Publications by authors named "Jean-Michel Rozet"

69 Publications

YIF1B mutations cause a post-natal neurodevelopmental syndrome associated with Golgi and primary cilium alterations.

Brain 2020 10;143(10):2911-2928

INSERM UMR894, Center for Psychiatry and Neuroscience, Paris F-75014, Université Paris Descartes, Sorbonne Paris Cité - Paris 5, France.

Human post-natal neurodevelopmental delay is often associated with cerebral alterations that can lead, by themselves or associated with peripheral deficits, to premature death. Here, we report the clinical features of 10 patients from six independent families with mutations in the autosomal YIF1B gene encoding a ubiquitous protein involved in anterograde traffic from the endoplasmic reticulum to the cell membrane, and in Golgi apparatus morphology. The patients displayed global developmental delay, motor delay, visual deficits with brain MRI evidence of ventricle enlargement, myelination alterations and cerebellar atrophy. A similar profile was observed in the Yif1b knockout (KO) mouse model developed to identify the cellular alterations involved in the clinical defects. In the CNS, mice lacking Yif1b displayed neuronal reduction, altered myelination of the motor cortex, cerebellar atrophy, enlargement of the ventricles, and subcellular alterations of endoplasmic reticulum and Golgi apparatus compartments. Remarkably, although YIF1B was not detected in primary cilia, biallelic YIF1B mutations caused primary cilia abnormalities in skin fibroblasts from both patients and Yif1b-KO mice, and in ciliary architectural components in the Yif1b-KO brain. Consequently, our findings identify YIF1B as an essential gene in early post-natal development in human, and provide a new genetic target that should be tested in patients developing a neurodevelopmental delay during the first year of life. Thus, our work is the first description of a functional deficit linking Golgipathies and ciliopathies, diseases so far associated exclusively to mutations in genes coding for proteins expressed within the primary cilium or related ultrastructures. We therefore propose that these pathologies should be considered as belonging to a larger class of neurodevelopmental diseases depending on proteins involved in the trafficking of proteins towards specific cell membrane compartments.
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http://dx.doi.org/10.1093/brain/awaa235DOI Listing
October 2020

Loss of Function of RIMS2 Causes a Syndromic Congenital Cone-Rod Synaptic Disease with Neurodevelopmental and Pancreatic Involvement.

Am J Hum Genet 2020 06 28;106(6):859-871. Epub 2020 May 28.

Laboratory of Genetics in Ophthalmology, INSERM UMR 1163, Institute of Genetic Diseases, Imagine and Paris University, 75015 Paris, France. Electronic address:

Congenital cone-rod synaptic disorder (CRSD), also known as incomplete congenital stationary night blindness (iCSNB), is a non-progressive inherited retinal disease (IRD) characterized by night blindness, photophobia, and nystagmus, and distinctive electroretinographic features. Here, we report bi-allelic RIMS2 variants in seven CRSD-affected individuals from four unrelated families. Apart from CRSD, neurodevelopmental disease was observed in all affected individuals, and abnormal glucose homeostasis was observed in the eldest affected individual. RIMS2 regulates synaptic membrane exocytosis. Data mining of human adult bulk and single-cell retinal transcriptional datasets revealed predominant expression in rod photoreceptors, and immunostaining demonstrated RIMS2 localization in the human retinal outer plexiform layer, Purkinje cells, and pancreatic islets. Additionally, nonsense variants were shown to result in truncated RIMS2 and decreased insulin secretion in mammalian cells. The identification of a syndromic stationary congenital IRD has a major impact on the differential diagnosis of syndromic congenital IRD, which has previously been exclusively linked with degenerative IRD.
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http://dx.doi.org/10.1016/j.ajhg.2020.04.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273530PMC
June 2020

Genetic Deciphering of Early-Onset and Severe Retinal Dystrophy Associated with Sensorineural Hearing Loss.

Adv Exp Med Biol 2019 ;1185:233-238

Laboratory of Genetics in Ophthalmology, Imagine Institute, Paris Descartes, Sorbonne Paris Cité University, Paris, France.

The specific association of Leber congenital amaurosis (LCA) or early-onset severe retinal dystrophy (LCA-like) with sensorineural hearing loss (SHL) is uncommon. Recently, we ascribed some of these distinctive associations to dominant and de novo mutations in the β-tubulin 4B isotype-encoding gene (TUBB4B), providing a link between a sensorineural disease and anomalies in microtubules behavior. Here, we report 12 sporadic cases with LCA/SHL or LCA-like/SHL and no TUBB4B mutation. Trio-based whole exome sequencing (WES) identified disease-causing mutations in 5/12 cases. Four out of five carried biallelic mutations in PEX1 (1/4) or PEX6 (3/4), involved in peroxisome biogenesis disorders from Zellweger syndrome characterized by severe neurologic and neurosensory dysfunctions, craniofacial abnormalities, and liver dysfunction to Heimler syndrome associating SHL, enamel hypoplasia of the secondary dentition, nail abnormalities, and occasional retinal disease. Upon reexamination, the index case carrying PEX1 mutations, a 4-year-old girl, presented additional symptoms consistent with Zellweger syndrome. Reexamination of individuals with PEX6 mutations (1/3 unavailable) revealed normal nails but enamel hypoplasia affecting one primary teeth in a 4-year-old girl and severe enamel hypoplasia of primary teeth hidden by dental prosthesis in a 50-year-old male, describing a novel PEX6-associated disease of the Zellweger/Heimler spectrum. Finally, hemizygosity for a CACNA1F mutation was identified in an 18-year-old male addressed for LCA/SHL, redirecting the retinal diagnosis to congenital stationary night blindness (CSNB2A). Consistent with the pure CSNB2A retinal involvement, SHL was ascribed to biallelic mutations in another gene, STRC, involved in nonprogressive DFNB16 deafness.
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http://dx.doi.org/10.1007/978-3-030-27378-1_38DOI Listing
February 2020

Description of Two Siblings with Apparently Severe CEP290 Mutations and Unusually Mild Retinal Disease Unrelated to Basal Exon Skipping or Nonsense-Associated Altered Splicing.

