41 results on '"Gaël Manes"'
Search Results
2. Generation of a human iPSC line, INMi002-A, carrying the most prevalent USH2A variant associated with Usher syndrome type 2
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Carla Sanjurjo-Soriano, Nejla Erkilic, Gaël Manes, Gregor Dubois, Christian P. Hamel, Isabelle Meunier, and Vasiliki Kalatzis
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Biology (General) ,QH301-705.5 - Abstract
We generated an induced pluripotent stem cell (iPSC) line using dermal fibroblasts from a patient with Usher syndrome type 2 (USH2). This individual was homozygous for the most prevalent variant reported in the USH2A gene, c.2299delG localized in exon 13. Reprogramming was performed using the non-integrative Sendai virus reprogramming method and the human OSKM transcription factor cocktail under feeder-free culture conditions. This iPSC line will be an invaluable tool for studying the pathophysiology of USH2 and for testing the efficacy of novel treatments.
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- 2018
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3. Generation of a human iPSC line, INMi003-A, with a missense mutation in CRX associated with autosomal dominant cone-rod dystrophy
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Nejla Erkilic, Carla Sanjurjo-Soriano, Michalitsa Diakatou, Gaël Manes, Gregor Dubois, Christian P. Hamel, Isabelle Meunier, and Vasiliki Kalatzis
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Biology (General) ,QH301-705.5 - Abstract
We generated an induced pluripotent stem cell (iPSC) line using dermal fibroblasts from a 53 year-old patient with autosomal dominant cone-rod dystrophy (CRD) caused by a missense mutation, c.121C > T, in the CRX gene. Patient fibroblasts were reprogrammed using the non-integrative Sendai virus reprogramming system and the human OSKM transcription factor cocktail. The generated iPSCs contained the congenital mutation in exon 3 of CRX and were pluripotent and genetically stable. This iPSC line will be an important tool for retinal differentiation studies to better understand the CRD phenotype caused by the mutant p.Arg41Trp CRX protein.
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- 2019
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4. Generation of a human iPSC line, INMi004-A, with a point mutation in CRX associated with autosomal dominant Leber congenital amaurosis
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Nejla Erkilic, Carla Sanjurjo-Soriano, Gaël Manes, Gregor Dubois, Christian P. Hamel, Isabelle Meunier, and Vasiliki Kalatzis
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Biology (General) ,QH301-705.5 - Abstract
The human induced pluripotent stem cell (iPSC) line, INMi004-A, was generated using dermal fibroblasts from a 6 year-old patient with autosomal dominant Leber Congenital Amaurosis (LCA) caused by the point mutation c.695delC (p.Pro232Argfs*139) in the CRX gene. We used non-integrative Sendai virus vectors containing the human OSKM transcription factor cocktail to reprogram patient fibroblasts. The generated iPSC line contained the congenital deletion c.695delC in exon 4 of CRX, had a normal karyotype, and was capable of differentiation into all three germ layers. This cell line represents an important tool to study the pathophysiology of CRX-associated LCA.
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- 2019
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5. Genome Editing as a Treatment for the Most Prevalent Causative Genes of Autosomal Dominant Retinitis Pigmentosa
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Michalitsa Diakatou, Gaël Manes, Beatrice Bocquet, Isabelle Meunier, and Vasiliki Kalatzis
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Inherited retinal dystrophies ,autosomal dominant retinitis pigmentosa ,photoreceptors ,loss-of-function ,gain-of-function ,dominant-negative ,CRISPR/Cas ,gene supplementation ,genome-editing ,AAV vector ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Inherited retinal dystrophies (IRDs) are a clinically and genetically heterogeneous group of diseases with more than 250 causative genes. The most common form is retinitis pigmentosa. IRDs lead to vision impairment for which there is no universal cure. Encouragingly, a first gene supplementation therapy has been approved for an autosomal recessive IRD. However, for autosomal dominant IRDs, gene supplementation therapy is not always pertinent because haploinsufficiency is not the only cause. Disease-causing mechanisms are often gain-of-function or dominant-negative, which usually require alternative therapeutic approaches. In such cases, genome-editing technology has raised hopes for treatment. Genome editing could be used to (i) invalidate both alleles, followed by supplementation of the wild type gene, (ii) specifically invalidate the mutant allele, with or without gene supplementation, or (iii) to correct the mutant allele. We review here the most prevalent genes causing autosomal dominant retinitis pigmentosa and the most appropriate genome-editing strategy that could be used to target their different causative mutations.
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- 2019
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6. A truncated form of rod photoreceptor PDE6 β-subunit causes autosomal dominant congenital stationary night blindness by interfering with the inhibitory activity of the γ-subunit.
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Gaël Manes, Pallavi Cheguru, Anurima Majumder, Béatrice Bocquet, Audrey Sénéchal, Nikolai O Artemyev, Christian P Hamel, and Philippe Brabet
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Medicine ,Science - Abstract
Autosomal dominant congenital stationary night blindness (adCSNB) is caused by mutations in three genes of the rod phototransduction cascade, rhodopsin (RHO), transducin α-subunit (GNAT1), and cGMP phosphodiesterase type 6 β-subunit (PDE6B). In most cases, the constitutive activation of the phototransduction cascade is a prerequisite to cause adCSNB. The unique adCSNB-associated PDE6B mutation found in the Rambusch pedigree, the substitution p.His258Asn, leads to rod photoreceptors desensitization. Here, we report a three-generation French family with adCSNB harboring a novel PDE6B mutation, the duplication, c.928-9_940dup resulting in a tyrosine to cysteine substitution at codon 314, a frameshift, and a premature termination (p.Tyr314Cysfs*50). To understand the mechanism of the PDE6β1-314fs*50 mutant, we examined the properties of its PDE6-specific portion, PDE6β1-313. We found that PDE6β1-313 maintains the ability to bind noncatalytic cGMP and the inhibitory γ-subunit (Pγ), and interferes with the inhibition of normal PDE6αβ catalytic subunits by Pγ. Moreover, both truncated forms of the PDE6β protein, PDE6β1-313 and PDE6β1-314fs*50 expressed in rods of transgenic X. laevis are targeted to the phototransduction compartment. We hypothesize that in affected family members the p.Tyr314Cysfs*50 change results in the production of the truncated protein, which binds Pγ and causes constitutive activation of the phototransduction thus leading to the absence of rod adaptation.
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- 2014
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7. SPACR Encoded by
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Guillaume, Olivier, Philippe, Brabet, Nelly, Pirot, Morgane, Broyon, Laurent, Guillou, Chantal, Cazevieille, Chamroeun, Sar, Melanie, Quiles, Emmanuelle, Sarzi, Marie, Pequignot, Ervann, Andreo, Agathe, Roubertie, Isabelle, Meunier, Agnès, Muller, Vasiliki, Kalatzis, and Gaël, Manes
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Extracellular Matrix Proteins ,Mice ,Retinaldehyde ,Animals ,Photoreceptor Cells ,Proteoglycans ,Retinal Pigment Epithelium ,Eye Proteins ,Retinal Pigments ,Retinitis Pigmentosa ,Extracellular Matrix ,Vitelliform Macular Dystrophy - Abstract
Several pathogenic variants have been reported in the
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- 2022
8. A ROD–CONE DYSTROPHY IS SYSTEMATICALLY ASSOCIATED TO THE RTN4IP1 RECESSIVE OPTIC ATROPHY
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Patrizia Amati-Bonneau, Xavier Zanlonghi, Claire-Marie Dhaenens, Gaël Manes, Béatrice Bocquet, Agathe Roubertie, Isabelle Meunier, Guy Lenaers, Majida Charif, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Mohamed 1 Oujda MAROC, UF Génopathies - Laboratoire de Biochimie et Biologie Moléculaire [Lille] (LBBM), Université de Lille, Sciences et Technologies-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Département de Biochimie et Génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Clinique Jules-Vernes [Nantes], MitoVasc - Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), and LENAERS, Guy
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Male ,Visual acuity ,genetic structures ,[SDV]Life Sciences [q-bio] ,DNA Mutational Analysis ,Visual Acuity ,inherited optic neuropathy ,RTN4IP1 ,Original Study ,Fluorescein Angiography ,Child ,rod–cone dystrophy ,medicine.diagnostic_test ,General Medicine ,Middle Aged ,Pedigree ,[SDV] Life Sciences [q-bio] ,Phenotype ,Mitochondrial respiratory chain ,Female ,medicine.symptom ,Tomography, Optical Coherence ,Adult ,medicine.medical_specialty ,Adolescent ,Fundus Oculi ,Retinal ganglion ,Mitochondrial Proteins ,Young Adult ,Atrophy ,Ophthalmology ,Electroretinography ,medicine ,Rod-cone dystrophy ,Humans ,Retrospective Studies ,Cerebellar ataxia ,business.industry ,recessive disease ,Dystrophy ,DNA ,medicine.disease ,eye diseases ,Mutation ,sense organs ,Visual Fields ,Carrier Proteins ,business ,Cone-Rod Dystrophies - Abstract
Although RTN4IP1 has been firmly associated to recessive optic atrophies, we identified by systematic examination of the 55° fundus autofluorescence frames and the peripheral spectral-domain optical coherence tomographic images, a progressive rod–cone dystrophy in all individuals with biallelic RTN4IP1 mutations., Purpose: RTN4IP1 biallelic mutations cause a recessive optic atrophy, sometimes associated to more severe neurological syndromes, but so far, no retinal phenotype has been reported in RTN4IP1 patients, justifying their reappraisal. Methods: Seven patients from four families carrying biallelic RTN4IP1 variants were retrospectively reviewed, with emphasis on their age of onset, visual acuity, multimodal imaging including color and autofluorescence frames, spectral-domain optical coherence tomography with RNFL and macular analyses. Results: Seven patients from four RTN4IP1 families developed in their first decade of life a bilateral recessive optic atrophy with severe central visual loss, and primary nystagmus developed in 5 of 7 patients. Six patients were legally blind. In a second stage, the seven individuals developed a rod–cone dystrophy, sparing the macular zone and the far periphery. This retinal damage was identified by 55° field fundus autofluorescence frames and also by spectral-domain optical coherence tomography scans of the temporal part of the macular zone in five of the seven patients. Full-field electroretinography measurements disclosed reduced b-wave amplitude of the rod responses in all patients but two. Family 4 with the p.R103H and c.601A > T (p.K201*) truncating mutation had further combined neurological signs with cerebellar ataxia, seizures, and intellectual disability. Conclusion: RTN4IP1 recessive optic atrophy is systematically associated to a rod–cone dystrophy, which suggests that both the retinal ganglion cells and the rods are affected as a result of a deficit in the mitochondrial respiratory chain. Thus, systematic widefield autofluorescence frames and temporal macular scans are recommended for the evaluation of patients with optic neuropathies.
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- 2020
9. SPACR Encoded by IMPG1 Is Essential for Photoreceptor Survival by Interplaying between the Interphotoreceptor Matrix and the Retinal Pigment Epithelium
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Guillaume Olivier, Philippe Brabet, Nelly Pirot, Morgane Broyon, Laurent Guillou, Chantal Cazevieille, Chamroeun Sar, Melanie Quiles, Emmanuelle Sarzi, Marie Pequignot, Ervann Andreo, Agathe Roubertie, Isabelle Meunier, Agnès Muller, Vasiliki Kalatzis, and Gaël Manes
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IMPG1 ,IMPG2 ,SPACR ,SPACRCAN ,vitelliform macular dystrophy ,retinitis pigmentosa ,Genetics ,Genetics (clinical) - Abstract
Several pathogenic variants have been reported in the IMPG1 gene associated with the inherited retinal disorders vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). IMPG1 and its paralog IMPG2 encode for two proteoglycans, SPACR and SPACRCAN, respectively, which are the main components of the interphotoreceptor matrix (IPM), the extracellular matrix surrounding the photoreceptor cells. To determine the role of SPACR in the pathological mechanisms leading to RP and VMD, we generated a knockout mouse model lacking Impg1, the mouse ortholog. Impg1-deficient mice show abnormal accumulation of autofluorescent deposits visible by fundus imaging and spectral-domain optical coherence tomography (SD-OCT) and attenuated electroretinogram responses from 9 months of age. Furthermore, SD-OCT of Impg1−/− mice shows a degeneration of the photoreceptor layer, and transmission electron microscopy shows a disruption of the IPM and the retinal pigment epithelial cells. The decrease in the concentration of the chromophore 11-cis-retinal supports this loss of photoreceptors. In conclusion, our results demonstrate the essential role of SPACR in maintaining photoreceptors. Impg1−/− mice provide a novel model for mechanistic investigations and the development of therapies for VMD and RP caused by IMPG1 pathogenic variants.
