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1. Development of a new expanded next‐generation sequencing panel for genetic diseases involved in dyslipidemia

Author

Philippe Moulin, Igor Tauveron, Mathilde Di Filippo, Christophe Marçais, Chantal Jacobs, Alexandre Janin, Anne-Sophie Wozny, O. Marmontel, X. Vanhoye, Sabrina Dumont, Pierre Poinsot, Thomas Simonet, Cyrielle Caussy, Gilles Millat, Muriel Mahl, Nicolas Chatron, Sybil Charrière, Delphine Collin-Chavagnac, Noël Peretti, Claire Bardel, Pierre Antoine Rollat-Farnier, Séverine Nony, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), and Hospices Civils de Lyon

Subjects
Male, 0301 basic medicine, Candidate gene, DNA Copy Number Variations, Computational biology, 030105 genetics & heredity, Biology, genetic risk score, DNA sequencing, 03 medical and health sciences, Exon, molecular diagnosis, Genetics, medicine, Humans, copy number variant, Genetic Testing, Copy-number variation, Genetic risk, Gene, Genetics (clinical), Dyslipidemias, hypercholesterolemia, dyslipidemia, Genetic Diseases, Inborn, High-Throughput Nucleotide Sequencing, hypobetalipoproteinemia, Sequence Analysis, DNA, medicine.disease, 030104 developmental biology, targeted next generation sequencing, Female, Dyslipidemia, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; The aim of this study was to provide an efficient tool: reliable, able to increase the molecular diagnosis performance, to facilitate the detection of copy number variants (CNV), to assess genetic risk scores (wGRS) and to offer the opportunity to explore candidate genes. Custom SeqCap EZ libraries, NextSeq500 sequencing and a homemade pipeline enable the analysis of 311 dyslipidemia-related genes. In the training group (48 DNA from patients with a well-established molecular diagnosis), this next-generation sequencing (NGS) workflow showed an analytical sensitivity >99% (n = 532 variants) without any false negative including a partial deletion of one exon. In the prospective group, from 25 DNA from patients without prior molecular analyses, 18 rare variants were identified in the first intention panel genes, allowing the diagnosis of monogenic dyslipidemia in 11 patients. In six other patients, the analysis of minor genes and wGRS determination provided a hypothesis to explain the dyslipidemia. Remaining data from the whole NGS workflow identified four patients with potentially deleterious variants. This NGS process gives a major opportunity to accede to an enhanced understanding of the genetic of dyslipidemia by simultaneous assessment of multiple genetic determinants.

Published
2020

2. PCSK9 post-transcriptional regulation: Role of a 3′UTR microRNA-binding site variant in linkage disequilibrium with c.1420G

Author

Claire Bardel, O. Marmontel, Manon Muntaner, Eléonore Divry, Philippe Moulin, Mathilde Di Filippo, Séverine Nony, Bertrand Cariou, Nicolas Chatron, Sybil Charrière, Charlotte Decourt, Alexandre Janin, Marine Moindrot, Luc Dauchet, Sabrina Dumont, Aline Meirhaeghe, Hospices Civils de Lyon (HCL), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, 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), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université de Lyon-Université de Lyon-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Unité de recherche de l'institut du thorax (ITX-lab), 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), Lille University Hospital (CHU de Lille, Lille, France) Region Hauts-de-France European Regional Development Fund (ERDF-FEDER Presage) as part of the CPER Institut de Recherche en ENvironnement Industriel (IRENI) program 36,034CLIMIBIO CPER research project Pfizer, 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)-Nantes Université - UFR de Médecine et des Techniques Médicales (Nantes Univ - UFR MEDECINE), Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ)-Nantes Université - pôle Santé, Nantes Université (Nantes Univ)-Nantes Université (Nantes Univ), Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d’Investigation Clinique de Nantes (CIC Nantes), Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre hospitalier universitaire de Nantes (CHU Nantes), CCSD, Accord Elsevier, Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), and Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)

Subjects
0301 basic medicine, Untranslated region, Linkage disequilibrium, Luciferase assay, Hypercholesterolemia, MiRNA binding, 030204 cardiovascular system & hematology, Biology, Linkage Disequilibrium, PCSK9, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.CSC]Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, Humans, Allele, Post-transcriptional regulation, 3' Untranslated Regions, miRNA, Genetics, Binding Sites, rs562556, Proprotein convertase, Loss of function, [SDV.MHEP.CSC] Life Sciences [q-bio]/Human health and pathology/Cardiology and cardiovascular system, MicroRNAs, 030104 developmental biology, Kexin, Proprotein Convertase 9, Cardiology and Cardiovascular Medicine
Abstract

