletion: a new, rare mechanism causing brain calcification with leukoencephalopathy

Author: Louis Vernier, Anne Rovelet-Lecrux, Dominique Campion, David Wallon, Thierry Frebourg, Gaël Nicolas, Cyril Pottier, Françoise Chapon, Gérard Landemore, Didier Hannequin, Olivier Martinaud, Elisabeth Tournier-Lasserve, and Carol Prieto-Morin
Subjects: Genetics, Heterozygote, PDGFB, Sodium-Phosphate Cotransporter Proteins, Type III, Point mutation, Autosomal dominant trait, Calcinosis, PDGFRB, Locus (genetics), Neurodegenerative Diseases, General Medicine, Exons, Proto-Oncogene Proteins c-sis, Biology, Cellular and Molecular Neuroscience, Basal Ganglia Diseases, Leukoencephalopathies, Cancer research, Humans, Female, Copy-number variation, Allele, Cognitive decline, Gene Deletion, Aged
Abstract: Idiopathic basal ganglia calcification (IBGC) is a progressive cerebral disorder with diverse motor, cognitive, and psychiatric expression. It is inherited as an autosomal dominant trait. Three IBGC-causing genes have been identified in the past 2 years: SLC20A2, PDGFRB, and PDGFB. Biological and genetic evidence showed that loss of function of either SLC20A2 or the PDGFB/PDGFRB pathway was the mechanism underlying calcification in patients with a mutation. Recently, in a study focusing on SLC20A2, a large deletion at this locus was reported. No study has systematically searched for copy number variants (CNV) involving these three genes. We designed a quantitative PCR assay of multiple short fluorescent fragments (QMPSF) to detect CNVs involving one of these three genes in a single assay. Among the 27 unrelated patients from our IBGC case series with no mutation in SLC20A2, PDGFRB, and PDGFB, we identified in one patient a heterozygous partial deletion involving exons 2 to 5 of PDGFB. This patient exhibited both strio-pallido-dentate calcification and white matter hyperintensity of presumed vascular origin, associated with mood disorder, subtle cognitive decline, and gait disorder. We confirmed by RT-PCR experiments that the allele carrying the deletion was transcribed. The resulting cDNA lacks sequence for several critical functional domains of the protein. Intragenic deletion of PDGFB is a new and rare mechanism causing IBGC. CNVs involving the three IBGC-causing genes should be investigated in patients with no point mutation.
Published: 2014

50. Partial deletions of the GRN gene are a cause of frontotemporal lobar degeneration

Author: Isabelle Le Ber, Agnès Camuzat, Foudil Lamari, Ludmila Jornea, Dominique Campion, Eric LeGuern, Fabienne Clot, Anne Rovelet-Lecrux, Béatrice Laudier, Anne de Septenville, Alexis Brice, Boris Keren, Paola Caroppo, Cécile Cazeneuve, Sandrine Noël, and A Michon
Subjects: Genetics, Breakpoint, Intron, Loss of Heterozygosity, Frontotemporal lobar degeneration, Middle Aged, Biology, medicine.disease, Molecular biology, Pedigree, Frameshift mutation, Loss of heterozygosity, Cellular and Molecular Neuroscience, Exon, Progranulins, mental disorders, medicine, Humans, Intercellular Signaling Peptides and Proteins, Multiplex ligation-dependent probe amplification, Frontotemporal Lobar Degeneration, Gene, Gene Deletion, Genetics (clinical)
Abstract: Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD). Most known GRN mutations are null mutations, such as nonsense and frameshift mutations, which create a premature stop codon resulting in loss of function of the progranulin protein. Complete or near-complete genomic GRN deletions have also been found in three families, but heterozygous partial deletions that remove only one or two exons have not been reported to date. In this study, we analysed three unrelated FTLD patients with low plasma progranulin levels but no point GRN mutations by multiplex ligation-dependent probe amplification (MLPA) and quantitative multiplex polymerase chain reaction of short fluorescent fragments (QMPSF). We detected two heterozygous partial GRN deletions in two patients. One deletion removed exon 1 and part of intron 1. The second deletion was complex: it removed 1,410 bp extending from the part of intron 1 to the part of exon 3, with a small 5-bp insertion at the breakpoint junction (c.-7-1121_159delinsGATCA). Our findings illustrate the usefulness of a quantitative analysis in addition to GRN gene sequencing for a comprehensive genetic diagnosis of FTLD, particularly in patients with low plasma progranulin levels.
Published: 2014

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