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- 2022
10. Pathogenic variants in IMPG1 cause autosomal dominant and autosomal recessive retinitis pigmentosa
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Guylène Le Meur, Susanne Roosing, Panagiotis I. Sergouniotis, Marta Corton, Sandro Banfi, Graeme C.M. Black, Ivan Conte, Hélène Naacke, Carmen Ayuso, Christian Hamel, Almudena Avila-Fernandez, Agnès Muller, Guillaume Olivier, Daniela Intartaglia, Claire-Marie Dhaenens, Gaël Manes, Sanne K Verbakel, Jeroen Klevering, Isabelle Meunier, Béatrice Bocquet, Carel B. Hoyng, Agathe Roubertie, Audrey Sénéchal, Xavier Zanlonghi, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Universidad Autónoma de Madrid (UAM), CIBER de Enfermedades Raras (CIBERER), Università degli studi della Campania 'Luigi Vanvitelli' = University of the Study of Campania Luigi Vanvitelli, Radboud University Medical Center [Nijmegen], Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester], Centre hospitalier universitaire de Nantes (CHU Nantes), Equipe 3 - Facteurs de persistance des cellules leucémique - (INSERM U837), Institut pour la Recherche sur le Cancer de Lille (U837 INSERM - IRCL), Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut pour la recherche sur le cancer de Lille [Lille] (IRCL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lille Neurosciences & Cognition - U 1172 (LilNCog), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Clinique Saint-Joseph Angoulême (CSJA), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hôpital Gui de Chauliac [CHU Montpellier], University of Naples Federico II = Università degli studi di Napoli Federico II, Clinique Jules-Vernes [Nantes], Hôpital Gui de Chauliac [Montpellier], Michel-Avella, Amandine, Olivier, Guillaume, Corton, Marta, Intartaglia, Daniela, Verbakel, Sanne K, Sergouniotis, Panagiotis I, Le Meur, Guylène, Dhaenens, Claire-Marie, Naacke, Hélène, Avila-Fernández, Almudena, Hoyng, Carel B, Klevering, Jeroen, Bocquet, Béatrice, Roubertie, Agathe, Sénéchal, Audrey, Banfi, Sandro, Muller, Agnè, Hamel, Christian L, Black, Graeme C, Conte, Ivan, Roosing, Susanne, Zanlonghi, Xavier, Ayuso, Carmen, Meunier, Isabelle, and Manes, Gaël
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0301 basic medicine ,MESH: Extracellular Matrix Proteins ,sequence analysis ,[SDV]Life Sciences [q-bio] ,eye disease ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,0302 clinical medicine ,Benign concentric annular macular dystrophy ,MESH: Eye Proteins ,Missense mutation ,genetics ,Genetics (clinical) ,Exome sequencing ,Genetics ,MESH: Aged ,MESH: Exome ,MESH: Middle Aged ,medicine.diagnostic_test ,MESH: Retina ,MESH: Genetic Predisposition to Disease ,[SDV] Life Sciences [q-bio] ,MESH: Proteoglycans ,MESH: Mutation ,Sequence analysis ,MESH: Pedigree ,MESH: Arthrogryposis ,Vitelliform macular dystrophy ,Biology ,MESH: Phenotype ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,MESH: Whole Exome Sequencing ,Retinitis pigmentosa ,medicine ,MESH: Macular Degeneration ,MESH: Genes, Recessive ,Genetic testing ,MESH: Humans ,Genetic heterogeneity ,eye diseases ,MESH: Retrospective Studies ,medicine.disease ,MESH: Male ,ophthalmology ,030104 developmental biology ,030221 ophthalmology & optometry ,MESH: Retinitis Pigmentosa ,genetic ,MESH: Inheritance Patterns ,MESH: Female - Abstract
BackgroundInherited retinal disorders are a clinically and genetically heterogeneous group of conditions and a major cause of visual impairment. Common disease subtypes include vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). Despite the identification of over 90 genes associated with RP, conventional genetic testing fails to detect a molecular diagnosis in about one third of patients with RP.MethodsExome sequencing was carried out for identifying the disease-causing gene in a family with autosomal dominant RP. Gene panel testing and exome sequencing were performed in 596 RP and VMD families to identified additional IMPG1 variants. In vivo analysis in the medaka fish system by knockdown assays was performed to screen IMPG1 possible pathogenic role.ResultsExome sequencing of a family with RP revealed a splice variant in IMPG1. Subsequently, the same variant was identified in individuals from two families with either RP or VMD. A retrospective study of patients with RP or VMD revealed eight additional families with different missense or nonsense variants in IMPG1. In addition, the clinical diagnosis of the IMPG1 retinopathy-associated variant, originally described as benign concentric annular macular dystrophy, was also revised to RP with early macular involvement. Using morpholino-mediated ablation of Impg1 and its paralog Impg2 in medaka fish, we confirmed a phenotype consistent with that observed in the families, including a decreased length of rod and cone photoreceptor outer segments.ConclusionThis study discusses a previously unreported association between monoallelic or biallelic IMPG1 variants and RP. Notably, similar observations have been reported for IMPG2.
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- 2021
11. Generation of a human iPSC line, INMi002-A, carrying the most prevalent USH2A variant associated with Usher syndrome type 2
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Christian P. Hamel, Gaël Manes, Isabelle Meunier, Gregor Dubois, Carla Sanjurjo-Soriano, Nejla Erkilic, Vasiliki Kalatzis, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Michel-Avella, Amandine, and Institut des Neurosciences de Montpellier (INM)
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0301 basic medicine ,Usher syndrome ,[SDV]Life Sciences [q-bio] ,Induced Pluripotent Stem Cells ,030105 genetics & heredity ,03 medical and health sciences ,Exon ,medicine ,Humans ,Induced pluripotent stem cell ,Gene ,Transcription factor ,lcsh:QH301-705.5 ,biology ,Cell Biology ,General Medicine ,Middle Aged ,medicine.disease ,biology.organism_classification ,Sendai virus ,3. Good health ,[SDV] Life Sciences [q-bio] ,lcsh:Biology (General) ,Cancer research ,Female ,Usher Syndromes ,Ipsc line ,Reprogramming ,Developmental Biology - Abstract
International audience; We generated an induced pluripotent stem cell (iPSC) line using dermal fibroblasts from a patient with Usher syndrome type 2 (USH2). This individual was homozygous for the most prevalent variant reported in the USH2A gene, c.2299delG localized in exon 13. Reprogramming was performed using the non-integrative Sendai virus reprogramming method and the human OSKM transcription factor cocktail under feeder-free culture conditions. This iPSC line will be an invaluable tool for studying the pathophysiology of USH2 and for testing the efficacy of novel treatments.
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- 2018
12. Optic neuropathy linked to ACAD9 pathogenic variants: A potentially riboflavin-responsive disorder?
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Naïg Gueguen, Pascal Amedro, Julie Piarroux, Pascal Reynier, Guy Lenaers, Isabelle Meunier, Mehdi Benkirane, Michel Koenig, Nicolas Leboucq, Cécile Delettre, Pierre Meyer, Agathe Roubertie, Emmanuelle Sarzi, Gaël Manes, Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
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0301 basic medicine ,Male ,Heterozygote ,Mitochondrial disease ,[SDV]Life Sciences [q-bio] ,Riboflavin ,Cardiomyopathy ,Exercise intolerance ,Compound heterozygosity ,Optic neuropathy ,03 medical and health sciences ,0302 clinical medicine ,Acyl-CoA Dehydrogenases ,Optic Nerve Diseases ,Medicine ,Humans ,Age of Onset ,Child ,Frameshift Mutation ,Molecular Biology ,Beta oxidation ,ComputingMilieux_MISCELLANEOUS ,business.industry ,Cell Biology ,medicine.disease ,3. Good health ,030104 developmental biology ,Peripheral neuropathy ,Treatment Outcome ,Lactic acidosis ,Immunology ,Molecular Medicine ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
Mitochondrial complex I (CI) deficiencies (OMIM 252010) are the commonest inherited mitochondrial disorders in children. Acyl-CoA dehydrogenase 9 (ACAD9) is a flavoenzyme involved chiefly in CI assembly and possibly in fatty acid oxidation. Biallelic pathogenic variants result in CI dysfunction, with a phenotype ranging from early onset and sometimes fatal mitochondrial encephalopathy with lactic acidosis to late-onset exercise intolerance. Cardiomyopathy is often associated. We report a patient with childhood-onset optic and peripheral neuropathy without cardiac involvement, related to CI deficiency. Genetic analysis revealed compound heterozygous pathogenic variants in ACAD9, expanding the clinical spectrum associated to ACAD9 mutations. Importantly, riboflavin treatment (15 mg/kg/day) improved long-distance visual acuity and demonstrated significant rescue of CI activity in vitro.
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- 2021
13. Pathogenic variants in
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Guillaume, Olivier, Marta, Corton, Daniela, Intartaglia, Sanne K, Verbakel, Panagiotis I, Sergouniotis, Guylène, Le Meur, Claire-Marie, Dhaenens, Hélène, Naacke, Almudena, Avila-Fernández, Carel B, Hoyng, Jeroen, Klevering, Béatrice, Bocquet, Agathe, Roubertie, Audrey, Sénéchal, Sandro, Banfi, Agnès, Muller, Christian L, Hamel, Graeme C, Black, Ivan, Conte, Susanne, Roosing, Xavier, Zanlonghi, Carmen, Ayuso, Isabelle, Meunier, and Gaël, Manes
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Arthrogryposis ,Male ,Extracellular Matrix Proteins ,Inheritance Patterns ,Genes, Recessive ,Middle Aged ,Retina ,Pedigree ,Macular Degeneration ,Phenotype ,Mutation ,Exome Sequencing ,Humans ,Exome ,Female ,Genetic Predisposition to Disease ,Proteoglycans ,Eye Proteins ,Retinitis Pigmentosa ,Aged ,Retrospective Studies - Abstract
Inherited retinal disorders are a clinically and genetically heterogeneous group of conditions and a major cause of visual impairment. Common disease subtypes include vitelliform macular dystrophy (VMD) and retinitis pigmentosa (RP). Despite the identification of over 90 genes associated with RP, conventional genetic testing fails to detect a molecular diagnosis in about one third of patients with RP.Exome sequencing was carried out for identifying the disease-causing gene in a family with autosomal dominant RP. Gene panel testing and exome sequencing were performed in 596 RP and VMD families to identified additionalExome sequencing of a family with RP revealed a splice variant inThis study discusses a previously unreported association between monoallelic or biallelic
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- 2020
14. Hereditary spastic paraplegia and prominent sensorial involvement: think MAG mutations!
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Gaël Manes, Isabelle Meunier, Agathe Roubertie, Guy Lenaers, Nicolas Leboucq, Cécile Delettre, Agnès Guichet, Emmanuelle Sarzi, François Rivier, Pierre Meyer, Raul Junta Morales, Majida Charif, Guillaume Taieb, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de neurologie [Montpellier], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), MORNET, Dominique, and Institut des Neurosciences de Montpellier (INM)
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Hereditary spastic paraplegia ,[SDV]Life Sciences [q-bio] ,Neurosciences. Biological psychiatry. Neuropsychiatry ,Brief Communication ,medicine.disease_cause ,Compound heterozygosity ,03 medical and health sciences ,0302 clinical medicine ,Atrophy ,Intellectual disability ,medicine ,Spastic ,Humans ,Child ,RC346-429 ,ComputingMilieux_MISCELLANEOUS ,Paraplegia ,Mutation ,Spastic Paraplegia, Hereditary ,business.industry ,General Neuroscience ,Brain ,medicine.disease ,Magnetic Resonance Imaging ,Pedigree ,nervous system diseases ,[SDV] Life Sciences [q-bio] ,Myelin-Associated Glycoprotein ,Phenotype ,030104 developmental biology ,nervous system ,Female ,Cerebellar atrophy ,Neurology (clinical) ,Neurology. Diseases of the nervous system ,Brief Communications ,business ,030217 neurology & neurosurgery ,RC321-571 - Abstract
Homozygous mutations in MAG, encoding the myelin‐associated glycoprotein, a transmembrane component of the myelin sheath, have been associated with SPG 75 recessive spastic paraplegia. Here, we report the first patient with two compound heterozygous novel MAG mutations (p.A151V and p.S373R) and early developmental delay with a progressive complex phenotype characterized by spastic paraplegia, peripheral sensorimotor neuropathy, intellectual disability, and sensorial dysfunctions with severe optic atrophy and hearing involvement. Brain imaging showed progressive global cerebellar atrophy. We propose that complex hereditary spastic paraplegia, with axonal and demyelinating polyneuropathy, sensorial impairment and intellectual disability might suggest MAG mutations.
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- 2019
15. Generation of a human iPSC line, INMi003-A, with a missense mutation in CRX associated with autosomal dominant cone-rod dystrophy
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Isabelle Meunier, Nejla Erkilic, Michalitsa Diakatou, Carla Sanjurjo-Soriano, Gregor Dubois, Gaël Manes, Christian P. Hamel, and Vasiliki Kalatzis
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Male ,0301 basic medicine ,Induced Pluripotent Stem Cells ,Mutant ,Mutation, Missense ,Biology ,medicine.disease_cause ,Cell Line ,03 medical and health sciences ,Exon ,0302 clinical medicine ,medicine ,Humans ,Missense mutation ,Cellular Reprogramming Techniques ,Induced pluripotent stem cell ,lcsh:QH301-705.5 ,Homeodomain Proteins ,Mutation ,Dystrophy ,Cell Biology ,General Medicine ,Fibroblasts ,Middle Aged ,Cell biology ,030104 developmental biology ,Amino Acid Substitution ,lcsh:Biology (General) ,Trans-Activators ,Reprogramming ,Cone-Rod Dystrophies ,030217 neurology & neurosurgery ,Developmental Biology - Abstract
We generated an induced pluripotent stem cell (iPSC) line using dermal fibroblasts from a 53 year-old patient with autosomal dominant cone-rod dystrophy (CRD) caused by a missense mutation, c.121C > T, in the CRX gene. Patient fibroblasts were reprogrammed using the non-integrative Sendai virus reprogramming system and the human OSKM transcription factor cocktail. The generated iPSCs contained the congenital mutation in exon 3 of CRX and were pluripotent and genetically stable. This iPSC line will be an important tool for retinal differentiation studies to better understand the CRD phenotype caused by the mutant p.Arg41Trp CRX protein.