International audience; Background and aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in cholesterol homeostasis. A common variant, the G allele in position c.1420 (c.1420G), has been associated with a decrease of both plasma PCSK9 and LDL-cholesterol concentrations. However, the functional effect of this variant is currently not well understood. We hypothesized that it could be explained by functional variants in linkage disequilibrium (LD), more specifically, by variants located in the PCSK9 3' UTR as targets for miR regulation of PCSK9 expression.Methods: Variations in LD with c.1420G were studied in 1029 patients followed for dyslipidaemia. In silico studies identified potential miRNA binding sites induced by PCSK9 3'UTR variants in LD with c.1420G. Their functionality was studied with a luciferase reporter assay in HuH-7 cells and confirmed by cotransfection of anti-miRNAs.Results: The c.*571C and c.*234T variants located in the PCSK9 3'UTR were found in tight LD with c.1420G (D' = 0.962; LOD = 163.06). The haplotype carrying c.*571C showed a 6.7% decrease in luciferase activity (p = 0.003). Inhibition of hsa-miR-1228-3p and hsa-miR-143-5p counteracted their effect on the haplotype carrying c.*571C allele, suggesting that PCSK9 expression was decreased by the endogenous binding of hsa-miR-1228-3p and hsa-miR-143-5p on its 3'UTR.Conclusions: This post-transcriptional regulation might contribute towards the association between plasma PCSK9 levels and c.1420G. Such regulation of PCSK9 expression may open new perspectives for the treatment of hypercholesterolemia and atherosclerosis cardiovascular diseases.

Published
2020

3. Involvement of a homozygous exon 6 deletion of LMF1 gene in intermittent severe hypertriglyceridemia

Author

Mathilde Di Filippo, Muriel Mahl, Sybil Charrière, Anne-Sophie Wozny, Oriane Marmontel, Philippe Moulin, C. Marcais, Thomas Simonet, Marine Serveaux Dancer, Sabrina Dumont, CarMeN, laboratoire, Hospices Civils de Lyon (HCL), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Lyon, Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RA), Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA), Service de Biochimie et Biologie Moléculaire Grand Est [HCL, Lyon] (Centre de Biologie et de Pathologie), and Université de Lyon-Université de Lyon-CHU Grenoble-Hospices Civils de Lyon (HCL)-CHU Saint-Etienne-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Grenoble Alpes (UGA)

Subjects
medicine.medical_specialty, Severe hypertriglyceridemia, Endocrinology, Diabetes and Metabolism, media_common.quotation_subject, [SDV]Life Sciences [q-bio], Nonsense, Pcr cloning, 030204 cardiovascular system & hematology, 03 medical and health sciences, Exon, 0302 clinical medicine, Internal medicine, Internal Medicine, medicine, Multifactorial chylomicronemia syndrome, Humans, 030212 general & internal medicine, Copy-number variation, Gene, media_common, Sequence Deletion, Hypertriglyceridemia, Nutrition and Dietetics, business.industry, Homozygote, Triglyceride, Membrane Proteins, Exons, medicine.disease, Phenotype, 3. Good health, [SDV] Life Sciences [q-bio], Lipolysis, Endocrinology, Familial chylomicronemia syndrome, Female, Cardiology and Cardiovascular Medicine, business, Copy number variation, lmf1
Abstract

International audience; Severe hypertriglyceridemia (HTG), characterized by triglycerides (TG) permanently over 10 mmol/L, may correspond to familial chylomicronemia syndrome (FCS), a rare disorder. However, hypertriglyceridemic patients more often present multifactorial chylomicronemia syndrome (MCS), characterized by highly variable TG. A few nonsense variants of LMF1 gene were reported in literature in FCS patients. In this study, we described a woman with an intermittent severe HTG. NGS analysis and the sequencing of a long range PCR product revealed a homozygous deletion of 6507 base pairs in LMF1 gene, c.730-1528\₈98-3417del, removing exon 6, predicted to create an in-frame deletion of 56 amino acids, p.(Thr244_Gln299del). Despite an exon 6 homozygous deletion of LMF1, the patient's highly variable lipid phenotype was suggestive of MCS diagnosis.