Adv Exp Med Biol 2019 ;1185:189-195

Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetics Diseases, Imagine and Paris Descartes University, Paris, France.

CEP290 mutations cause a spectrum of ciliopathies, including Leber congenital amaurosis. Milder retinal diseases have been ascribed to exclusion of CEP290 mutant exons through basal exon skipping (BES) and/or nonsense-associated altered splicing (NAS). Here, we report two siblings with some preserved vision despite biallelism for presumably severe CEP290 mutations: a maternal splice site change in intron 18 (c.1824 + 3A > G) and a paternal c.6869dup (p.Asn2290Lysfs∗6) in exon 50 that introduces a premature termination codon (PTC) within the same exon. Analyzing mRNAs from fibroblasts of the two siblings, we detected no BES or NAS which could have enabled the production of PTC-free CEP290 isoforms from the paternal allele. In contrast, we reveal partial alteration of exon 18 donor splice site, allowing the transcription of some correctly spliced CEP290 mRNAs from the maternal allele which likely account for the mild retinal disease. This observation adds further variability to the mechanisms underlying CEP290 pleiotropy.
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http://dx.doi.org/10.1007/978-3-030-27378-1_31DOI Listing
February 2020

AON-Mediated Exon Skipping to Bypass Protein Truncation in Retinal Dystrophies Due to the Recurrent c.4723A > T Mutation. Fact or Fiction?

Genes (Basel) 2019 05 14;10(5). Epub 2019 May 14.

Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetics Diseases, Imagine and Paris Descartes University, 75015 Paris, France.

Mutations in encoding a centrosomal protein important to cilia formation cause a spectrum of diseases, from isolated retinal dystrophies to multivisceral and sometimes embryo-lethal ciliopathies. In recent years, endogenous and/or selective non-canonical exon skipping of mutant exons have been documented in attenuated retinal disease cases. This observation led us to consider targeted exon skipping to bypass protein truncation resulting from a recurrent mutation in exon 36 (c.4723A > T, p.Lys1575*) causing isolated retinal ciliopathy. Here, we report two unrelated individuals (P1 and P2), carrying the mutation in homozygosity but affected with early-onset severe retinal dystrophy and congenital blindness, respectively. Studying skin-derived fibroblasts, we observed basal skipping and nonsense associated-altered splicing of exon 36, producing low (P1) and very low (P2) levels of CEP290 products. Consistent with a more severe disease, fibroblasts from P2 exhibited reduced ciliation compared to P1 cells displaying normally abundant cilia; both lines presented however significantly elongated cilia, suggesting altered axonemal trafficking. Antisense oligonucleotides (AONs)-mediated skipping of exon 36 increased the abundance of the premature termination codon (PTC)-free mRNA and protein, reduced axonemal length and improved cilia formation in P2 but not in P1 expressing higher levels of skipped mRNA, questioning AON-mediated exon skipping to treat patients carrying the recurrent c.4723A > T mutation.
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http://dx.doi.org/10.3390/genes10050368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6562928PMC
May 2019

GENETICS OF LARGE PIGMENT EPITHELIAL DETACHMENTS IN NEOVASCULAR AGE-RELATED MACULAR DEGENERATION.

Retina 2020 Apr;40(4):663-671

Department of Ophthalmology, University Paris Est Creteil, Centre Hospitalier Intercommunal de Créteil, Créteil, France.

Purpose: We hypothesized that severe forms of neovascular age-related macular degeneration (AMD) such as large pigment epithelial detachments poorly responding to anti-vascular endothelial growth factor therapy might present a distinct genotype compared with overall series of neovascular AMD.

Methods: This is a multicenter genetic association study. Sixty-eight patients presenting pigment epithelial detachments resistant to ranibizumab (issued from ARI2 study, register number NCT02157077 on clinicaltrials.gov) were compared with two series of patients derived from previously published clinical studies, presenting neovascular AMD (NAT2 study n = 300 and PHRC study n = 1,127), and with healthy controls (n = 441). The phenotype of neovascular AMD groups was based on visual acuity measurement, fundus examination, spectral-domain optical coherence tomography, and angiographic data. All samples were genotyped for three single-nucleotide polymorphisms: CFH (rs1061170), ARMS2 (rs10490924), and C3 (rs2230199). Significant difference in allele frequency between participants with neovascular AMD and control was the main outcome measurement.

Results: The GG genotype of the C3 rs2230199 was significantly more frequent in the ARI2 group (55.9%) than the PHRC group (6.0%, P < 0.0001; odds ratio = 24.0 [95% confidence interval 10.4-55.0]) and the NAT2 group (5.1%, P < 0.0001; odds ratio = 16.1 [95% confidence interval 5.0-51.9]). The repartition of patients carrying a T allele of the ARMS2 (rs10490924) or patients carrying a C allele of the CFH (rs1061170) was similar in the ARI2 group when compared with the NAT2 and PHRC groups.

Conclusion: In our series, the genotype GG of C3 rs2230199 was more significantly associated with the phenotype of large vascularized pigment epithelial detachment poorly responding to anti-vascular endothelial growth factor therapy than in global AMD series.
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http://dx.doi.org/10.1097/IAE.0000000000002454DOI Listing
April 2020

DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients.

JIMD Rep 2019 17;44:85-92. Epub 2018 Aug 17.

Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.