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- 2019
16. Natural models for retinitis pigmentosa progressive retinal atrophy in dog breeds
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Gaël Manes, Philippe Brabet, Laetitia Lagoutte, Catherine André, Philippe Pilorge, Gilles Chaudieu, Nadine Botherel, Morgane Bunel, Pascale Quignon, Christian P. Hamel, Institut de Génétique et Développement de Rennes (IGDR), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Clinique vétérinaire Pole Sante Chanturgue, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Clinique vétérinaire Rive Ouest, Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), and Institut des Neurosciences de Montpellier (INM)
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Male ,Retinal Disorder ,[SDV]Life Sciences [q-bio] ,Biology ,03 medical and health sciences ,Dogs ,Retinal Rod Photoreceptor Cells ,Retinitis pigmentosa ,Genetics ,medicine ,Animals ,Humans ,Genetic Predisposition to Disease ,Dog Diseases ,Allele ,Gene ,Genotyping ,Genetics (clinical) ,030304 developmental biology ,Progressive retinal atrophy ,0303 health sciences ,Genetic heterogeneity ,Retinal Degeneration ,030305 genetics & heredity ,medicine.disease ,Human genetics ,Disease Models, Animal ,Female ,Retinitis Pigmentosa - Abstract
International audience; Retinitis pigmentosa (RP) is a heterogeneous group of inherited retinal disorders eventually leading to blindness with different ages of onset, progression and severity. Human RP, first characterized by the progressive degeneration of rod photoreceptor cells, shows high genetic heterogeneity with more than 90 genes identified. However, about one-third of patients have no known genetic causes. Interestingly, dogs are also severely affected by similar diseases, called progressive retinal atrophy (PRA). Indeed, RP and PRA have comparable clinical signs, physiopathology and outcomes, similar diagnosis methods and most often, orthologous genes are involved. The many different dog PRAs often segregate in specific breeds. Indeed, undesired alleles have been selected and amplified through drastic selection and excessive use of inbreeding. Out of the 400 breeds, nearly 100 have an inherited form of PRA, which are natural animal models that can be used to investigate the genetics, disease progression and therapies in dogs for the benefit of both dogs and humans. Recent knowledge on the canine genome and access to new genotyping and sequencing technologies now efficiently allows the identification of mutations involved in canine genetic diseases. To date, PRA genes identified in dog breeds correspond to the same genes in humans and represent relevant RP models, and new genes found in dogs represent good candidate for still unknown human RP. We present here a review of the main advantages of the dog models for human RP with the genes already identified and an X-linked PRA in the Border collie as a model for orphan X-linked RPs in human. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.
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- 2019
17. Dominant mutations in mtDNA maintenance gene SSBP1 cause optic atrophy and foveopathy
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Cécile Delettre, Gaël Manes, Mélanie Quiles, Guy Lenaers, Marie O. Pequignot, Ulrich Kellner, Béatrice Bocquet, Helmut Wilhelm, Chantal Cazevieille, Audrey Sénéchal, Maria Solà, Fenna Hensen, Bernd Wissinger, Emmanuelle Sarzi, Camille Piro-Mégy, Xavier Zanlonghi, Aleix Tarrés-Solé, David Goudenège, Agathe Roubertie, Nicole Weisschuh, Christian P. Hamel, Majida Charif, Johannes N. Spelbrink, Arka Chakraborty, Agnès Muller, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Neuroimmunologie des annélides (NA), Université de Lille, Sciences et Technologies-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Institute for Ophthalmic Research [Tübingen, Germany] (Centre for Ophthalmology), University of Tübingen, Service Exploration Fonctionnelle de la Vision, Clinique Sourdille, Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), Ministerio de Ciencia, Innovación y Universidades (España), Ministerio de Economía y Competitividad (España), Generalitat de Catalunya, European Commission, Ministerio de Educación y Formación Profesional (España), LENAERS, Guy, and Institut des Neurosciences de Montpellier (INM)
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0301 basic medicine ,Male ,genetic structures ,[SDV]Life Sciences [q-bio] ,Mitochondrion ,GTP Phosphohydrolases ,0302 clinical medicine ,Missense mutation ,Child ,ComputingMilieux_MISCELLANEOUS ,Genetics ,Aged, 80 and over ,Neurodegeneration ,Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] ,General Medicine ,Middle Aged ,3. Good health ,Mitochondria ,[SDV] Life Sciences [q-bio] ,DNA-Binding Proteins ,030220 oncology & carcinogenesis ,Female ,Research Article ,Adult ,DNA Replication ,Mitochondrial DNA ,Adolescent ,Mutation, Missense ,Biology ,DNA-binding protein ,DNA, Mitochondrial ,Mitochondrial Proteins ,03 medical and health sciences ,Atrophy ,All institutes and research themes of the Radboud University Medical Center ,Optic Atrophy, Autosomal Dominant ,Exome Sequencing ,medicine ,Humans ,Gene ,Aged ,Binding protein ,medicine.disease ,eye diseases ,Ophthalmology ,030104 developmental biology ,Commentary ,sense organs - Abstract
© 2020, Piro-Mégy et al., Mutations in genes encoding components of the mitochondrial DNA (mtDNA) replication machinery cause mtDNA depletion syndromes (MDSs), which associate ocular features with severe neurological syndromes. Here, we identified heterozygous missense mutations in single-strand binding protein 1 (SSBP1) in 5 unrelated families, leading to the R38Q and R107Q amino acid changes in the mitochondrial single-stranded DNA-binding protein, a crucial protein involved in mtDNA replication. All affected individuals presented optic atrophy, associated with foveopathy in half of the cases. To uncover the structural features underlying SSBP1 mutations, we determined a revised SSBP1 crystal structure. Structural analysis suggested that both mutations affect dimer interactions and presumably distort the DNA-binding region. Using patient fibroblasts, we validated that the R38Q variant destabilizes SSBP1 dimer/tetramer formation, affects mtDNA replication, and induces mtDNA depletion. Our study showing that mutations in SSBP1 cause a form of dominant optic atrophy frequently accompanied with foveopathy brings insights into mtDNA maintenance disorders., This study was supported by the Spanish Ministry of Science, Innovation and Universities, MINECO (BFU2015-70645-R, RTI2018-101015-B-100 to MS), the Generalitat de Catalunya (2014-SGR-997 and 2017-SGR-1192 to MS), and the European Union (FP7-HEALTH-2012-306029-2 to MS). ATS was awarded with an FPU fellowship from the Ministry of Education, Professional Formation (MEFP). The Structural Biology Unit at IBMB-CSIC is a “Maria de Maeztu” Unit of Excellence awarded by MINECO (MDM-2014-0435). This work was supported by the “Prinses Beatrix Spierfonds” and the “Stichting Spieren voor Spieren” (W.OR15-05 to JNS).
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- 2019
18. Generation of an iPSC line, INMi001-A, carrying the two most common USH2A mutations from a compound heterozygote with non-syndromic retinitis pigmentosa
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Vasiliki Kalatzis, Nejla Erkilic, Carla Sanjurjo-Soriano, Isabelle Meunier, Gaël Manes, Christian P. Hamel, Gregor Dubois, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Michel-Avella, Amandine, and Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM)
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0301 basic medicine ,Heterozygote ,Induced Pluripotent Stem Cells ,Compound heterozygosity ,medicine.disease_cause ,03 medical and health sciences ,Exon ,Retinitis pigmentosa ,medicine ,otorhinolaryngologic diseases ,Humans ,Induced pluripotent stem cell ,lcsh:QH301-705.5 ,Aged ,Genetics ,Mutation ,[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology ,biology ,Heterozygote advantage ,Cell Biology ,General Medicine ,biology.organism_classification ,medicine.disease ,Sendai virus ,3. Good health ,030104 developmental biology ,lcsh:Biology (General) ,Female ,Reprogramming ,Usher Syndromes ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology ,Retinitis Pigmentosa ,Developmental Biology - Abstract
International audience; We generated an induced pluripotent stem cell (iPSC) line from a patient with non-syndromic retinitis pigmentosa who is a compound heterozygote for the two most frequent USH2A variants, c.2276G > T and c.2299delG localized in exon 13. Patient fibroblasts were reprogrammed using the non-integrative Sendai virus reprogramming method and the human OSKM transcription factor cocktail. The generated cells were pluripotent and genetically stable. This iPSC line will be an important tool for studying the pathogenesis of these USH2A mutations and for developing treatments that, due their high prevalence, will target a large patient population.
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- 2018
19. AP4 deficiency: A novel form of neurodegeneration with brain iron accumulation?
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Bernard Echenne, Lydie Burglen, Nelson Hieu, Claire Guissart, Charles-Joris Roux, Cecilia Marelli, Agathe Roubertie, François Rivier, Christian P. Hamel, Nicolas Leboucq, Gaël Manes, Guy Lenaers, Pierre Meyer, Cyril Goizet, Rita Horvath, Majida Charif, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Département de Neuroradiologie[Montpellier], Hôpital Gui de Chauliac [Montpellier]-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)-Université de Montpellier (UM), CHU Bordeaux [Bordeaux], Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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 Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier]-Université de Montpellier (UM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), MORNET, Dominique, Horvath, Rita [0000-0002-9841-170X], and Apollo - University of Cambridge Repository
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0301 basic medicine ,Pathology ,medicine.medical_specialty ,Candidate gene ,Hereditary spastic paraplegia ,Neurodegeneration with brain iron accumulation ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Nonsense mutation ,32 Biomedical and Clinical Sciences ,030105 genetics & heredity ,Biology ,Neurodegenerative ,[SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics ,Article ,03 medical and health sciences ,0302 clinical medicine ,Rare Diseases ,Neuroimaging ,Clinical Research ,medicine ,Genetics ,2.1 Biological and endogenous factors ,Genetics (clinical) ,2 Aetiology ,FOS: Clinical medicine ,Neurosciences ,[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,medicine.disease ,3211 Oncology and Carcinogenesis ,Phenotype ,Brain Disorders ,Globus pallidus ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,FOS: Biological sciences ,Susceptibility weighted imaging ,Neurological ,Neurology (clinical) ,030217 neurology & neurosurgery - Abstract
ObjectiveTo describe the clinico-radiological phenotype of 3 patients harboring a homozygous novel AP4M1 pathogenic mutation.MethodsThe 3 patients from an inbred family who exhibited early-onset developmental delay, tetraparesis, juvenile motor function deterioration, and intellectual deficiency were investigated by magnetic brain imaging using T1-weighted, T2-weighted, T2*-weighted, fluid-attenuated inversion recovery, susceptibility weighted imaging (SWI) sequences. Whole-exome sequencing was performed on the 3 patients.ResultsIn the 3 patients, brain imaging identified the same pattern of bilateral SWI hyposignal of the globus pallidus, concordant with iron accumulation. A novel homozygous nonsense mutation was identified in AP4M1, segregating with the disease and leading to truncation of half of the adap domain of the protein.ConclusionsOur results suggest that AP4M1 represents a new candidate gene that should be considered in the neurodegeneration with brain iron accumulation (NBIA) spectrum of disorders and highlight the intersections between hereditary spastic paraplegia and NBIA clinical presentations.
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- 2018
20. Identification of Inherited Retinal Disease-Associated Genetic Variants in 11 Candidate Genes
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Lonneke Haer-Wigman, Chris F. Inglehearn, L. Ingeborgh van den Born, Manir Ali, Susanne Roosing, M Imran Khan, Frans P.M. Cremers, Graeme C.M. Black, Galuh D.N. Astuti, Carmel Toomes, Béatrice Bocquet, Carel B. Hoyng, Martin McKibbin, Mathieu Quinodoz, Gaël Manes, Mohammed E El-Asrag, Christian P. Hamel, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université de Montpellier (UM), Service d'Ophtalmologie [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Guy de Chauliac, Centre de référence des affections sensorielles d'origine génétique, and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac
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0301 basic medicine ,Candidate gene ,lcsh:QH426-470 ,inherited retinal diseases ,[SDV]Life Sciences [q-bio] ,Biology ,Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12] ,Article ,whole exome sequencing ,candidate retinal disease genes ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,Inherited retinal diseases ,parasitic diseases ,Genetics ,Exome ,Gene ,Genetics (clinical) ,Exome sequencing ,Candidate retinal disease genes ,Genetic heterogeneity ,Whole exome sequencing ,Disease gene identification ,Minor allele frequency ,lcsh:Genetics ,030104 developmental biology ,Small nuclear ribonucleoprotein - Abstract
Inherited retinal diseases (IRDs) display an enormous genetic heterogeneity. Whole exome sequencing (WES) recently identified genes that were mutated in a small proportion of IRD cases. Consequently, finding a second case or family carrying pathogenic variants in the same candidate gene often is challenging. In this study, we searched for novel candidate IRD gene-associated variants in isolated IRD families, assessed their causality, and searched for novel genotype-phenotype correlations. Whole exome sequencing was performed in 11 probands affected with IRDs. Homozygosity mapping data was available for five cases. Variants with minor allele frequencies ≤ 0.5% in public databases were selected as candidate disease-causing variants. These variants were ranked based on their: (a) presence in a gene that was previously implicated in IRD; (b) minor allele frequency in the Exome Aggregation Consortium database (ExAC); (c) in silico pathogenicity assessment using the combined annotation dependent depletion (CADD) score; and (d) interaction of the corresponding protein with known IRD-associated proteins. Twelve unique variants were found in 11 different genes in 11 IRD probands. Novel autosomal recessive and dominant inheritance patterns were found for variants in Small Nuclear Ribonucleoprotein U5 Subunit 200 ( javax.xml.bind.JAXBElement@ccb913c ) and Zinc Finger Protein 513 ( javax.xml.bind.JAXBElement@1d5964bc ), respectively. Using our pathogenicity assessment, a variant in DEAH-Box Helicase 32 ( javax.xml.bind.JAXBElement@7e33d494 ) was the top ranked novel candidate gene to be associated with IRDs, followed by eight medium and lower ranked candidate genes. The identification of candidate disease-associated sequence variants in 11 single families underscores the notion that the previously identified IRD-associated genes collectively carry > 90% of the defects implicated in IRDs. To identify multiple patients or families with variants in the same gene and thereby provide extra proof for pathogenicity, worldwide data sharing is needed.