Published
2020

4. Single, short in-del, and copy number variations detection in monogenic dyslipidemia using a next-generation sequencing strategy

Author

Philippe Moulin, Séverine Nony, Sybil Charrière, O. Marmontel, Muriel Mahl, Chantal Jacobs, Alain Lachaux, Thomas Simonet, Kaddour Chabane, Gilles Millat, C. Marçais, Sabrina Dumont, M. Di Filippo, Claire Bardel, Alexandre Janin, Dominique Bozon, Véronique Bonnet, Noël Peretti, Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS), Biostatistiques santé, Département biostatistiques et modélisation pour la santé et l'environnement [LBBE], Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de Recherche en Informatique et en Automatique (Inria)-VetAgro Sup - Institut national d'enseignement supérieur et de recherche en alimentation, santé animale, sciences agronomiques et de l'environnement (VAS)-Centre National de la Recherche Scientifique (CNRS)-Laboratoire de Biométrie et Biologie Evolutive - UMR 5558 (LBBE), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), hospices civils de Lyon, Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Institut National de la Recherche Agronomique (INRA)

Subjects
0301 basic medicine, genotype phenotype correlation, [SDV]Life Sciences [q-bio], Comorbidity, monogenic dyslipidemia, Familial hypercholesterolemia, 030204 cardiovascular system & hematology, Workflow, autosomal-dominant hypercholesterolemia, 0302 clinical medicine, INDEL Mutation, targeted next-generation sequencing, Medicine, Copy-number variation, Child, Genetics (clinical), Aged, 80 and over, Genetics & Heredity, apo-b gene, familial hypercholesterolemia, copy number variation, Ion torrent PGM, High-Throughput Nucleotide Sequencing, Middle Aged, 3. Good health, Child, Preschool, combined hypolipidemia, Adult, Adolescent, DNA Copy Number Variations, ldl-c levels, hypertriglyceridemia, In silico, density-lipoprotein-receptor, Computational biology, apolipoprotein-b, DNA sequencing, Diagnosis, Differential, Young Adult, 03 medical and health sciences, lipid disorders, Genetics, Humans, Genetic Predisposition to Disease, Mutation detection, Genetic Testing, Genetic Association Studies, Aged, Dyslipidemias, business.industry, PCSK9, severe, Hypertriglyceridemia, medicine.disease, 030104 developmental biology, coronary-heart-disease, business, Biomarkers, Dyslipidemia
Abstract

International audience; Optimal molecular diagnosis of primary dyslipidemia is challenging to confirm the diagnosis, test and identify at risk relatives. The aim of this study was to test the application of a single targeted next-generation sequencing (NGS) panel for hypercholesterolemia, hypocholesterolemia, and hypertriglyceridemia molecular diagnosis. NGS workflow based on a custom AmpliSeq panel was designed for sequencing the most prevalent dyslipidemia-causing genes (ANGPTL3, APOA5, APOC2, APOB, GPIHBP1, LDLR, LMF1, LPL, PCSK9) on the Ion PGM Sequencer. One hundred and forty patients without molecular diagnosis were studied. In silico analyses were performed using the NextGENe software and homemade tools for detection of copy number variations (CNV). All mutations were confirmed using appropriate tools. Eighty seven variations and 4 CNV were identified, allowing a molecular diagnosis for 40/116 hypercholesterolemic patients, 5/13 hypocholesterolemic patients, and 2/11, hypertriglyceridemic patients respectively. This workflow allowed the detection of CNV contrary to our previous strategy. Some variations were found in previously unexplored regions providing an added value for genotype-phenotype correlation and familial screening. In conclusion, this new NGS process is an effective mutation detection method and allows better understanding of phenotype. Consequently this assay meets the medical need for individualized diagnosis of dyslipidemia.