Pathogenic mutations in DPAGT1 cause a rare type of a congenital disorder of glycosylation termed DPAGT1-CDG or, alternatively, a milder version with only myasthenia known as DPAGT1-CMS. Fourteen disease-causing mutations in 28 patients from 10 families have previously been reported to cause the systemic form, DPAGT1-CDG. We here report on another 11 patients from 8 families and add 10 new mutations. Most patients have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death. We also present data on three affected females that are young adults and have a somewhat milder, stable disease. Our findings expand both the molecular and clinical knowledge of previously published data but also widen the phenotypic spectrum of DPAGT1-CDG.
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http://dx.doi.org/10.1007/8904_2018_128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323016PMC
August 2018

Basal exon skipping and nonsense-associated altered splicing allows bypassing complete CEP290 loss-of-function in individuals with unusually mild retinal disease.

Hum Mol Genet 2018 08;27(15):2689-2702

Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetics Diseases.

CEP290 mutations cause a spectrum of ciliopathies from Leber congenital amaurosis type 10 (LCA10) to embryo-lethal Meckel syndrome (MKS). Using panel-based molecular diagnosis testing for inherited retinal diseases, we identified two individuals with some preserved vision despite biallelism for presumably truncating CEP290 mutations. The first one carried a homozygous 1 base pair deletion in Exon 17, introducing a premature termination codon (PTC) in Exon 18 (c.1666del; p.Ile556Phefs*17). mRNA analysis revealed a basal exon skipping (BES) of Exon 18, providing mutant cells with the ability to escape protein truncation, while disrupting the reading frame in controls. The second individual harbored compound heterozygous nonsense mutations in Exon 8 (c.508A>T, p.Lys170*) and Exon 32 (c.4090G>T, p.Glu1364*), respectively. Some CEP290 lacking Exon 8 were detected in mutant fibroblasts but not in controls whereas some skipping of Exon 32 occurred in both lines, but with higher amplitude in the mutant. Considering that the deletion of either exon maintains the reading frame in either line, skipping in mutant cells likely involves nonsense-associated altered splicing alone (Exon 8), or with BES (Exon 32). Skipping of PTC-containing exons in mutant cells allowed production of CEP290 isoforms with preserved ability to assemble into a high molecular weight complex and to interact efficiently with proteins important for cilia formation and intraflagellar trafficking. In contrast, studying LCA10 and MKS fibroblasts we show moderate to severe cilia alterations, providing support for a correlation between disease severity and the ability of cells to express shortened, yet functional, CEP290 isoforms.
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http://dx.doi.org/10.1093/hmg/ddy179DOI Listing
August 2018

Whole-genome sequencing in patients with ciliopathies uncovers a novel recurrent tandem duplication in IFT140.

Hum Mutat 2018 07 8;39(7):983-992. Epub 2018 May 8.

Laboratoire de Génétique médicale, UMR_S INSERM U1112, IGMA, Faculté de Médecine FMTS, Université de Strasbourg, Strasbourg, France.

Ciliopathies represent a wide spectrum of rare diseases with overlapping phenotypes and a high genetic heterogeneity. Among those, IFT140 is implicated in a variety of phenotypes ranging from isolated retinis pigmentosa to more syndromic cases. Using whole-genome sequencing in patients with uncharacterized ciliopathies, we identified a novel recurrent tandem duplication of exon 27-30 (6.7 kb) in IFT140, c.3454-488_4182+2588dup p.(Tyr1152_Thr1394dup), missed by whole-exome sequencing. Pathogenicity of the mutation was assessed on the patients' skin fibroblasts. Several hundreds of patients with a ciliopathy phenotype were screened and biallelic mutations were identified in 11 families representing 12 pathogenic variants of which seven are novel. Among those unrelated families especially with a Mainzer-Saldino syndrome, eight carried the same tandem duplication (two at the homozygous state and six at the heterozygous state). In conclusion, we demonstrated the implication of structural variations in IFT140-related diseases expanding its mutation spectrum. We also provide evidences for a unique genomic event mediated by an Alu-Alu recombination occurring on a shared haplotype. We confirm that whole-genome sequencing can be instrumental in the ability to detect structural variants for genomic disorders.
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http://dx.doi.org/10.1002/humu.23539DOI Listing
July 2018

Mutations in TUBB4B Cause a Distinctive Sensorineural Disease.

Am J Hum Genet 2017 Dec 30;101(6):1006-1012. Epub 2017 Nov 30.

Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine and Paris Descartes University, 75015 Paris, France.

Leber congenital amaurosis (LCA) is a neurodegenerative disease of photoreceptor cells that causes blindness within the first year of life. It occasionally occurs in syndromic metabolic diseases and plurisystemic ciliopathies. Using exome sequencing in a multiplex family and three simplex case subjects with an atypical association of LCA with early-onset hearing loss, we identified two heterozygous mutations affecting Arg391 in β-tubulin 4B isotype-encoding (TUBB4B). Inspection of the atomic structure of the microtubule (MT) protofilament reveals that the β-tubulin Arg391 residue contributes to a binding pocket that interacts with α-tubulin contained in the longitudinally adjacent αβ-heterodimer, consistent with a role in maintaining MT stability. Functional analysis in cultured cells overexpressing FLAG-tagged wild-type or mutant TUBB4B as well as in primary skin-derived fibroblasts showed that the mutant TUBB4B is able to fold, form αβ-heterodimers, and co-assemble into the endogenous MT lattice. However, the dynamics of growing MTs were consistently altered, showing that the mutations have a significant dampening impact on normal MT growth. Our findings provide a link between sensorineural disease and anomalies in MT behavior and describe a syndromic LCA unrelated to ciliary dysfunction.
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http://dx.doi.org/10.1016/j.ajhg.2017.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812887PMC
December 2017

Neurologic Phenotypes Associated With Mutations in RTN4IP1 (OPA10) in Children and Young Adults.

JAMA Neurol 2018 01;75(1):105-113

MitoLab Team, Unités Mixtes de Recherche Centre National de la Recherche Scientifique 6015-INSERM U1083, Institut MitoVasc, Angers University and Hospital, Angers, France.