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- 2018
21. A novel duplication of PRMD13 causes North Carolina macular dystrophy: overexpression of PRDM13 orthologue in drosophila eye reproduces the human phenotype
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Jose A. Sahel, Gaël Manes, Thomas Guignard, Christina Zeitz, Jean-François Deleuze, Anne Boland, David Geneviève, Béatrice Bocquet, Isabelle Meunier, Chantal Cazevieille, Audrey Sénéchal, Vasily Smirnov, Carl Arndt, Sabine Defoort-Dhellemmes, Sylvie Berthemy, Xavier Zanlonghi, Hélène Blanché-Koch, Willy Joly, Patrick Carroll, Christian P. Hamel, Isabelle Audo, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Université de Montpellier (UM), Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts (CHNO), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), 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), Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)
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0301 basic medicine ,Adult ,Male ,Corneal Dystrophies ,Genetic Linkage ,Locus (genetics) ,Chromosomes ,03 medical and health sciences ,0302 clinical medicine ,Cyclin C ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Gene duplication ,Genetics ,Humans ,Animals ,Eye Proteins ,Molecular Biology ,Gene ,Genetics (clinical) ,Corneal Dystrophies, Hereditary ,biology ,Whole Genome Sequencing ,Chromosome Mapping ,General Medicine ,Histone-Lysine N-Methyltransferase ,Macular dystrophy ,biology.organism_classification ,Phenotype ,Pedigree ,PR-SET Domains ,030104 developmental biology ,Drosophila melanogaster ,Hereditary ,Haplotypes ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,030221 ophthalmology & optometry ,Eye development ,Chromosomes, Human, Pair 6 ,Female ,Tandem exon duplication ,Pair 6 ,Human - Abstract
International audience; In this study, we report a novel duplication causing North Carolina macular dystrophy (NCMD) identified applying whole genome sequencing performed on eight affected members of two presumed unrelated families mapping to the MCDR1 locus. In our families, the NCMD phenotype was associated with a 98.4 kb tandem duplication encompassing the entire CCNC and PRDM13 genes and a common DNase 1 hypersensitivity site. To study the impact of PRDM13 or CCNC dysregulation, we used the Drosophila eye development as a model. Knock-down and overexpression of CycC and CG13296, Drosophila orthologues of CCNC and PRDM13, respectively, were induced separately during eye development. In flies, eye development was not affected, while knocking down either CycC or CG13296 mutant models. Overexpression of CycC also had no effect. Strikingly, overexpression of CG13296 in Drosophila leads to a severe loss of the imaginal eye-antennal disc. This study demonstrated for the first time in an animal model that overexpression of PRDM13 alone causes a severe abnormal retinal development. It is noteworthy that mutations associated with this autosomal dominant foveal developmental disorder are frequently duplications always including an entire copy of PRDM13, or variants in one DNase 1 hypersensitivity site at this locus.
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- 2017
22. Mutations in IMPG1 Cause Vitelliform Macular Dystrophies
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Hélène Dollfus, Susanne Kohl, Maxime Hebrard, Philippe Brabet, Isabelle Meunier, Audrey Sénéchal, Elfride De Baere, Carmen Ayuso García, Christina Zeitz, Béatrice Bocquet, Sandro Banfi, Guylène Le Meur, Claire Marie Dhaenens, Delphine Allorge, Frans P.M. Cremers, Francesca Simonelli, Michel Weber, Joe G. Hollyfield, Saddek Mohand-Said, Christian P. Hamel, Gaël Manes, Marta Corton, Xavier Zanlonghi, Robert K. Koenekoop, Gilles Labesse, Almudena Avila-Fernandez, José-Alain Sahel, Isabelle Audo, Manes, G, Meunier, I, Avila Fernández, A, Banfi, Sandro, Le Meur, G, Zanlonghi, X, Corton, M, Simonelli, Francesca, Brabet, P, Labesse, G, Audo, I, Mohand Said, S, Zeitz, C, Sahel, Ja, Weber, M, Dollfus, H, Dhaenens, Cm, Allorge, D, De Baere, E, Koenekoop, Rk, Kohl, S, Cremers, Fp, Hollyfield, Jg, Sénéchal, A, Hebrard, M, Bocquet, B, Ayuso García, C, and Hamel, Cp
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Adult ,Male ,Proband ,Genetics and epigenetic pathways of disease [NCMLS 6] ,genetic structures ,Fundus Oculi ,Molecular Sequence Data ,Inheritance Patterns ,Vitelliform macular dystrophy ,Biology ,Interphotoreceptor matrix ,medicine.disease_cause ,Compound heterozygosity ,Young Adult ,Report ,medicine ,Genetics ,Chromosomes, Human ,Humans ,Genetic Predisposition to Disease ,Genetics(clinical) ,Amino Acid Sequence ,Eye Proteins ,Genetics (clinical) ,Extracellular Matrix Proteins ,Mutation ,Base Sequence ,Genetic heterogeneity ,Middle Aged ,Macular dystrophy ,medicine.disease ,eye diseases ,Pedigree ,Vitelliform Macular Dystrophy ,Phenotype ,Female ,Proteoglycans ,sense organs ,Retinal Dystrophies - Abstract
Item does not contain fulltext Vitelliform macular dystrophies (VMD) are inherited retinal dystrophies characterized by yellow, round deposits visible upon fundus examination and encountered in individuals with juvenile Best macular dystrophy (BMD) or adult-onset vitelliform macular dystrophy (AVMD). Although many BMD and some AVMD cases harbor mutations in BEST1 or PRPH2, the underlying genetic cause remains unknown for many affected individuals. In a large family with autosomal-dominant VMD, gene mapping and whole-exome sequencing led to the identification of a c.713T>G (p.Leu238Arg) IMPG1 mutation, which was subsequently found in two other families with autosomal-dominant VMD and the same phenotype. IMPG1 encodes the SPACR protein, a component of the rod and cone photoreceptor extracellular matrix domains. Structural modeling indicates that the p.Leu238Arg substitution destabilizes the conserved SEA1 domain of SPACR. Screening of 144 probands who had various forms of macular dystrophy revealed three other IMPG1 mutations. Two individuals from one family affected by autosomal-recessive VMD were homozygous for the splice-site mutation c.807+1G>T, and two from another family were compound heterozygous for the mutations c.461T>C (p.Leu154Pro) and c.1519C>T (p.Arg507( *)). Most cases had a normal or moderately decreased electrooculogram Arden ratio. We conclude that IMPG1 mutations cause both autosomal-dominant and -recessive forms of VMD, thus indicating that impairment of the interphotoreceptor matrix might be a general cause of VMD.
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- 2013
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23. A dominant mutation in MAPKAPK3 , an actor of p38 signaling pathway, causes a new retinal dystrophy involving Bruch's membrane and retinal pigment epithelium
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A. Jean-Charles, Salomon Y. Cohen, Agnès Fichard, Isabelle Meunier, Natalia Ronkina, Camille Piro-Mégy, Mélanie Quiles, Béatrice Bocquet, Marie O. Pequignot, Aurélie Cubizolle, J. Simon C. Arthur, Chantal Cazevieille, Matthias Gaestel, Claire-Marie Dhaenens, Harold Merle, Gaël Manes, Corinne Baudoin, Guy Lenaers, Alain Gaudric, Gilles Labesse, Christian P. Hamel, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU de la Martinique [Fort de France], CHI Créteil, Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), Centre de Biochimie Structurale [Montpellier] (CBS), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), 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), Université Paris Diderot - Paris 7 (UPD7)-Hôpital Lariboisière-Fernand-Widal [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
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0301 basic medicine ,Male ,Models, Molecular ,Retinal Pigment Epithelium ,Bruch's membrane ,Protein Structure, Secondary ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Exome ,Age of Onset ,Genetics (clinical) ,Genetics ,Aged, 80 and over ,Mice, Knockout ,Intracellular Signaling Peptides and Proteins ,General Medicine ,Middle Aged ,3. Good health ,Cell biology ,Pedigree ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM] ,medicine.anatomical_structure ,Female ,Signal transduction ,Martinique ,Retinal Dystrophies ,Signal Transduction ,Adult ,Molecular Sequence Data ,Biology ,Protein Serine-Threonine Kinases ,03 medical and health sciences ,Retinitis pigmentosa ,medicine ,Animals ,Humans ,Amino Acid Sequence ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,Molecular Biology ,Retinal pigment epithelium ,Siblings ,Retinal ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,Macular degeneration ,medicine.disease ,eye diseases ,030104 developmental biology ,HEK293 Cells ,chemistry ,Gene Expression Regulation ,[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics ,Mutation ,030221 ophthalmology & optometry ,Bruch Membrane ,sense organs ,Sequence Alignment - Abstract
International audience; Inherited retinal dystrophies are clinically and genetically heterogeneous with significant number of cases remaining genetically unresolved. We studied a large family from the West Indies islands with a peculiar retinal disease, the Martinique crinkled retinal pigment epitheliopathy that begins around the age of 30 with retinal pigment epithelium (RPE) and Bruch's membrane changes resembling a dry desert land and ends with a retinitis pigmentosa. Whole-exome sequencing identified a heterozygous c.518T>C (p.Leu173Pro) mutation in MAPKAPK3 that segregates with the disease in 14 affected and 28 unaffected siblings from three generations. This unknown variant is predicted to be damaging by bioinformatic predictive tools and the mutated protein to be non-functional by crystal structure analysis. MAPKAPK3 is a serine/threonine protein kinase of the p38 signaling pathway that is activated by a variety of stress stimuli and is implicated in cellular responses and gene regulation. In contrast to other tissues, MAPKAPK3 is highly expressed in the RPE, suggesting a crucial role for retinal physiology. Expression of the mutated allele in HEK cells revealed a mislocalization of the protein in the cytoplasm, leading to cytoskeleton alteration and cytodieresis inhibition. In Mapkapk3-/- mice, Bruch's membrane is irregular with both abnormal thickened and thinned portions. In conclusion, we identified the first pathogenic mutation in MAPKAPK3 associated with a retinal disease. These findings shed new lights on Bruch's membrane/RPE pathophysiology and will open studies of this signaling pathway in diseases with RPE and Bruch's membrane alterations, such as age-related macular degeneration.
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- 2016
24. Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies
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Sylvie Gerber, Maxime Hebrard, Patrick Yu-Wai-Man, Josseline Kaplan, Yasmina Talmat-Amar, Gaël Manes, Claire Angebault, Dominique Bonneau, Mireille Rossel, Jean-Michel Rozet, Abdelhamid Barakat, Guy Lenaers, Naïg Gueguen, François Halloy, Christian P. Hamel, Pierre-Olivier Guichet, Isabelle Meunier, Birgit Lorenz, Valerio Carelli, Camille Piro-Mégy, Marisa Teigell, Agathe Roubertie, Mélanie Quiles, Pascal Reynier, Patrick F. Chinnery, Béatrice Bocquet, Lucas Fares-Taie, Markus N. Preising, Majida Charif, Patrizia Amati-Bonneau, Cécile Delettre, Pascale Bomont, David Moore, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Mécanismes moléculaires dans les démences neurodégénératives (MMDN), Université de Montpellier (UM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Montpellier 2 - Sciences et Techniques (UM2)-École pratique des hautes études (EPHE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Angebault, Claire, Guichet, Pierre-Olivier, Talmat-Amar, Yasmina, Charif, Majida, Gerber, Sylvie, Fares-Taie, Luca, Gueguen, Naig, Halloy, Françoi, Moore, David, Amati-Bonneau, Patrizia, Manes, Gael, Hebrard, Maxime, Bocquet, Béatrice, Quiles, Mélanie, Piro-Mégy, Camille, Teigell, Marisa, Delettre, Cécile, Rossel, Mireille, Meunier, Isabelle, Preising, Marku, Lorenz, Birgit, Carelli, Valerio, Chinnery, Patrick F, Yu-Wai-Man, Patrick, Kaplan, Josseline, Roubertie, Agathe, Barakat, Abdelhamid, Bonneau, Dominique, Reynier, Pascal, Rozet, Jean-Michel, Bomont, Pascale, Hamel, Christian P, and Lenaers, Guy
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Male ,Retinal Ganglion Cells ,genetic structures ,[SDV]Life Sciences [q-bio] ,Mitochondrion ,medicine.disease_cause ,Optic neuropathy ,syndromic optic neuropathy ,Mice ,0302 clinical medicine ,RTN4IP1 ,inherited optic neuropathy ,Optic Nerve Diseases ,Genetics(clinical) ,Zebrafish ,Genetics (clinical) ,Cells, Cultured ,Genetics ,0303 health sciences ,Mutation ,biology ,Blindness/etiology ,ACO2 ,Prognosis ,Cell biology ,Mitochondria ,Pedigree ,medicine.anatomical_structure ,Retinal ganglion cell ,Female ,Erratum ,Molecular Sequence Data ,Morphogenesis ,Genes, Recessive ,Mitochondrial Proteins ,03 medical and health sciences ,Report ,medicine ,Gene silencing ,Animals ,Humans ,Amino Acid Sequence ,030304 developmental biology ,Electron Transport Complex I ,Sequence Homology, Amino Acid ,recessive ,Fibroblasts ,medicine.disease ,biology.organism_classification ,Human genetics ,eye diseases ,Case-Control Studies ,Nerve Degeneration ,sense organs ,Carrier Proteins ,030217 neurology & neurosurgery ,Follow-Up Studies - Abstract
International audience; Autosomal-recessive optic neuropathies are rare blinding conditions related to retinal ganglion cell (RGC) and optic-nerve degeneration, for which only mutations in TMEM126A and ACO2 are known. In four families with early-onset recessive optic neuropathy, we identified mutations in RTN4IP1, which encodes a mitochondrial ubiquinol oxydo-reductase. RTN4IP1 is a partner of RTN4 (also known as NOGO), and its ortholog Rad8 in C.elegans is involved in UV light response. Analysis of fibroblasts from affected individuals with a RTN4IP1 mutation showed loss of the altered protein, a deficit of mitochondrial respiratory complex I and IV activities, and increased susceptibility to UV light. Silencing of RTN4IP1 altered the number and morphogenesis of mouse RGC dendrites invitro and the eye size, neuro-retinal development, and swimming behavior in zebrafish invivo. Altogether, these data point to a pathophysiological mechanism responsible for RGC early degeneration and optic neuropathy and linking RTN4IP1 functions to mitochondrial physiology, response to UV light, and dendrite growth during eye maturation.