Published
2018

5. Postprandial lipid absorption in seven heterozygous carriers of deleterious variants of MTTP in two abetalipoproteinemic families

Author

Jacques Schmitz, Mathilde Di Filippo, Dominique Bonnefont-Rousselot, Sabrina Dumont, Latifa Ferkdadji, Catherine Boileau, Mathilde Varret, V. Boehm, Francisca Joly, Jean-Pierre Rabès, Laurent Abramowitz, Catherine Lenaerts, Marie-Elisabeth Samson-Bouma, Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Laboratoire de Recherche Vasculaire Translationnelle (LVTS (UMR_S_1148 / U1148)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP)-Université Sorbonne Paris Nord, Centre de recherche sur l'Inflammation (CRI (UMR_S_1149 / ERL_8252 / U1149)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Hôpital Robert Debré, AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Amiens-Picardie, Centre Régional de Lutte contre le Cancer François Baclesse [Caen] (UNICANCER/CRLC), UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU), CHU Necker - Enfants Malades [AP-HP], Service de Biochimie Métabolique [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), Université Paris Descartes - Paris 5 (UPD5), Unité de Technologies Chimiques et Biologiques pour la Santé (UTCBS - UM 4 (UMR 8258 / U1022)), Institut de Chimie du CNRS (INC)-Université de Paris (UP)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), CarMeN, laboratoire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Université Sorbonne Paris Nord, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Normandie Université (NU)-UNICANCER-Tumorothèque de Caen Basse-Normandie (TCBN), and 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 Paris Cité (UPCité)

Subjects
Male, Apolipoprotein B, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], Liver steatosis, 030204 cardiovascular system & hematology, Compound heterozygosity, Microsomal triglyceride transfer protein, chemistry.chemical_compound, 0302 clinical medicine, 030212 general & internal medicine, Child, Fat malabsorption, Sequence Deletion, Nutrition and Dietetics, biology, medicine.diagnostic_test, Postprandial, Middle Aged, Postprandial Period, Abetalipoproteinemia, Pedigree, 3. Good health, [SDV] Life Sciences [q-bio], Liver, Child, Preschool, Cardiology and Cardiovascular Medicine, Adult, Heterozygote, medicine.medical_specialty, Adolescent, Genotype, Young Adult, 03 medical and health sciences, Malabsorption Syndromes, Internal medicine, Internal Medicine, medicine, Humans, Apolipoproteins B, Polymorphism, Genetic, Triglyceride, business.industry, Infant, Lipid Metabolism, medicine.disease, Genetic hypocholesterolemia, Endocrinology, chemistry, biology.protein, Liver function, Steatosis, Carrier Proteins, Liver function tests, business
Abstract

International audience; BACKGROUND: Abetalipoproteinemia, a recessive disease resulting from deleterious variants in MTTP (microsomal triglyceride transfer protein), is characterized by undetectable concentrations of apolipoprotein B, extremely low levels of low-density lipoprotein cholesterol in the plasma, and a total inability to export apolipoprotein B-containing lipoproteins from both the intestine and the liver. OBJECTIVE: To study lipid absorption after a fat load and liver function in 7 heterozygous relatives from 2 abetalipoproteinemic families, 1 previously unreported. RESULTS: Both patients are compound heterozygotes for p.(Arg540His) and either c.708\₇09del p.(His236Glnfs*11) or c.1344+3\₁344+6del on the MTTP gene. The previously undescribed patient has been followed for 22 years with ultrastructure analyses of both the intestine and the liver. In these 2 families, 5 relatives were heterozygous for p.(Arg540His), 1 for p.(His236Glnfs*11) and 1 for c.1344+3\₁344+6del. In 4 heterozygous relatives, the lipid absorption was normal independent of the MTTP variant. In contrast, in 3 of them, the increase in triglyceride levels after fat load was abnormal. These subjects were additionally heterozygous carriers of Asp2213 APOB in-frame deletion, near the cytidine mRNA editing site, which is essential for intestinal apoB48 production. Liver function appeared to be normal in all the heterozygotes except for one who exhibited liver steatosis for unexplained reasons. CONCLUSION: Our study suggests that a single copy of the MTTP gene may be sufficient for human normal lipid absorption, except when associated with an additional APOB gene alteration. The hepatic steatosis reported in 1 patient emphasizes the need for liver function tests in all heterozygotes until the level of risk is established.