Importance: Neurologic disorders with isolated symptoms or complex syndromes are relatively frequent among mitochondrial inherited diseases. Recessive RTN4IP1 gene mutations have been shown to cause isolated and syndromic optic neuropathies.

Objective: To define the spectrum of clinical phenotypes associated with mutations in RTN4IP1 encoding a mitochondrial quinone oxidoreductase.

Design, Setting, And Participants: This study involved 12 individuals from 11 families with severe central nervous system diseases and optic atrophy. Targeted and whole-exome sequencing were performed-at Hospital Angers (France), Institute of Neurology Milan (Italy), Imagine Institute Paris (France), Helmoltz Zentrum of Munich (Germany), and Beijing Genomics Institute (China)-to clarify the molecular diagnosis of patients. Each patient's neurologic, ophthalmologic, magnetic resonance imaging, and biochemical features were investigated. This study was conducted from May 1, 2014, to June 30, 2016.

Main Outcomes And Measures: Recessive mutations in RTN4IP1 were identified. Clinical presentations ranged from isolated optic atrophy to severe encephalopathies.

Results: Of the 12 individuals in the study, 6 (50%) were male and 6 (50%) were female. They ranged in age from 5 months to 32 years. Of the 11 families, 6 (5 of whom were consanguineous) had a member or members who presented isolated optic atrophy with the already reported p.Arg103His or the novel p.Ile362Phe, p.Met43Ile, and p.Tyr51Cys amino acid changes. The 5 other families had a member or members who presented severe neurologic syndromes with a common core of symptoms, including optic atrophy, seizure, intellectual disability, growth retardation, and elevated lactate levels. Additional clinical features of those affected were deafness, abnormalities on magnetic resonance images of the brain, stridor, and abnormal electroencephalographic patterns, all of which eventually led to death before age 3 years. In these patients, novel and very rare homozygous and compound heterozygous mutations were identified that led to the absence of the protein and complex I disassembly as well as mild mitochondrial network fragmentation.

Conclusions And Relevance: A broad clinical spectrum of neurologic features, ranging from isolated optic atrophy to severe early-onset encephalopathies, is associated with RTN4IP1 biallelic mutations and should prompt RTN4IP1 screening in both syndromic neurologic presentations and nonsyndromic recessive optic neuropathies.
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http://dx.doi.org/10.1001/jamaneurol.2017.2065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5833489PMC
January 2018

Mutations in DNM1L, as in OPA1, result in dominant optic atrophy despite opposite effects on mitochondrial fusion and fission.

Brain 2017 10;140(10):2586-2596

MitoLab, Mitochondrial Medicine Research Centre, UMR CNRS 6015-INSERM 1083, Institut MitoVasc, University of Angers, 49933 Angers, France.

Dominant optic atrophy is a blinding disease due to the degeneration of the retinal ganglion cells, the axons of which form the optic nerves. In most cases, the disease is caused by mutations in OPA1, a gene encoding a mitochondrial large GTPase involved in cristae structure and mitochondrial network fusion. Using exome sequencing, we identified dominant mutations in DNM1L on chromosome 12p11.21 in three large families with isolated optic atrophy, including the two families that defined the OPA5 locus on chromosome 19q12.1-13.1, the existence of which is denied by the present study. Analyses of patient fibroblasts revealed physiological abundance and homo-polymerization of DNM1L, forming aggregates in the cytoplasm and on highly tubulated mitochondrial network, whereas neither structural difference of the peroxisome network, nor alteration of the respiratory machinery was noticed. Fluorescence microscopy of wild-type mouse retina disclosed a strong DNM1L expression in the ganglion cell layer and axons, and comparison between 3-month-old wild-type and Dnm1l+/- mice revealed increased mitochondrial length in retinal ganglion cell soma and axon, but no degeneration. Thus, our results disclose that in addition to OPA1, OPA3, MFN2, AFG3L2 and SPG7, dominant mutations in DNM1L jeopardize the integrity of the optic nerve, suggesting that alterations of the opposing forces governing mitochondrial fusion and fission, similarly affect retinal ganglion cell survival.
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http://dx.doi.org/10.1093/brain/awx219DOI Listing
October 2017

RETINOCHOROIDAL ANASTOMOSIS ASSOCIATED WITH ENHANCED S-CONE SYNDROME.

Retin Cases Brief Rep 2019 ;13(4):295-299

Department of Ophthalmology, Hopital Intercommunal de Creteil, University Paris Est, Creteil, France.

Purpose: To describe the phenotype and genotype of a 10-year-old boy affected with enhanced S-cone syndrome associated with neovascularization.

Methods: Fundus autofluorescence, fluorescein angiography, indocyanine green angiography, spectral domain optical coherence tomography, full-field electroretinogram and NR2E3 molecular testing were performed.

Results: Best-corrected visual acuity was measured as 20/32, right eye and 20/20, left eye. Fluorescein and indocyanine green angiographies showed unilateral macular retinochoroidal anastomosis on his right eye, and spectral domain optical coherence tomography showed typical signs of subretinal exudation and foveolar pseudoschisis consistent with the diagnosis of enhanced S-cone syndrome. Genetic analysis revealed biparental transmission of mutations in the enhanced S-cone syndrome-causing gene, NR2E3, namely, c.194_202del (p.Asn65_Cys67del), and c.932 G>A (p.Arg311Gln), supporting an autosomal recessive inheritance. The patient received three intravitreal injections of anti-VEGF agents.

Conclusion: Evidence of retinochoroidal anastomosis in an individual affected with enhanced S-cone syndrome supports the view that neovascularization can occur early in the course of the disease, and raises the question to know whether it might be responsible for previously described enhanced S-cone syndrome-associated hemorrhage-induced fibrosis.
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http://dx.doi.org/10.1097/ICB.0000000000000594DOI Listing
March 2020

Compound heterozygosity for severe and hypomorphic mutations cause non-syndromic LHON-like optic neuropathy.