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- 2015
25. High prevalence of PRPH2 in autosomal dominant retinitis pigmentosa in France and characterization of biochemical and clinical features
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Hélène Dollfus, Jean-Louis Dufier, Tremeur Guillaumie, Sabine Defoort-Dhellemmes, Isabelle Meunier, Gaël Manes, Laurence Faivre, Virginie Marquette, Saddek Mohand Said, Christina Zeitz, Guylène Le Meur, José-Alain Sahel, Sylvie Odent, Xavier Zanlonghi, Audrey Sénéchal, Isabelle Audo, John B. C. Findlay, Christophe Béroud, Werner L. Vos, Béatrice Bocquet, Bernard Puech, Christian P. Hamel, Aurore Devos, Francine Behar Cohen, Corinne Baudoin, Coralie Verdier, Michel Weber, Josseline Kaplan, Marie-Christine Picot, Claire-Marie Dhaenens, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Genetics of Sensory Diseases, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), The Marie Curie Laboratory for Membrane Proteins, National University of Ireland Maynooth (Maynooth University), UF Génopathies, Laboratoire de Biochimie et Biologie Moléculaire, Université de Lille, Sciences et Technologies-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de la Vision, 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), Clinique Sourdille, Laboratoire de Neurosciences Fonctionnelles et Pathologies (LNFP), Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR), Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Centre de Référence pour les Affections Rares en Génétique Ophtalmologique (CARGO) et Service de Génétique Médicale, Hôpitaux Universitaires de Strasbourg, Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'ophtalmologie [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service d'ophtalmologie [Nantes], Hôtel-Dieu, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Génétique Médicale et Génomique Fonctionnelle (GMGF), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Clinical Investigation Centre, Financial disclosures: C. Zeitz: Rétina France (Colomiers, France) (financial support), Fondation pour la recherche Médicale (Paris, France) (financial support), J.A. Sahel: Pixium Vision (Paris, France) (consultancy, stock options), GenSight Biologics (Paris, France) (consultancy, stock options), Sanofi-fovea (Paris, France) (consultancy), Genesignal (Lausanne, Switzerland) (consultancy) and patents (FR_10_53381, FR99/02346, EP_04_291067, EP 2005/005242, PCT/EP2005/005184, EP2006/005323, PCT/EP2008/057031, PCT/EP2008/058672, PCT/EP2008/066878, PCT/EP2009/058447, PCT/EP2009/061764, PCT/EP2009/061464, PCT/EP2010/055053, PCT/EP2010/058622, PCT/EP2010/059059, PCT/EP2011/051378, PCT/EP2011/054071). This project was supported by Union Nationale des Aveugles et Déficients Visuels (UNADEV) (Bordeaux, France), Programme Hospitalier de Recherche Clinique (PHRC, 12-014-0041) (Paris, France), foundation Voir et Entendre (Paris, France), and foundation Fighting Blindness (Columbia, MD, USA) (FFB, CD-CL-0808-0466-CHNO (IA) and C-CMM-0907-0428-INSERM04), Fondation Dalloz (Paris, France) (prix pour la recherche en ophtalmologie), Ville de Paris and Région Ile de France and Labex (Paris, France), LIFESENSES (Paris, France) (ANR-10-LABX-65), and French state funds managed by the Agence Nationale de la Recherche within the Investissements d'Avenir program (Paris, France) (ANR-11-IDEX-0004-0)., Institut des Neurosciences de Montpellier (INM), UF Génopathies - Laboratoire de Biochimie et Biologie Moléculaire [Lille] (LBBM), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS), ANR-11-IDEX-0004,SUPER,Sorbonne Universités à Paris pour l'Enseignement et la Recherche(2011), ANR-10-LABX-0065,LIFESENSES,DES SENS POUR TOUTE LA VIE(2010), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs ( INM ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Montpellier ( UM ), Centre Hospitalier Régional Universitaire [Montpellier] ( CHRU Montpellier ), National University of Ireland Maynooth ( NUIM ), Université de Lille, Sciences et Technologies-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), CIC - Quinze-Vingts, Institut National de la Santé et de la Recherche Médicale ( INSERM ), 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 ), Laboratoire de Neurosciences Fonctionnelles et Pathologies ( LNFP ), Hôpital Roger Salengro-Université Lille Nord (France)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Institut de Génétique et Développement de Rennes ( IGDR ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -IFR140-Centre National de la Recherche Scientifique ( CNRS ), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement ( Inserm U781 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Génétique Médicale et Génomique Fonctionnelle ( GMGF ), Aix Marseille Université ( AMU ) -Assistance Publique - Hôpitaux de Marseille ( APHM ) - Hôpital de la Timone [CHU - APHM] ( TIMONE ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Rennes 1 (UR1), and Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)
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Male ,Pathology ,genetic structures ,Genetic Linkage ,DNA Mutational Analysis ,Peripherins ,Gene Expression ,Fundus (eye) ,medicine.disease_cause ,Genotype ,Prevalence ,Fluorescein Angiography ,Sanger sequencing ,Mutation ,education.field_of_study ,medicine.diagnostic_test ,Macular dystrophy ,Middle Aged ,3. Good health ,Pedigree ,[ SDV.MHEP.OS ] Life Sciences [q-bio]/Human health and pathology/Sensory Organs ,symbols ,Female ,France ,Retinitis Pigmentosa ,Tomography, Optical Coherence ,Adult ,medicine.medical_specialty ,Adolescent ,Population ,Blotting, Western ,symbols.namesake ,Genetic linkage ,Aged ,Electroretinography ,France/epidemiology ,Humans ,Microsatellite Repeats ,Molecular Biology ,Peripherins/genetics ,Retinitis Pigmentosa/diagnosis ,Retinitis Pigmentosa/epidemiology ,Retrospective Studies ,Visual Field Tests ,medicine ,[SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs ,education ,business.industry ,eye diseases ,Ophthalmology ,sense organs ,business - Abstract
International audience; PURPOSE:To assess the prevalence of PRPH2 in autosomal dominant retinitis pigmentosa (adRP), to report six novel mutations, to characterize the biochemical features of a recurrent novel mutation and to study the clinical features of adRP patients.DESIGN:Retrospective clinical and molecular genetic study.METHODS:Clinical investigations included visual field testing, fundus examination, high-resolution spectral-domain optical coherence tomography (OCT), fundus autofluorescence imaging and electroretinogram (ERG) recording. PRPH2 was screened by Sanger sequencing in a cohort of 310 French families with adRP. Peripherin-2 protein was produced in yeast and analyzed by Western blot.RESULTS:We identified 15 mutations, including 6 novel and 9 previously reported changes in 32 families, accounting for a prevalence of 10.3% in this adRP population. We showed that a new recurrent p.Leu254Gln mutation leads to protein aggregation, suggesting abnormal folding. The clinical severity of the disease in examined patients was moderate with 78% of the eyes having 1 to 0.5 of visual acuity and 52% of the eyes retaining more than 50% of the visual field. Some patients characteristically showed vitelliform deposits or macular involvement. In some families, pericentral RP or macular dystrophy were found in family members while widespread RP was present in other members of the same families.CONCLUSIONS:The mutations in PRPH2 account for 10.3% of adRP in the French population, which is higher than previously reported (0-8%) This makes PRPH2 the second most frequent adRP gene after RHO in our series. PRPH2 mutations cause highly variable phenotypes and moderate forms of adRP, including mild cases which could be underdiagnosed.
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- 2015
26. Mutation in NDUFA13/GRIM19 leads to early onset hypotonia, dyskinesia and sensorial deficiencies, and mitochondrial complex I instability
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Majida Charif, Pierre-Olivier Guichet, Naig Guegen, Claire Angebault, François Rivier, Guy Lenaers, Nicolas Leboucq, Camille Piro-Mégy, Bénédicte Mousson de Camaret, Gaël Manes, Vincent Procaccio, Agathe Roubertie, Maxime Hebrard, Christian P. Hamel, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046] (PhyMedExp), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
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medicine.medical_specialty ,NDUFA13 ,Mitochondrial Diseases ,Muscle Hypotonia ,[SDV]Life Sciences [q-bio] ,Mitochondrion ,Biology ,Optic neuropathy ,Open Reading Frames ,Internal medicine ,Image Processing, Computer-Assisted ,Genetics ,medicine ,Humans ,NADH, NADPH Oxidoreductases ,Leigh disease ,Child ,Molecular Biology ,Genetics (clinical) ,ComputingMilieux_MISCELLANEOUS ,Dyskinesias ,Electron Transport Complex I ,General Medicine ,medicine.disease ,Magnetic Resonance Imaging ,Hypotonia ,Pedigree ,Endocrinology ,Dyskinesia ,Child, Preschool ,Mutation ,Female ,medicine.symptom ,Apoptosis Regulatory Proteins ,Optic nerve disorder ,Follow-Up Studies - Abstract
International audience; Mitochondrial complex I (CI) deficiencies are causing debilitating neurological diseases, among which, the Leber Hereditary Optic Neuropathy and Leigh Syndrome are the most frequent. Here, we describe the first germinal pathogenic mutation in the NDUFA13/GRIM19 gene encoding a CI subunit, in two sisters with early onset hypotonia, dyskinesia and sensorial deficiencies, including a severe optic neuropathy. Biochemical analysis revealed a drastic decrease in CI enzymatic activity in patient muscle biopsies, and reduction of CI-driven respiration in fibroblasts, while the activities of complex II, III and IV were hardly affected. Western blots disclosed that the abundances of NDUFA13 protein, CI holoenzyme and super complexes were drastically reduced in mitochondrial fractions, a situation that was reproduced by silencing NDUFA13 in control cells. Thus, we established here a correlation between the first mutation yet identified in the NDUFA13 gene, which induces CI instability and a severe but slowly evolving clinical presentation affecting the central nervous system.
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- 2015
27. Neuroradiological findings expand the phenotype of OPA1-related mitochondrial dysfunction
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Michel Pagès, Catherine Blanchet, Christian P. Hamel, H. Brunel, Agathe Roubertie, Gaël Manes, Emmanuelle Le Bars, Michel Mondain, Marie Christine Picot, Guy Lenaers, Claire Angebault Prouteau, Nicolas Leboucq, Erika Nogue, Hugues Chevassus, Emmanuelle Sarzi, Isabelle Meunier, Max Villain, Patrizia Amati-Bonneau, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), CHU de Montpellier, and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
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Male ,Pathology ,medicine.medical_specialty ,Magnetic Resonance Spectroscopy ,Visual acuity ,Mitochondrial Diseases ,Adolescent ,Optic nerve ,[SDV]Life Sciences [q-bio] ,Brain imaging ,Neurological examination ,Fluid-attenuated inversion recovery ,Motor Activity ,OPA1 ,Retinal ganglion ,GTP Phosphohydrolases ,White matter ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Atrophy ,Optic Atrophy, Autosomal Dominant ,medicine ,Humans ,dominant optic atrophy ,Child ,Hearing Loss ,030304 developmental biology ,Neurologic Examination ,Mitochondrial disorders ,0303 health sciences ,medicine.diagnostic_test ,business.industry ,Brain ,medicine.disease ,Magnetic Resonance Imaging ,eye diseases ,3. Good health ,medicine.anatomical_structure ,Neurology ,Child, Preschool ,Cerebellar atrophy ,Female ,Neurology (clinical) ,medicine.symptom ,business ,030217 neurology & neurosurgery - Abstract
International audience; OBJECTIVE: OPA1 mutations are responsible for more than half of autosomal dominant optic atrophy (ADOA), a blinding disease affecting the retinal ganglion neurons. In most patients the clinical presentation is restricted to the optic nerve degeneration, albeit in 20% of them, additional neuro-sensorial symptoms might be associated to the loss of vision, as frequently encountered in mitochondrial diseases. This study describes clinical and neuroradiological features of OPA1 patients.METHODS: Twenty two patients from 17 families with decreased visual acuity related to optic atrophy and carrying an OPA1 mutation were enrolled. Patients underwent neuro-ophthalmological examinations. Brain magnetic resonance imaging (T1, T2 and flair sequences) was performed on a 1.5-Tesla MR Unit. Twenty patients underwent 2-D proton spectroscopic imaging.RESULTS: Brain imaging disclosed abnormalities in 12 patients. Cerebellar atrophy mainly involving the vermis was observed in almost a quarter of the patients; other abnormalities included unspecific white matter hypersignal, hemispheric cortical atrophy, and lactate peak. Neurological examination disclosed one patient with a transient right hand motor deficit and ENT examination revealed hearing impairment in 6 patients. Patients with abnormal MRI were characterized by: (i) an older age (ii) more severe visual impairment with chronic visual acuity deterioration, and (iii) more frequent associated deafness.CONCLUSIONS: Our results demonstrate that brain imaging abnormalities are common in OPA1 patients, even in those with normal neurological examination. Lactate peak, cerebellar and cortical atrophies are consistent with the mitochondrial dysfunction related to OPA1 mutations and might result from widespread neuronal degeneration.