Published
2019

6. Normal serum ApoB48 and red cells vitamin E concentrations after supplementation in a novel compound heterozygous case of abetalipoproteinemia

Author

Mathilde Di Filippo, Sophie Collardeau Frachon, Oriane Marmontel, Alexandre Janin, Charlotte Cuerq, Dominique Bozon, Séverine Nony, Sabrina Dumont, Alain Lachaux, Sybil Charrière, Noël Peretti, Charlotte Decourt, Philippe Moulin, Amandine Rubio, M. Mahmood Hussain, Sujith Rajan, Hôpital Louis Pradel [CHU - HCL], Hospices Civils de Lyon (HCL), Cardiovasculaire, métabolisme, diabétologie et nutrition (CarMeN), Institut National de la Recherche Agronomique (INRA)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hospices Civils de Lyon (HCL), Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), AZTI-Tecnalia (Marine Research Division), AZTI-Tecnalia, Centre de Recherche en Cancérologie / Nantes - Angers (CRCNA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM)-Hôtel-Dieu de Nantes-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Laennec-Centre National de la Recherche Scientifique (CNRS)-Faculté de Médecine d'Angers-Centre hospitalier universitaire de Nantes (CHU Nantes), Département de pédiatrie [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Université de Lyon, Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon, Hospices Civils de Lyon (HCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Institut National des Sciences Appliquées (INSA)-Université de Lyon-Institut National des Sciences Appliquées (INSA)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Institut National de la Recherche Agronomique (INRA), Centre de Recherche en Nutrition Humaine Rhône-Alpes (CRNH-RA), Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Recherche Agronomique (INRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Jean Monnet [Saint-Étienne] (UJM)-CHU Saint-Etienne-Hospices Civils de Lyon (HCL)-CHU Grenoble, Laboratory of Fundamental and Applied Bioenergetics = Laboratoire de bioénergétique fondamentale et appliquée (LBFA), and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)

Subjects
0301 basic medicine, Heterozygote, Erythrocytes, [SDV]Life Sciences [q-bio], 030204 cardiovascular system & hematology, Biology, Compound heterozygosity, Splicing, Microsomal triglyceride transfer protein, 03 medical and health sciences, Exon, symbols.namesake, 0302 clinical medicine, Blood serum, Chylomicrons, medicine, Humans, Vitamin E, Child, Sanger sequencing, Functional analysis, Infant, Newborn, Abetalipoproteinemia, medicine.disease, Molecular biology, Familial hypocholesterolemia, 3. Good health, Hypocholesterolemia, 030104 developmental biology, Mutation, symbols, biology.protein, Female, Mttp, Apolipoprotein B-48, Carrier Proteins, Cardiology and Cardiovascular Medicine, Follow-Up Studies, Minigene
Abstract

International audience; BACKGROUND AND AIMS: Abetalipoproteinemia (ABL) is a rare recessive monogenic disease due to MTTP (microsomal triglyceride transfer protein) mutations leading to the absence of plasma apoB-containing lipoproteins. Here we characterize a new ABL case with usual clinical phenotype, hypocholesterolemia, hypotriglyceridemia but normal serum apolipoprotein B48 (apoB48) and red blood cell vitamin E concentrations. METHODS: Histology and MTP activity measurements were performed on intestinal biopsies. Mutations in MTTP were identified by Sanger sequencing, quantitative digital droplet and long-range PCR. Functional consequences of the variants were studied in vitro using a minigene splicing assay, measurement of MTP activity and apoB48 secretion. RESULTS: Intestinal steatosis and the absence of measurable lipid transfer activity in intestinal protein extract supported the diagnosis of ABL. A novel MTTP c.1868G\textgreaterT variant inherited from the patient's father was identified. This variant gives rise to three mRNA transcripts: one normally spliced, found at a low frequency in intestinal biopsy, carrying the p.(Arg623Leu) missense variant, producing in vitro 65% of normal MTP activity and apoB48 secretion, and two abnormally spliced transcripts resulting in a non-functional MTP protein. Digital droplet PCR and long-range sequencing revealed a previously described c.1067+1217\₁141del allele inherited from the mother, removing exon 10. Thus, the patient is compound heterozygous for two dysfunctional MTTP alleles. The p.(Arg623Leu) variant may maintain residual secretion of apoB48. CONCLUSIONS: Complex cases of primary dyslipidemia require the use of a cascade of different methodologies to establish the diagnosis in patients with non-classical biological phenotypes and provide better knowledge on the regulation of lipid metabolism.

Published
2019

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