J Med Genet 2017 05 28;54(5):346-356. Epub 2016 Dec 28.

Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Institute of Genetic Diseases, Imagine, Paris Descartes University, Paris, France.

Background: Non-syndromic hereditary optic neuropathy (HON) has been ascribed to mutations in mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial DNA-encoded respiratory enzyme genes or nuclear genes of poorly known mitochondrial function. However, the disease causing gene remains unknown in many families. The objective of the present study was to identify the molecular cause of non-syndromic LHON-like disease in siblings born to non-consanguineous parents of French origin.

Methods: We used a combination of genetic analysis (gene mapping and whole-exome sequencing) in a multiplex family of non-syndromic HON and of functional analyses in patient-derived cultured skin fibroblasts and the yeast .

Results: We identified compound heterozygote disease-causing mutations (p.Tyr53Cys; p.Tyr308Cys). Studies using patient-derived cultured skin fibroblasts revealed mildly decreased NDUFS2 and complex I abundance but apparently normal respiratory chain activity. In the yeast ortholog , the mutations resulted in absence of complex I and moderate reduction in nicotinamide adenine dinucleotide-ubiquinone oxidoreductase activity, respectively.

Conclusions: Biallelism for mutations causing severe complex I deficiency has been previously reported to cause Leigh syndrome with optic neuropathy. Our results are consistent with the view that compound heterozygosity for severe and hypomorphic mutations can cause non-syndromic HON. This observation suggests a direct correlation between the severity of mutations and that of the disease and further support that there exist a genetic overlap between non-syndromic and syndromic HON due to defective mitochondrial function.
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http://dx.doi.org/10.1136/jmedgenet-2016-104212DOI Listing
May 2017

Recessive and Dominant De Novo ITPR1 Mutations Cause Gillespie Syndrome.

Am J Hum Genet 2016 May 21;98(5):971-980. Epub 2016 Apr 21.

Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, Imagine - Institute of Genetic Diseases, Paris Descartes University, 75015 Paris, France.

Gillespie syndrome (GS) is a rare variant form of aniridia characterized by non-progressive cerebellar ataxia, intellectual disability, and iris hypoplasia. Unlike the more common dominant and sporadic forms of aniridia, there has been no significant association with PAX6 mutations in individuals with GS and the mode of inheritance of the disease had long been regarded as uncertain. Using a combination of trio-based whole-exome sequencing and Sanger sequencing in five simplex GS-affected families, we found homozygous or compound heterozygous truncating mutations (c.4672C>T [p.Gln1558(∗)], c.2182C>T [p.Arg728(∗)], c.6366+3A>T [p.Gly2102Valfs5(∗)], and c.6664+5G>T [p.Ala2221Valfs23(∗)]) and de novo heterozygous mutations (c.7687_7689del [p.Lys2563del] and c.7659T>G [p.Phe2553Leu]) in the inositol 1,4,5-trisphosphate receptor type 1 gene (ITPR1). ITPR1 encodes one of the three members of the IP3-receptors family that form Ca(2+) release channels localized predominantly in membranes of endoplasmic reticulum Ca(2+) stores. The truncation mutants, which encompass the IP3-binding domain and varying lengths of the modulatory domain, did not form functional channels when produced in a heterologous cell system. Furthermore, ITPR1 p.Lys2563del mutant did not form IP3-induced Ca(2+) channels but exerted a negative effect when co-produced with wild-type ITPR1 channel activity. In total, these results demonstrate biallelic and monoallelic ITPR1 mutations as the underlying genetic defects for Gillespie syndrome, further extending the spectrum of ITPR1-related diseases.
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http://dx.doi.org/10.1016/j.ajhg.2016.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4863566PMC
May 2016

Nonsyndromic Retinal Dystrophy due to Bi-Allelic Mutations in the Ciliary Transport Gene IFT140.

Invest Ophthalmol Vis Sci 2016 Mar;57(3):1053-62

University College London Institute of Ophthalmology, London, United Kingdom 2Moorfields Eye Hospital, London, United Kingdom 12Ophthalmology, University of California, San Francisco, California, United States.

Purpose: Mutations in the ciliary transporter gene IFT140, usually associated with a severe syndromic ciliopathy, may also cause isolated retinal dystrophy. A series of patients with nonsyndromic retinitis pigmentosa (RP) due to IFT140 was investigated in this study.

Methods: Five probands and available affected family members underwent detailed phenotyping including retinal imaging and electrophysiology. Whole exome sequencing was performed on two probands, a targeted sequencing panel of 176 retinal genes on a further two, and whole genome sequencing on the fifth. Missense mutations of IFT140 were further investigated in vitro using transient plasmid transfection of hTERT-RPE1 cells.

Results: Eight affected patients from five families had preserved visual acuity until at least the second decade; all had normal development without skeletal manifestations or renal failure at age 13 to 67 years (mean, 42 years; median, 44.5 years). Bi-allelic mutations in IFT140 were identified in all families including two novel mutations: c.2815T > C (p.Ser939Pro) and c.1422_23insAA (p.Arg475Asnfs*14). Expression studies demonstrated a significantly reduced number of cells showing localization of mutant IFT140 with the basal body for two nonsyndromic mutations and two syndromic mutations compared with the wild type and a polymorphism.

Conclusions: This study highlights the phenotype of nonsyndromic RP due to mutations in IFT140 with milder retinal dystrophy than that associated with the syndromic disease.
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http://dx.doi.org/10.1167/iovs.15-17976DOI Listing
March 2016

Incomplete penetrance of biallelic ALDH1A3 mutations.

Eur J Med Genet 2016 Apr 10;59(4):215-8. Epub 2016 Feb 10.