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- 2014
28. Frequency and clinical pattern of vitelliform macular dystrophy caused by mutations of interphotoreceptor matrix IMPG1 and IMPG2 genes
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Gaël Manes, Xavier Zanlonghi, Isabelle Audo, Guylène Le Meur, Isabelle Meunier, Carl Arndt, Virginie Marquette, Béatrice Bocquet, Sabine Defoort-Dhellemmes, Bernard Puech, Corinne Baudoin, Claire-Marie Dhaenens, Christian P. Hamel, and Robert Verdet
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Adult ,Male ,medicine.medical_specialty ,Visual acuity ,genetic structures ,Visual Acuity ,Single-nucleotide polymorphism ,Vitelliform macular dystrophy ,Retinal Pigment Epithelium ,Interphotoreceptor matrix ,medicine.disease_cause ,Ophthalmology ,medicine ,Humans ,Genetic Predisposition to Disease ,Eye Proteins ,Aged ,Retrospective Studies ,Genetics ,Mutation ,Extracellular Matrix Proteins ,Retinal pigment epithelium ,business.industry ,Dystrophy ,Macular dystrophy ,Middle Aged ,medicine.disease ,eye diseases ,Vitelliform Macular Dystrophy ,Electrooculography ,medicine.anatomical_structure ,Phenotype ,Case-Control Studies ,Female ,Proteoglycans ,sense organs ,medicine.symptom ,business ,Tomography, Optical Coherence - Abstract
Purpose To assess the frequency of and to characterize the clinical spectrum and optical coherence tomography findings of vitelliform macular dystrophy linked to IMPG1 and IMPG2 , 2 new causal genes expressed in the interphotoreceptor matrix. Design Retrospective epidemiologic, clinical, electrophysiologic, and molecular genetic study. Participants The database of a national referral center specialized in genetic sensory diseases was screened for patients with a macular vitelliform dystrophy without identified mutation or small deletion or large rearrangement in BEST1 and PRPH2 genes. Forty-nine families were included. Methods Clinical, imaging, and electro-oculogram findings were reviewed. Mutation screening of IMPG1 and IMPG2 genes were performed systematically. Main Outcome Measures Frequency, inheritance, and clinical pattern of vitelliform dystrophy associated with IMPG1 and IMPG2 mutations were characterized. Results IMPG1 was the causal gene in 3 families ( IMPG1 1–3, 11 patients) and IMPG2 in a fourth family (2 patients). With an autosomal dominant transmission, families 1 and 2 had the c.713T→G (p.Leu238Arg) mutation in IMPG1 and family 4 had the c.3230G→T (p.Cys1077Phe) mutation in IMPG2 . Patients with IMPG1 or IMPG2 mutations had a late onset and moderate visual impairment (mean visual acuity, 20/40; mean age of onset, 42 years), even in the sporadic case of family 3 with a presumed recessive transmission (age at onset, 38 years; mean visual acuity, 20/50). Drusen-like lesions adjacent to the vitelliform deposits were observed in 9 of 13 patients. The vitelliform material was above the retinal pigment epithelium (RPE) at any stage of the macular dystrophy, and this epithelium was well preserved and maintained its classical reflectivity on spectral-domain optical coherence tomography (SD-OCT). Electro-oculogram results were normal or borderline in 9 cases. Conclusions IMPG1 and IMPG2 are new causal genes in 8% of families negative for BEST1 and PRPH2 mutations. These genes should be screened in adult-onset vitelliform dystrophy with (1) moderate visual impairment, (2) drusen-like lesions, (3) normal reflectivity of the RPE line on SD-OCT, and (4) vitelliform deposits located between ellipsoid and interdigitation lines on SD-OCT. These clinical characteristics are not observed in the classical forms of BEST1 or PRPH2 vitelliform dystrophies.
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- 2014
29. A truncated form of rod photoreceptor PDE6 β-subunit causes autosomal dominant congenital stationary night blindness by interfering with the inhibitory activity of the γ-subunit
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Nikolai O. Artemyev, Gaël Manes, Philippe Brabet, Audrey Sénéchal, Anurima Majumder, Christian P. Hamel, Pallavi Cheguru, and Béatrice Bocquet
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Visual System ,Agricultural Biotechnology ,Xenopus ,lcsh:Medicine ,Biochemistry ,Animals, Genetically Modified ,Xenopus laevis ,Night Blindness ,Catalytic Domain ,Medicine and Health Sciences ,Myopia ,lcsh:Science ,GNAT1 ,Multidisciplinary ,Genetically Modified Organisms ,Agriculture ,Eye Diseases, Hereditary ,Genetic Diseases, X-Linked ,Animal Models ,Heterotrimeric GTP-Binding Proteins ,Sensory Systems ,Rhodopsin ,Vertebrates ,Frogs ,Retinal Disorders ,Transducin ,Transgenic Animals ,Research Article ,Visual phototransduction ,Light Signal Transduction ,Nonsense mutation ,Biology ,Research and Analysis Methods ,Frameshift mutation ,Amphibians ,Model Organisms ,PDE6B ,Retinitis pigmentosa ,Genetics ,medicine ,Animals ,Humans ,Inherited Eye Disorders ,Cyclic Nucleotide Phosphodiesterases, Type 6 ,lcsh:R ,Organisms ,Biology and Life Sciences ,Proteins ,medicine.disease ,Molecular biology ,Ophthalmology ,Mutation ,biology.protein ,lcsh:Q ,sense organs ,Neuroscience - Abstract
Autosomal dominant congenital stationary night blindness (adCSNB) is caused by mutations in three genes of the rod phototransduction cascade, rhodopsin (RHO), transducin α-subunit (GNAT1), and cGMP phosphodiesterase type 6 β-subunit (PDE6B). In most cases, the constitutive activation of the phototransduction cascade is a prerequisite to cause adCSNB. The unique adCSNB-associated PDE6B mutation found in the Rambusch pedigree, the substitution p.His258Asn, leads to rod photoreceptors desensitization. Here, we report a three-generation French family with adCSNB harboring a novel PDE6B mutation, the duplication, c.928-9_940dup resulting in a tyrosine to cysteine substitution at codon 314, a frameshift, and a premature termination (p.Tyr314Cysfs*50). To understand the mechanism of the PDE6β1-314fs*50 mutant, we examined the properties of its PDE6-specific portion, PDE6β1-313. We found that PDE6β1-313 maintains the ability to bind noncatalytic cGMP and the inhibitory γ-subunit (Pγ), and interferes with the inhibition of normal PDE6αβ catalytic subunits by Pγ. Moreover, both truncated forms of the PDE6β protein, PDE6β1-313 and PDE6β1-314fs*50 expressed in rods of transgenic X. laevis are targeted to the phototransduction compartment. We hypothesize that in affected family members the p.Tyr314Cysfs*50 change results in the production of the truncated protein, which binds Pγ and causes constitutive activation of the phototransduction thus leading to the absence of rod adaptation.
- Published
- 2014
30. Rat messenger RNA for the retinal pigment epithelium-specific protein RPE65 gradually accumulates in two weeks from late embryonic days1
- Author
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Clair Florent Schmitt-Bernard, Christian P. Hamel, Gaël Manes, Jérôme Kucharczak, Régine Leducq, and Anne Pagès
- Subjects
Messenger RNA ,Retina ,Opsin ,Retinal pigment epithelium ,Biophysics ,Retinal ,Cell Biology ,Biology ,Biochemistry ,Molecular biology ,eye diseases ,chemistry.chemical_compound ,medicine.anatomical_structure ,RPE65 ,chemistry ,Structural Biology ,Complementary DNA ,Genetics ,medicine ,sense organs ,Molecular Biology ,Gene - Abstract
The RPE65 protein appears late during the retinal development. To study the basis for this regulation, the rat RPE65 cDNA was sequenced and the mRNA subsequently quantitated at various stages by competitive RT-PCR. RPE65 mRNA was detected as early as E18 (36 copies/ng of whole eye total RNA). It gradually accumulates up to P12 (27 000 copies/ng) at which point it reaches a steady state level. This increase is interrupted for 3 days (P2–P4) during which the levels of mRNA remain stable. This timing and rate of accumulation parallels that of rat and mouse opsin mRNA and suggests that common factors may control the activation of genes in photoreceptors and retinal pigment epithelium cells.
- Published
- 1998
31. Relative Frequencies of Inherited Retinal Dystrophies and Optic Neuropathies in Southern France: Assessment of 21-year Data Management
- Author
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Véronique Paquis-Flucklinger, Corinne Baudoin, Maxime Hebrard, José-Alain Sahel, Christina Zeitz, Bernd Wissinger, Jean-Michel Rozet, Anne-Françoise Roux, Isabelle Audo, Isabelle Perrault, Pascal Reynier, Hélène Dollfus, Claire-Marie Dhaenens, Mireille Claustres, Cécile Delettre, Christian P. Hamel, Dominique Bonneau, Catherine Blanchet, Benoit Arveiler, Béatrice Bocquet, Patrizia Amati-Bonneau, Audrey Sénéchal, Jean-Paul Bonnefont, Marie-Odile Surget, Isabelle Meunier, Suzanne Kohl, Gaël Manes, Virginie Marquette, Josseline Kaplan, Annie Lacroux, Patrick Calvas, Neuroimmunologie des annélides (NA), Université de Lille, Sciences et Technologies-Centre National de la Recherche Scientifique (CNRS), Épidémiologie et prévention : environnement et efficacité des interventions (EPIPREV), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Méthodes et Algorithmes pour la Bioinformatique (MAB), Laboratoire d'Informatique de Robotique et de Microélectronique de Montpellier (LIRMM), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer (JPArc - U837 Inserm), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université Lille 2 - Faculté de Médecine, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique et épigénétique des maladies métaboliques, neurosensorielles et du développement (Inserm U781), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Mitochondrie : Régulations et Pathologie, Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de génétique [Angers], Université d'Angers (UA)-Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de la Vision, 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), Institut de Recherche sur le Cancer et le Vieillissement (IRCAN), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Nice Sophia Antipolis (... - 2019) (UNS), Université Côte d'Azur (UCA)-Université Côte d'Azur (UCA), CHU Toulouse [Toulouse], Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, Molecular Genetics Laboratory [Tuebingen, Germany] (Centre for Ophthalmology), Institute for Ophthalmic Research [Tuebingen, Germany]-University Clinics Tuebingen [Germany], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Institut des Neurosciences de Montpellier (INM), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, 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 Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université d'Angers (UA), Université Nice Sophia Antipolis (... - 2019) (UNS), University Clinics Tuebingen [Germany]-Institute for Ophthalmic Research [Tuebingen, Germany], and Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
- Subjects
Male ,Pathology ,genetic structures ,Epidemiology ,Usher syndrome ,[SDV]Life Sciences [q-bio] ,DNA Mutational Analysis ,Peripherins ,MESH: Intermediate Filament Proteins/genetics ,MESH: Eye Proteins/genetics ,MESH: Molecular Diagnostic Techniques ,MESH: Membrane Glycoproteins/genetics ,MESH: Optic Nerve Diseases/diagnosis ,Polymerase Chain Reaction ,Optic neuropathy ,0302 clinical medicine ,MESH: Aged, 80 and over ,Intermediate Filament Proteins ,MESH: Child ,Optic Nerve Diseases ,Outpatient clinic ,MESH: DNA Mutational Analysis ,Child ,Aged, 80 and over ,MESH: Aged ,0303 health sciences ,Extracellular Matrix Proteins ,MESH: Retinal Dystrophies/genetics ,Membrane Glycoproteins ,macular dystrophy ,MESH: Middle Aged ,MESH: France/epidemiology ,Inherited retinal dystrophies ,Eye Diseases, Hereditary ,Macular dystrophy ,Middle Aged ,inherited optic neuropathies ,MESH: Infant ,3. Good health ,MESH: Optic Nerve Diseases/genetics ,Molecular Diagnostic Techniques ,MESH: Young Adult ,Child, Preschool ,Myosin VIIa ,MESH: ATP-Binding Cassette Transporters/genetics ,Female ,France ,MESH: Peripherins ,MESH: Retinal Dystrophies/epidemiology ,Retinal Dystrophies ,Retinopathy ,Adult ,medicine.medical_specialty ,MESH: Mutation ,Adolescent ,Nerve Tissue Proteins ,Myosins ,03 medical and health sciences ,Young Adult ,Retinitis pigmentosa ,molecular diagnosis ,medicine ,Humans ,MESH: Myosin VIIa ,pigmentary retinopathy ,Eye Proteins ,030304 developmental biology ,Aged ,MESH: Adolescent ,MESH: Extracellular Matrix Proteins/genetics ,MESH: Humans ,business.industry ,MESH: Child, Preschool ,Infant ,MESH: Adult ,MESH: Eye Diseases, Hereditary/epidemiology ,MESH: Polymerase Chain Reaction ,medicine.disease ,Dermatology ,MESH: Myosins/genetics ,MESH: Nerve Tissue Proteins/genetics ,eye diseases ,MESH: Male ,Stargardt disease ,Ophthalmology ,Mutation ,030221 ophthalmology & optometry ,MESH: Eye Diseases, Hereditary/genetics ,ATP-Binding Cassette Transporters ,sense organs ,MESH: Optic Nerve Diseases/epidemiology ,business ,MESH: Retinal Dystrophies/diagnosis ,MESH: Female ,MESH: Eye Diseases, Hereditary/diagnosis - Abstract
International audience; PURPOSE:Inherited retinal dystrophies (IRDs) and inherited optic neuropathies (IONs) are rare diseases defined by specific clinical and molecular features. The relative prevalence of these conditions was determined in Southern France.METHODS:Patients recruited from a specialized outpatient clinic over a 21-year period underwent extensive clinical investigations and 107 genes were screened by polymerase chain reaction/sequencing.RESULTS:There were 1957 IRD cases (1481 families) distributed in 70% of pigmentary retinopathy cases (56% non-syndromic, 14% syndromic), 20% maculopathies and 7% stationary conditions. Patients with retinitis pigmentosa were the most frequent (47%) followed by Usher syndrome (10.8%). Among non-syndromic pigmentary retinopathy patients, 84% had rod-cone dystrophy, 8% cone-rod dystrophy and 5% Leber congenital amaurosis. Macular dystrophies were encountered in 398 cases (30% had Stargardt disease and 11% had Best disease). There were 184 ION cases (127 families) distributed in 51% with dominant optic neuropathies, 33% with recessive/sporadic forms and 16% with Leber hereditary optic neuropathy. Positive molecular results were obtained in 417/609 families with IRDs (68.5%) and in 27/58 with IONs (46.5%). The sequencing of 5 genes (ABCA4, USH2A, MYO7A, RPGR and PRPH2) provided a positive molecular result in 48% of 417 families with IRDs. Except for autosomal retinitis pigmentosa, in which less than half the families had positive molecular results, about 75% of families with other forms of retinal conditions had a positive molecular diagnosis.CONCLUSIONS:Although gene discovery considerably improved molecular diagnosis in many subgroups of IRDs and IONs, retinitis pigmentosa, accounting for almost half of IRDs, remains only partly molecularly defined.
- Published
- 2013
32. A strategy for molecular diagnosis and search for new genes/loci in autosomal dominant retinitis pigmentosa
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Cm Dhaenens, Ac Richard, Béatrice Bocquet, Isabelle Meunier, Christian P. Hamel, Gaël Manes, Maxime Hebrard, V Marquette, and Corinne Baudoin
- Subjects
Proband ,Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,education.field_of_study ,PRPF31 ,Population ,General Medicine ,Biology ,Autosomal dominant retinitis pigmentosa ,eye diseases ,Ophthalmology ,Mutation (genetic algorithm) ,Intronic Mutation ,education ,Gene ,Exome sequencing - Abstract
Purpose Autosomal dominant retinitis pigmentosa (adRP) affects approximately 1 in 12,000 individuals. To date, 24 adRP genes have been identified accounting theoretically for 44.7% of adRP families; therefore, genetic defects in many patients are yet to be identified. This study was intended to provide information on prevalence of known adRP genes in France and to localize new genes and loci. Methods The 10 most frequently mutated adRP genes (in full for RHO and RDS, in hot spots only for PRPF31, RP1, PRPF8, IMPDH1, NRL, PRPF3, NR2E3 and SNRNP200) were screened by systematic sequencing to determine the causative mutation in a cohort of 232 French families affected by adRP. We also performed a pilot experiment on 12 families by using whole exome sequencing (WES). Results The direct sequencing approach was performed on 232 proband DNAs. A causative mutation was found for 99 families (42.7 %), among which 35 out of 68 (51.5 %) were novel. Among the 133 remaining families with no mutation (57.3 %), 12 probands were subjected to WES. This allowed to identify 7 additional families with a causative mutation. Conclusion The prevalence of the genes was similar to that of the literature for most genes (e.g. RHO with 16 %), but were unexpected for others (e.g. NR2E3 with 3.9 %). The WES approach allowed us to identify a causative gene in 58.3 % of a population previously screened by direct sequencing approach. The 5 remaining families, negative with WES screen, are potentially carrying a mutation in one or more new adRP genes although an intronic mutation cannot be excluded. These 5 families are under active investigation.
- Published
- 2012
33. Search for the identification of new genes causing autosomal recessive retinitis pigmentosa
- Author
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Béatrice Bocquet, Christian P. Hamel, Gaël Manes, Nour Al Dain Marzouka, V Marquette, Isabelle Meunier, Maxime Hebrard, Audrey Sénéchal, and Corinne Baudoin
- Subjects
Genetics ,Ophthalmology ,Candidate gene ,SNP ,Microsatellite ,Single-nucleotide polymorphism ,General Medicine ,Biology ,Allele ,Disease gene identification ,Genotyping ,eye diseases ,Exome sequencing - Abstract
Purpose The molecular diagnosis of autosomal recessive Retinitis Pigmentosa (arRP) is challenging because of the large genetic and clinical heterogeneity of this disease: to date, 36 arRP genes as well as 3 loci have been identified accounting for approximately 60 % of arRP families. Two major genes, USH2A and EYS, are responsible for 13 to 19 % of the cases, the other genes being minority. Here, we developed a strategy to search for new genes/loci causing arRP in a series of consanguineous families. Methods Inbred families were genotyped using microsatellite markers specific for USH2A and EYS genes. Families resulting from this first screening were analyzed using 250K SNP microarrays with TASE software (Transmitted Allele Search Engine). Known genes in homozygous regions were PCR/sequenced. Whole Exome Sequencing is running for a few families. Results A total of 44 inbred families were analyzed. Among them, 14 (32 %) were fully or partly homozygous for EYS or USH2A markers. We selected 16/30 of the remaining families for SNPs genotyping and homozygosity mapping. We found the causative mutation in 7 families (43 %) in a known gene (RP1, RLBP1, NR2E3, CNGB1, IMPG2, PDE6A) while in 6 others sequencing of known genes in homozygous regions is still ongoing. For the 3 remaining families, potentially new loci were found (in chromosomes 3, 10 and 21) for which the results of whole exome sequencing is being analysed. Conclusion About 43 % of the tested consanguineous families had a positive molecular diagnosis and a candidate gene approach is ongoing for the 3 loci.
- Published
- 2012
34. Combining gene mapping and phenotype assessment for fast mutation finding in non-consanguineous autosomal recessive retinitis pigmentosa families
- Author
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Gaël Manes, Isabelle Meunier, Maxime Hebrard, Diana Zelenika, Audrey Sénéchal, Béatrice Bocquet, Delphine Coustes-Chazalette, Anne Bolland-Augé, Christian P. Hamel, Emilie Hérald, Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut des Neurosciences de Montpellier (INM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
- Subjects
Adult ,Male ,Candidate gene ,Adolescent ,Fundus Oculi ,Genome-wide association study ,Biology ,Compound heterozygosity ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,0302 clinical medicine ,Gene mapping ,Genotype ,Retinitis pigmentosa ,Genetics ,medicine ,Humans ,Child ,Gene ,Genetics (clinical) ,030304 developmental biology ,0303 health sciences ,Base Sequence ,Chromosome Mapping ,autosomal recessive inheritance ,gene mapping ,Sequence Analysis, DNA ,Middle Aged ,medicine.disease ,Phenotype ,Pedigree ,non consanguineous families ,phenotype characterization ,Child, Preschool ,Mutation ,030221 ophthalmology & optometry ,Female ,Retinitis Pigmentosa ,Genome-Wide Association Study - Abstract
Among inherited retinal dystrophies, autosomal recessive retinitis pigmentosa (arRP) is the most genetically heterogenous condition with 32 genes currently known that account for ∼60 % of patients. Molecular diagnosis thus requires the tedious systematic sequencing of 506 exons. To rapidly identify the causative mutations, we devised a strategy that combines gene mapping and phenotype assessment in small non-consanguineous families. Two unrelated sibships with arRP had whole-genome scan using SNP microchips. Chromosomal regions were selected by calculating a score based on SNP coverage and genotype identity of affected patients. Candidate genes from the regions with the highest scores were then selected based on phenotype concordance of affected patients with previously described phenotype for each candidate gene. For families RP127 and RP1459, 33 and 40 chromosomal regions showed possible linkage, respectively. By comparing the scores with the phenotypes, we ended with one best candidate gene for each family, namely tubby-like protein 1 (TULP1) and C2ORF71 for RP127 and RP1459, respectively. We found that RP127 patients were compound heterozygous for two novel TULP1 mutations, p.Arg311Gln and p.Arg342Gln, and that RP1459 patients were compound heterozygous for two novel C2ORF71 mutations, p.Leu777PhefsX34 and p.Leu777AsnfsX28. Phenotype assessment showed that TULP1 patients had severe early onset arRP and that C2ORF71 patients had a cone rod dystrophy type of arRP. Only two affected individuals in each sibship were sufficient to lead to mutation identification by screening the best candidate gene selected by a combination of gene mapping and phenotype characterization.
- Published
- 2011
35. A novel locus (CORD12) for autosomal dominant cone-rod dystrophy on chromosome 2q24.2-2q33.1
- Author
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Gaël Manes, Anne Bolland-Augé, Béatrice Bocquet, Maxime Hebrard, Isabelle Meunier, Delphine Coustes-Chazalette, Christian P. Hamel, Diana Zelenika, Audrey Sénéchal, Institut des Neurosciences de Montpellier (INM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), The work was supported by private foundations (Information Recherche sur la Rétinite Pigmentaire, Retina France, SOS Rétinite and UNADEV), Centre National de Génotypage and INSERM. Special thanks to UNADEV which supports fellowship for GM and MH., Institut des Neurosciences de Montpellier - Déficits sensoriels et moteurs (INM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, and BMC, Ed.
- Subjects
Male ,lcsh:Internal medicine ,medicine.medical_specialty ,lcsh:QH426-470 ,genetic structures ,Genetic Linkage ,Locus (genetics) ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,Biology ,Polymorphism, Single Nucleotide ,03 medical and health sciences ,0302 clinical medicine ,Genetic linkage ,Retinitis pigmentosa ,medicine ,Genetics ,Humans ,Genetics(clinical) ,lcsh:RC31-1245 ,Gene ,Genetics (clinical) ,030304 developmental biology ,Genes, Dominant ,0303 health sciences ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Cytogenetics ,Dystrophy ,Chromosome Mapping ,Middle Aged ,medicine.disease ,Molecular biology ,eye diseases ,Human genetics ,Pedigree ,lcsh:Genetics ,Chromosomes, Human, Pair 2 ,030221 ophthalmology & optometry ,Female ,sense organs ,Retinal Dystrophies ,Retinitis Pigmentosa ,Microsatellite Repeats ,Research Article - Abstract
Background Rod-cone dystrophy, also known as retinitis pigmentosa (RP), and cone-rod dystrophy (CRD) are degenerative retinal dystrophies leading to blindness. To identify new genes responsible for these diseases, we have studied one large non consanguineous French family with autosomal dominant (ad) CRD. Methods Family members underwent detailed ophthalmological examination. Linkage analysis using microsatellite markers and a whole-genome SNP analysis with the use of Affymetrix 250 K SNP chips were performed. Five candidate genes within the candidate region were screened for mutations by direct sequencing. Results We first excluded the involvement of known adRP and adCRD genes in the family by genotyping and linkage analysis. Then, we undertook a whole-genome scan on 22 individuals in the family. The analysis revealed a 41.3-Mb locus on position 2q24.2-2q33.1. This locus was confirmed by linkage analysis with specific markers of this region. The maximum LOD score was 2.86 at θ = 0 for this locus. Five candidate genes, CERKL, BBS5, KLHL23, NEUROD1, and SF3B1 within this locus, were not mutated. Conclusion A novel locus for adCRD, named CORD12, has been mapped to chromosome 2q24.2-2q33.1 in a non consanguineous French family.
- Published
- 2011
36. Identification of a new locus in autosomal dominant retinitis pigmentosa and strategy for molecular diagnosis
- Author
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D Coustes-Chazalette, Gaël Manes, Cm Dhaenens, Béatrice Bocquet, Christian P. Hamel, V Delaere, A Devos, Maxime Hebrard, and Isabelle Meunier
- Subjects
Proband ,Genetics ,congenital, hereditary, and neonatal diseases and abnormalities ,PRPF31 ,Locus (genetics) ,General Medicine ,Biology ,eye diseases ,Ophthalmology ,Genotype ,Microsatellite ,Genotyping ,Gene ,SNP array - Abstract
Purpose Autosomal dominant retinitis pigmentosa (adRP) affects approximately 1 in 12,000 individuals. To date, 21 adRP genes have been identified accounting theoretically for 44.7% of adRP families; therefore, genetic defects in many patients are yet to be identified. This study was intended to provide information on prevalence of known adRP genes in France and to localize new genes and loci. Methods Microsatellite markers for the 21 adRP genes were used to genotype large families. Non excluded genes were then sequenced. For some families, we performed a whole-genome SNP analysis using Affymetrix 250K or 6.0 chips. For small families, the 8 most frequently mutated adRP genes were sequenced (in full for RHO, in hot spots only for PRPF31, RDS, RP1, PRPF8, IMPDH1, NRL and PRPF3). Results Hitherto 18 adRP families were studied by indirect genotype analysis. Of these, 15 have shown mutations in known genes and 2 are still in progress. For the last family, one new locus was identified by whole-genome SNP analysis and confirmed by microsatellite genotyping defining a 43-Mb locus on chromosome 2. The direct sequencing approach was performed on 143 proband DNAs (completely for the first 50 patients and only RHO for the 93 other patients). A causative mutation was found for 20 families (14%), among which 9 out of 11 were novel. Conclusion The preliminary results, on this limited cohort, showed that the prevalence of known genes is probably underestimated in the literature because the causative mutation was found for 15 families out of 18 (83%). However one new locus has been identified and is under active investigation.