Genetics Department, Purpan University Hospital, France; UDEAR, UMR 1056 Inserm - Université de Toulouse, FRE 3742 CNRS, Toulouse, France. Electronic address:

The formation of a properly shaped eye is a complex developmental event that requires the coordination of many induction processes and differentiation pathways. Microphthalmia and anophthalmia (MA) represent the most severe defects that can affect the ocular globe during embryonic development. When genetic, these ocular disorders exhibit large genetic heterogeneity and extreme variable expressivity. Around 20 monogenic diseases are known to be associated with MA as main phenotype and the penetrance of mutations is usually full in the patients. Some of these genes encode proteins involved in the vitamin A pathway, tightly regulated during eye development. One of those retinoic acid synthesis genes is ALDH1A3 and biallelic mutations in that gene have been recently found to lead to MA phenotype in patients. Interestingly, we report here the lack of ocular defect in a girl carrying the same homozygous mutation in the ALDH1A3 gene than the affected members of her family. Thus, this report brings new information for the phenotype-genotype correlation of ALDH1A3 mutations and raises important questions, especially in terms of genetic counselling given to the patients and their families. Furthermore, these data contribute to the more general understanding that we have for the complex genetic inheritance of these MA phenotypes.
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http://dx.doi.org/10.1016/j.ejmg.2016.02.004DOI Listing
April 2016

Recessive Mutations in RTN4IP1 Cause Isolated and Syndromic Optic Neuropathies.

Am J Hum Genet 2015 Nov 22;97(5):754-60. Epub 2015 Oct 22.

INSERM U1051, Institut des Neurosciences de Montpellier, Université de Montpellier, 34090 Montpellier, France; INSERM U1083, CNRS 6214, Département de Biochimie et Génétique, Université LUNAM and Centre Hospitalier Universitaire, 49933 Angers, France. Electronic address:

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 in vitro and the eye size, neuro-retinal development, and swimming behavior in zebrafish in vivo. 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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http://dx.doi.org/10.1016/j.ajhg.2015.09.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667133PMC
November 2015

Antisense Oligonucleotide Therapy for Inherited Retinal Dystrophies.

Adv Exp Med Biol 2016 ;854:517-24

Department of Human Genetics (855), Radboud Institute for Molecular Life Sciences Radboud University Medical Center, Geert Grooteplein 10, 6525, Nijmegen, GA, The Netherlands.

Inherited retinal dystrophies (IRDs) are an extremely heterogeneous group of genetic diseases for which currently no effective treatment strategies exist. Over the last decade, significant progress has been made utilizing gene augmentation therapy for a few genetic subtypes of IRD, although several technical challenges so far prevent a broad clinical application of this approach for other forms of IRD. Many of the mutations leading to these retinal diseases affect pre-mRNA splicing of the mutated genes . Antisense oligonucleotide (AON)-mediated splice modulation appears to be a powerful approach to correct the consequences of such mutations at the pre-mRNA level , as demonstrated by promising results in clinical trials for several inherited disorders like Duchenne muscular dystrophy, hypercholesterolemia and various types of cancer. In this mini-review, we summarize ongoing pre-clinical research on AON-based therapy for a few genetic subtypes of IRD , speculate on other potential therapeutic targets, and discuss the opportunities and challenges that lie ahead to translate splice modulation therapy for retinal disorders to the clinic.
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http://dx.doi.org/10.1007/978-3-319-17121-0_69DOI Listing
April 2016

Intravitreal Injection of Splice-switching Oligonucleotides to Manipulate Splicing in Retinal Cells.

Mol Ther Nucleic Acids 2015 Sep 1;4:e250. Epub 2015 Sep 1.

Laboratory of Genetics in Ophthalmology, Inserm UMR1163, Institut Imagine, Université Paris Descartes Sorbonne Paris Cité, Hôpital Necker, Paris, France.

Leber congenital amaurosis is a severe hereditary retinal dystrophy responsible for neonatal blindness. The most common disease-causing mutation (c.2991+1655A>G; 10-15%) creates a strong splice donor site that leads to insertion of a cryptic exon encoding a premature stop codon. Recently, we reported that splice-switching oligonucleotides (SSO) allow skipping of the mutant cryptic exon and the restoration of ciliation in fibroblasts of affected patients, supporting the feasibility of a SSO-mediated exon skipping strategy to correct the aberrant splicing. Here, we present data in the wild-type mouse, which demonstrate that intravitreal administration of 2'-OMePS-SSO allows selective alteration of Cep290 splicing in retinal cells, including photoreceptors as shown by successful alteration of Abca4 splicing using the same approach. We show that both SSOs and Cep290 skipped mRNA were detectable for at least 1 month and that intravitreal administration of oligonucleotides did not provoke any serious adverse event. These data suggest that intravitreal injections of SSO should be considered to bypass protein truncation resulting from the c.2991+1655A>G mutation as well as other truncating mutations in genes which like CEP290 or ABCA4 have a mRNA size that exceed cargo capacities of US Food and Drug Administration (FDA)-approved adeno-associated virus (AAV)-vectors, thus hampering gene augmentation therapy.
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http://dx.doi.org/10.1038/mtna.2015.24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4877449PMC
September 2015

IFT81, encoding an IFT-B core protein, as a very rare cause of a ciliopathy phenotype.

J Med Genet 2015 Oct 14;52(10):657-65. Epub 2015 Aug 14.

Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA Howard Hughes Medical Institute, Chevy Chase, Maryland, USA.

Background: Bidirectional intraflagellar transport (IFT) consists of two major protein complexes, IFT-A and IFT-B. In contrast to the IFT-B complex, all components of IFT-A have recently been linked to human ciliopathies when defective. We therefore hypothesised that mutations in additional IFT-B encoding genes can be found in patients with multisystemic ciliopathies.

Methods: We screened 1628 individuals with reno-ocular ciliopathies by targeted next-generation sequencing of ciliary candidate genes, including all IFT-B encoding genes.