- Published
- 2010
37. Systematic screening of BEST1 and PRPH2 in juvenile and adult vitelliform macular dystrophies: a rationale for molecular analysis
- Author
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Isabelle Meunier, Gaël Manes, Claire-Marie Dhaenens, Emilie Mazoir, Bernard Puech, Christian P. Hamel, Delphine Chazalette, Sabine Defoort-Dhellemmes, Béatrice Bocquet, Carl Arndt, and Audrey Sénéchal
- Subjects
Adult ,Male ,Pediatrics ,medicine.medical_specialty ,genetic structures ,Fundus Oculi ,Eye disease ,DNA Mutational Analysis ,Peripherins ,Nerve Tissue Proteins ,Vitelliform macular dystrophy ,Intermediate Filament Proteins ,Chloride Channels ,Ophthalmology ,medicine ,Humans ,Genetic Testing ,Family history ,Bestrophins ,Fluorescein Angiography ,Eye Proteins ,Genetic testing ,Aged ,Retrospective Studies ,Membrane Glycoproteins ,medicine.diagnostic_test ,business.industry ,Fundus photography ,Retrospective cohort study ,DNA ,Middle Aged ,medicine.disease ,eye diseases ,Pedigree ,Vitelliform Macular Dystrophy ,Electrooculography ,Mutation (genetic algorithm) ,Mutation ,Female ,Age of onset ,business - Abstract
Purpose To evaluate a genetic approach of BEST1 and PRPH2 screening according to age of onset, family history, and Arden ratio in patients with juvenile vitelliform macular dystrophy (VMD2) or adult-onset vitelliform macular dystrophy (AVMD), which are characterized by autofluorescent deposits. Design Clinical, electrophysiologic, and molecular retrospective study. Participants The database of a clinic specialized in genetic sensory diseases was screened for patients with macular vitelliform dystrophy. Patients with an age of onset less than 40 years were included in the VMD2 group (25 unrelated patients), and patients with an age of onset more than 40 years were included in the AVMD group (19 unrelated patients). Methods Clinical, fundus photography, and electro-oculogram (EOG) findings were reviewed. Mutation screening of BEST1 and PRPH2 genes was systematically performed. Main Outcome Measures Relevance of age of onset, family history, and Arden ratio were reviewed. Results Patients with VMD2 carried a BEST1 mutation in 60% of the cases. Seven novel mutations in BEST1 (p.V9L, p.F80V, p.I73V, p.R130S, pF298C, pD302A, and p.179delN) were found. Patients with VMD2 with a positive family history or a reduced Arden ratio carried a BEST1 mutation in 70.5% of cases and in 83% if both criteria were fulfilled. Patients with AVMD carried a PRPH2 mutation in 10.5% of cases and did not carry a BEST1 mutation. The probability of finding a PRPH2 mutation increased in the case of a family history (2/5 patients). Electro-oculogram was normal in 3 of 15 patients with BEST1 mutations and reduced in the 3 patients with PRPH2 mutations. Conclusions Age of onset is a major criterion to distinguish VMD2 from AVMD. Electro-oculogram is not as relevant because decreased or normal Arden ratios have been associated with mutations in both genes and diseases. A positive family history increased the probability of finding a mutation. BEST1 screening should be recommended to patients with an age of onset less than 40 years, and PRPH2 screening should be recommended to patients with an age of onset more than 40 years. For an onset between 30 and 40 years, PRPH2 can be screened if no mutation has been detected in BEST1 . Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.
- Published
- 2010
38. Cyclin E and cyclin A are likely targets of Src for PDGF-induced DNA synthesis in fibroblasts
- Author
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Gaël Manes, Serge Roche, and Olivia Furstoss
- Subjects
DNA Replication ,Cyclin E ,Cyclin D ,Cyclin A ,Biophysics ,Cyclin B ,Biochemistry ,Retinoblastoma Protein ,Mice ,Cyclin D1 ,Structural Biology ,Genetics ,Animals ,Molecular Biology ,Cyclin ,Mice, Knockout ,Platelet-Derived Growth Factor ,biology ,DNA synthesis ,Chemistry ,E1A ,Cell Biology ,3T3 Cells ,PDGF ,Fibroblasts ,Molecular biology ,Cell biology ,src-Family Kinases ,Gene Expression Regulation ,Cyclin-dependent kinase complex ,biology.protein ,Cyclin A2 ,Src - Abstract
How tyrosine kinases of the Src family regulate platelet-derived growth factor (PDGF)-induced DNA synthesis remains elusive. Here we show that the E1A antigen of adenovirus 5 overrides the G1 block elicited by the kinase-inactive mutant SrcK−. This was dependent upon the CR2 region of E1A that upregulated cyclin E and cyclin A and inactivated the pocket protein pRb. E1A rescue was independent of pRb. Expression of SrcK− in fibroblasts prevented PDGF-induced expression of cyclins E and A. This effect was overcome by E1A. Constitutive expression of cyclins E and A, but not D1, restored mitogenesis that was inhibited by SrcK−. We conclude that both cyclin E and cyclin A are likely targets of Src mediating PDGF-induced DNA synthesis.
- Published
- 2002
39. Slap negatively regulates Src mitogenic function but does not revert Src-induced cell morphology changes
- Author
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Paul Bello, Serge Roche, and Gaël Manes
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Microinjections ,Proto-Oncogene Proteins c-jun ,Molecular Sequence Data ,Proto-Oncogene Proteins pp60(c-src) ,SH2 domain ,Cell morphology ,Proto-Oncogene Proteins c-fyn ,Myristic Acid ,SH3 domain ,Proto-Oncogene Proteins c-myc ,src Homology Domains ,Mice ,FYN ,Proto-Oncogene Proteins ,Animals ,Amino Acid Sequence ,Molecular Biology ,Cell Growth and Development ,biology ,Kinase ,G1 Phase ,Cell Biology ,3T3 Cells ,Molecular biology ,Recombinant Proteins ,Cell Transformation, Neoplastic ,biology.protein ,Mitogens ,Tyrosine kinase ,Protein Processing, Post-Translational ,Proto-Oncogene Proteins c-fos ,Platelet-derived growth factor receptor ,Proto-oncogene tyrosine-protein kinase Src - Abstract
Src-like adapter protein (Slap) is a recently identified protein that negatively regulates mitogenesis in murine fibroblasts (S. Roche, G. Alonso, A. Kazlausakas, V. M. Dixit, S. A. Courtneidge, and A. Pandey, Curr. Biol. 8:975-978, 1998) and comprises an SH3 and SH2 domain with striking identity to the corresponding Src domains. In light of this, we sought to investigate whether Slap could be an antagonist of all Src functions. Like Src, Slap was found to be myristylated in vivo and largely colocalized with Src when coexpressed in Cos7 cells. Microinjection of a Slap-expressing construct into quiescent NIH 3T3 cells inhibited platelet-derived growth factor (PDGF)-induced DNA synthesis, and the inhibition was rescued by the transcription factor c-Myc but not by c-Jun/c-Fos expression. Fyn (or Src) overexpression overrides the G(1)/S block induced by both SrcK- and a Slap mutant with a deletion of its C terminus (SlapDeltaC), but not the block induced by Slap or SlapDeltaSH3, implying that the C terminus is a noncompetitive inhibitor of Src mitogenic function. Furthermore, a chimeric adapter comprising SrcDeltaK fused to the Slap C terminus (Src/SlapC) also inhibited Src function during the PDGF response in a noncompetitive manner, as Src coexpression could not rescue PDGF signaling. Slap, however, did not reverse deregulated Src-induced cell transformation, as it was unable to inhibit depolymerization of actin stress fibers while still being able to inhibit SrcY527F-induced DNA synthesis. This was attributed to a distinct Slap SH3 binding specificity, since the chimeric Slap/SrcSH3 molecule, in which the Slap SH3 was replaced by the Src SH3 sequence, substantially restored stress fiber formation. Indeed, three amino acids important for ligand binding in Src SH3 were replaced in the Slap SH3 sequence; Slap SH3 did not bind to the Src SH3 partners p85alpha, Shc, and Sam68 in vitro, and the chimeric tyrosine kinase Slap/SrcK, composed of SlapDeltaC fused to the SH2 linker kinase sequence of Src, was not regulated in vivo. Furthermore, the Src SH3 domain is required for signaling during mitogenesis and since Slap/SrcK behaved as a dominant negative in the PDGF mitogenic response when microinjected into quiescent fibroblasts. We conclude that Slap is a negative regulator of Src during mitogenesis involving both the SH2 and the C terminus domains in a noncompetitive manner, but it does not regulate all Src function due to specific SH3 binding substrates.
- Published
- 2000
40. Hereditary spastic paraplegia and prominent sensorial involvement: think MAG mutations!
- Author
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Agathe Roubertie, Majida Charif, Pierre Meyer, Gael Manes, Isabelle Meunier, Guillaume Taieb, Raul Junta Morales, Agnès Guichet, Cecile Delettre, Emmanuelle Sarzi, Nicolas Leboucq, François Rivier, and Guy Lenaers
- Subjects
Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Homozygous mutations in MAG, encoding the myelin‐associated glycoprotein, a transmembrane component of the myelin sheath, have been associated with SPG 75 recessive spastic paraplegia. Here, we report the first patient with two compound heterozygous novel MAG mutations (p.A151V and p.S373R) and early developmental delay with a progressive complex phenotype characterized by spastic paraplegia, peripheral sensorimotor neuropathy, intellectual disability, and sensorial dysfunctions with severe optic atrophy and hearing involvement. Brain imaging showed progressive global cerebellar atrophy. We propose that complex hereditary spastic paraplegia, with axonal and demyelinating polyneuropathy, sensorial impairment and intellectual disability might suggest MAG mutations.
- Published
- 2019
- Full Text
- View/download PDF
41. Spectrum of Rhodopsin Mutations in French Autosomal Dominant Rod–Cone Dystrophy Patients
- Author
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Gaël Manes, Shomi S. Bhattacharya, Veselina Moskova-Doumanova, Christian P. Hamel, José-Alain Sahel, Saddek Mohand-Said, Isabelle Audo, Xavier Zanlonghi, Marie-Elise Lancelot, Olivier Poch, Anne Friedrich, Aline Antonio, Christina Zeitz, Institut de la Vision, 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), Department of Molecular Genetics, Institute of Ophthalmology, Physiopathologie et thérapie des déficits sensoriels et moteurs, Université Montpellier 2 - Sciences et Techniques (UM2)-IFR76-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service Exploration Fonctionnelle de la Vision, Clinique Sourdille, Centre de référence des affections sensorielles d'origine génétique, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui De Chaulliac, The project was financially supported by Foundation Fighting Blindness (I.A.), Foundation Voir et Entendre and BQR, Université Pierre et Marie Curie6 (C.Z), PHRC national adRP (C H)., Marazova, Katia, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)
- Subjects
Male ,Retinal degeneration ,genetic structures ,DNA Mutational Analysis ,Visual Acuity ,[SDV.GEN] Life Sciences [q-bio]/Genetics ,Gene mutation ,medicine.disease_cause ,Polymerase Chain Reaction ,0302 clinical medicine ,Prevalence ,Fluorescein Angiography ,Child ,Genes, Dominant ,Genetics ,0303 health sciences ,Mutation ,biology ,Middle Aged ,Pedigree ,3. Good health ,Phenotype ,Rhodopsin ,Female ,France ,Retinitis Pigmentosa ,Tomography, Optical Coherence ,Photoreceptor Cells, Vertebrate ,Adult ,Adolescent ,Genotype ,White People ,Article ,Young Adult ,03 medical and health sciences ,Retinitis pigmentosa ,Electroretinography ,medicine ,Rod-cone dystrophy ,Humans ,030304 developmental biology ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Genetic heterogeneity ,Point mutation ,medicine.disease ,eye diseases ,030221 ophthalmology & optometry ,biology.protein ,sense organs - Abstract
Rod-cone dystrophies, also called retinitis pigmentosa (RP), are a clinically and genetically heterogeneous group of inherited retinal disorders primarily affecting rods with secondary cone degeneration 1. RP patients initially often complain of night blindness. This is attributed to the primarily affected rods and clinical sign of the impaired rod function. Later on, when the secondary cone dysfunctions manifests, progressive visual field constriction, abnormal color vision and loss of central vision can be observed – signs of decreasing cone function. As the disease progresses and retinal dysfunction decreases, visual impairment increases: in some cases the disease may eventually result in very severe visual impairment or even blindness. RP is the most common inherited form of severe retinal degeneration, with a frequency of about 1 in 4000 births and more than 1 million affected individuals over the world. The mode of inheritance can be X-linked (5–15%) autosomal dominant (30–40%) or autosomal recessive (50–60%) The remaining patients represent isolated cases of which the inheritance trait can not be established 1. To date, 20 autosomal dominant RP (adRP) genes have been reported (http://www.sph.uth.tmc.edu/Retnet/). One of the major genes underlying this disorder is rhodopsin (RHO) coding for the light absorbing molecule that initiates the signal transmission cascade in rod photoreceptors. According to the literature, RHO mutation prevalence ranges from 0 to 50% cases of adRP in cohorts from various geographical origins, with higher numbers reported in the United States 2–18. The genetic and phenotypic heterogeneity is not only found in RP in general but also specifically reflected in adRP with RHO mutations: Over 120 mutations have been identified in different sites of the gene including specific hot spots (http://www.sph.uth.tmc.edu/Retnet/, http://www.hgmd.cf.ac.uk/ac/all.php, http://www.retina-international.org/sci-news/rhomut.htm) 19. Certain mutations in RHO lead to diffuse rod-cone dysfunction whereas other cases are implicated in a more restricted disease that may predominate in the inferior part of the retina such as in sector RP 20. Phenotypic classifications have been proposed to reflect this variability. In particular, Cideciyan and co-workers have distinguished two classes of disease expression with allele-specificity 21: class A mutants show severely generalized abnormal rod function early in life with a constant rate of cone disease progression across the retina with time. Class B mutants show more restricted disease and absent or lateonset night blindness. Other classifications have been proposed based on the underlying pathogenic mechanism involved in adRP due to RHO mutations. Mendes and co-workers classified the different types of mutations in 6 groups. Class I refers exclusively to rhodopsin mutations that fold correctly but are not transported to the outer segment. Class II, refers to mutations that misfold, are retained in the endopasmic reticulum (ER) and cannot easily reconstitute with 11-cis-retinal. Class III refers to mutations that affect endocytosis. Class IV mutations do not affect folding per se but might affect rhodopsin stability and posttranslational modification. Similarly, Class V mutations have no obvious folding defect but show an increased activation rate for transducin. Mutants that appear to fold correctly but lead to the constitutive activation of opsin in the absence of the chromophore and in the dark constitute Class VI. Other mutations with unclear biochemical or cellular defect, or uninvestigated defect were not classified 19. Our comprehensive study presented herein aim to investigate in detail a French adRP cohort coming from 2 different clinical centers, namely Quinze-Vingts hospital in Paris and the Centre Hospitalier Regional in Montpellier located in the south of France. We will present the prevalence of rhodopsin mutations in this cohort and show precise phenotype-genotype correlations. Novel mutations will be analyzed on its predicted pathogenic mechanism as well as frequently mutated sites will be presented as putative candidates for therapeutic approaches.
- Published
- 2010
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