Results: Consequently, we identified a homozygous mutation in IFT81 affecting an obligatory donor splice site in an individual with nephronophthisis and polydactyly. Further, we detected a loss-of-stop mutation with extension of the deduced protein by 10 amino acids in an individual with neuronal ceroid lipofuscinosis-1. This proband presented with retinal dystrophy and brain lesions including cerebellar atrophy, a phenotype to which the IFT81 variant might contribute. Cultured fibroblasts of this latter affected individual showed a significant decrease in ciliated cell abundance compared with controls and increased expression of the transcription factor GLI2 suggesting deranged sonic hedgehog signalling.

Conclusions: This work describes identification of mutations of IFT81 in individuals with symptoms consistent with the clinical spectrum of ciliopathies. It might represent the rare case of a core IFT-B complex protein found associated with human disease. Our data further suggest that defects in the IFT-B core are an exceedingly rare finding, probably due to its indispensable role for ciliary assembly in development.
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http://dx.doi.org/10.1136/jmedgenet-2014-102838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4621372PMC
October 2015

Understanding disease pleiotropy: From puzzle to solution.

Sci Transl Med 2015 Jun;7(291):291fs24

Laboratory of Genetics in Ophthalmology, INSERM UMR1163, Institute of Genetic Diseases, 75015 Paris, France. Paris Descartes University-Sorbonne Paris Cité, 75015 Paris, France.

The total amount of functional mutant protein produced by cells underpins disease pleiotropy in the ciliopathies.
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http://dx.doi.org/10.1126/scitranslmed.aac6504DOI Listing
June 2015

Submicroscopic deletions at 13q32.1 cause congenital microcoria.

Am J Hum Genet 2015 Apr 12;96(4):631-9. Epub 2015 Mar 12.

Laboratory of Genetics in Ophthalmology (LGO), INSERM UMR1163, IMAGINE - Institute of Genetic Diseases, Paris Descartes University, 75015 Paris, France. Electronic address:

Congenital microcoria (MCOR) is a rare autosomal-dominant disorder characterized by inability of the iris to dilate owing to absence of dilator pupillae muscle. So far, a dozen MCOR-affected families have been reported worldwide. By using whole-genome oligonucleotide array CGH, we have identified deletions at 13q32.1 segregating with MCOR in six families originating from France, Japan, and Mexico. Breakpoint sequence analyses showed nonrecurrent deletions in 5/6 families. The deletions varied from 35 kbp to 80 kbp in size, but invariably encompassed or interrupted only two genes: TGDS encoding the TDP-glucose 4,6-dehydratase and GPR180 encoding the G protein-coupled receptor 180, also known as intimal thickness-related receptor (ITR). Unlike TGDS which has no known function in muscle cells, GPR180 is involved in the regulation of smooth muscle cell growth. The identification of a null GPR180 mutation segregating over two generations with iridocorneal angle dysgenesis, which can be regarded as a MCOR endophenotype, is consistent with the view that deletions of this gene, with or without the loss of elements regulating the expression of neighboring genes, are the cause of MCOR.
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http://dx.doi.org/10.1016/j.ajhg.2015.01.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385178PMC
April 2015

Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy.

J Med Genet 2014 Dec 28;51(12):834-8. Epub 2014 Oct 28.

UMR1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France.

Background: Inherited optic neuropathy has been ascribed to mutations in mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial DNA-encoded respiratory enzyme genes or nuclear genes of poorly known mitochondrial function. However, the disease causing gene remains unknown in many families.

Methods: We used exome sequencing in order to identify the gene responsible for isolated or syndromic optic atrophy in five patients from three independent families.

Results: We found homozygous or compound heterozygous missense and frameshift mutations in the gene encoding mitochondrial aconitase (ACO2), a tricarboxylic acid cycle enzyme, catalysing interconversion of citrate into isocitrate. Unlike wild type ACO2, all mutant ACO2 proteins failed to complement the respiratory growth of a yeast aco1-deletion strain. Retrospective studies using patient-derived cultured skin fibroblasts revealed various degrees of deficiency in ACO2 activity, but also in ACO1 cytosolic activity.

Conclusions: Our study shows that autosomal recessive ACO2 mutations can cause either isolated or syndromic optic neuropathy. This observation identifies ACO2 as the second gene responsible for non-syndromic autosomal recessive optic neuropathies and provides evidence for a genetic overlap between isolated and syndromic forms, giving further support to the view that optic atrophy is a hallmark of defective mitochondrial energy supply.
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http://dx.doi.org/10.1136/jmedgenet-2014-102532DOI Listing
December 2014

Mutations in DOCK7 in individuals with epileptic encephalopathy and cortical blindness.

Am J Hum Genet 2014 Jun 8;94(6):891-7. Epub 2014 May 8.

Centre Hospitalier Universitaire Sainte-Justine Research Center, Montreal H3T 1C5, Canada. Electronic address:

Epileptic encephalopathies are increasingly thought to be of genetic origin, although the exact etiology remains uncertain in many cases. We describe here three girls from two nonconsanguineous families affected by a clinical entity characterized by dysmorphic features, early-onset intractable epilepsy, intellectual disability, and cortical blindness. In individuals from each family, brain imaging also showed specific changes, including an abnormally marked pontobulbar sulcus and abnormal signals (T2 hyperintensities) and atrophy in the occipital lobe. Exome sequencing performed in the first family did not reveal any gene with rare homozygous variants shared by both affected siblings. It did, however, show one gene, DOCK7, with two rare heterozygous variants (c.2510delA [p.Asp837Alafs(∗)48] and c.3709C>T [p.Arg1237(∗)]) found in both affected sisters. Exome sequencing performed in the proband of the second family also showed the presence of two rare heterozygous variants (c.983C>G [p.Ser328(∗)] and c.6232G>T [p.Glu2078(∗)]) in DOCK7. Sanger sequencing confirmed that all three individuals are compound heterozygotes for these truncating mutations in DOCK7. These mutations have not been observed in public SNP databases and are predicted to abolish domains critical for DOCK7 function. DOCK7 codes for a Rac guanine nucleotide exchange factor that has been implicated in the genesis and polarization of newborn pyramidal neurons and in the morphological differentiation of GABAergic interneurons in the developing cortex. All together, these observations suggest that loss of DOCK7 function causes a syndromic form of epileptic encephalopathy by affecting multiple neuronal processes.
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http://dx.doi.org/10.1016/j.ajhg.2014.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4121477PMC
June 2014

Multimodal analysis of the progression of Best vitelliform macular dystrophy.

Mol Vis 2014 27;20:575-92. Epub 2014 Apr 27.

Department of Ophthalmology, Hopital Intercommunal de Creteil, University Paris Est Creteil, France.

Purpose: To investigate the multimodal morphological features in the different stages of Best vitelliform macular dystrophy (VMD) in subjects harboring mutations in the BEST1 gene, and their changes during the progression of the disease.

Methods: In this retrospective observational study performed between January 2007 and December 2012, 21 patients (42 eyes) with Best VMD from eight families with the BEST1 mutation were included. Best-corrected visual acuity (BCVA), fundus autofluorescence (FAF), and spectral domain optical coherence tomography (SDOCT) were evaluated at study entry and at last visit.

Results: The mean age of patients was 26.3±17.4 years. Seven new missense mutations in BEST1 were identified. Mean follow-up was 41.1±18.5 months. Mean BCVA was 0.34±0.34 LogMAR at study entry and 0.32±0.33 LogMAR at last follow-up visit (p = 0.2). The overall lesion area on FAF increased from 6.62±4.9 mm² to 7.34±6.1 mm² (p = 0.05). At study entry, on SD-OCT, photoreceptor inner segment ellipsoid portion (ellipsoid zone, EZ) was normal in 15 eyes, disrupted in 14 eyes, and absent in 13 eyes. In two eyes, EZ changed from normal to disrupted during follow-up. Three eyes of three patients showing pseudohypopyon lesions at study entry progressed to vitelliruptive lesions at the last follow-up visit. Three eyes of three patients showing vitelliruptive lesion at study entry reverted to pseudohypopyon lesion with overall enlargement of the lesion size.

Conclusions: Multimodal analysis allowed documenting a continuous material accumulation and reabsorption in Best VMD progression. Blue FAF and SD-OCT could represent noninvasive imaging techniques to monitor Best VMD.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000718PMC
September 2014

Genetic association study of mitochondrial polymorphisms in neovascular age-related macular degeneration.

Mol Vis 2013 29;19:1132-40. Epub 2013 May 29.

Department of Ophthalmology, Hôpital Intercommunal de Creteil, University of Paris Est Creteil, France.

Purpose: Age-related macular degeneration (AMD) is a multifactorial disease involving genetic and environmental factors. Most of the genetic factors identified so far involve the nuclear genome. Recently, two studies in North America and Australia reported an association between advanced AMD and the mitochondrial T2 haplogroup. Our purpose was to assess this association in a large French population.

Methods: This case control study included 1,224 patients with neovascular AMD and 559 controls with normal fundus. Mitochondrial DNA polymorphisms at and around nucleotides 4917, 11,812, and 14,233 were determined using PCR amplification and direct sequencing of mitochondrial DNA.

Results: No association was found between the mitochondrial T2 haplogroup and neovascular AMD in the French population: 94/1,152 patients with neovascular AMD had the T2 haplogroup (8.2%) versus 34/482 controls (7.1%; odds ratio=0.9 [0.5-1.5], p=0.66).

Conclusions: An association between AMD and the T2 haplogroup, previously described in North American and Australian populations, was not confirmed in a large French population.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3669531PMC
September 2013

TMEM126A is a mitochondrial located mRNA (MLR) protein of the mitochondrial inner membrane.

Biochim Biophys Acta 2013 Jun 13;1830(6):3719-33. Epub 2013 Mar 13.

Départment de Génétique, Fondation Imagine, Université Paris Descartes-Sorbonne Paris Cité, Paris, France.

Background: Hereditary optic neuropathies (HONs) are a heterogeneous group of disorders that affect retinal ganglion cells (RGCs) and axons that form the optic nerve. Leber's Hereditary Optic Neuropathy and the autosomal dominant optic atrophy related to OPA1 mutations are the most common forms. Nonsyndromic autosomal recessive optic neuropathies are rare and their existence has been long debated. We recently identified the first gene responsible for these conditions, TMEM126A. This gene is highly expressed in retinal cellular compartments enriched in mitochondria and supposed to encode a mitochondrial transmembrane protein of unknown function.

Methods: A specific polyclonal antibody targeting the TMEM126A protein has been generated. Quantitative fluorescent in situ hybridization, cellular fractionation, mitochondrial membrane association study, mitochondrial sub compartmentalization analysis by both proteolysis assays and transmission electron microscopy, and expression analysis of truncated TMEM126A constructs by immunofluorescence confocal microscopy were carried out.

Results: TMEM126A mRNAs are strongly enriched in the vicinity of mitochondria and encode an inner mitochondrial membrane associated cristae protein. Moreover, the second transmembrane domain of TMEM126A is required for its mitochondrial localization.

Conclusions: TMEM126A is a mitochondrial located mRNA (MLR) that may be translated in the mitochondrial surface and the protein is subsequently imported to the inner membrane. These data constitute the first step toward a better understanding of the mechanism of action of TMEM126A in RGCs and support the importance of mitochondrial dysfunction in the pathogenesis of HON.

General Significance: Local translation of nuclearly encoded mitochondrial mRNAs might be a mechanism for rapid onsite supply of mitochondrial membrane proteins.
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http://dx.doi.org/10.1016/j.bbagen.2013.02.025DOI Listing
June 2013