Publications by authors named "Christel Condroyer"

40 Publications

A New Mouse Model for Complete Congenital Stationary Night Blindness Due to Deficiency.

Int J Mol Sci 2021 Apr 23;22(9). Epub 2021 Apr 23.

Institut de la Vision, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Sorbonne Université, F-75012 Paris, France.

Mutations in lead to autosomal recessive complete congenital stationary night blindness (cCSNB). This condition represents a signal transmission defect from the photoreceptors to the ON-bipolar cells. To confirm the phenotype, better understand the pathogenic mechanism in vivo, and provide a model for therapeutic approaches, a knock-out mouse model was genetically and functionally characterized. We confirmed that the insertion of a neo/lac Z cassette in intron 1 of disrupts the same gene. Spectral domain optical coherence tomography reveals no obvious retinal structure abnormalities. knock-out mice exhibit a so-called no-b-wave () phenotype with severely reduced b-wave amplitudes in the electroretinogram. Optomotor tests reveal decreased optomotor responses under scotopic conditions. Consistent with the genetic disruption of , GPR179 is absent at the dendritic tips of ON-bipolar cells. While proteins of the same signal transmission cascade (GRM6, LRIT3, and TRPM1) are correctly localized, other proteins (RGS7, RGS11, and GNB5) known to regulate GRM6 are absent at the dendritic tips of ON-bipolar cells. These results add a new model of cCSNB, which is important to better understand the role of GPR179, its implication in patients with cCSNB, and its use for the development of therapies.
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http://dx.doi.org/10.3390/ijms22094424DOI Listing
April 2021

CNGB1-related rod-cone dystrophy: a mutation review and update.

Hum Mutat 2021 Apr 12. Epub 2021 Apr 12.

Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Institut de la Vision, Paris, France.

CNGB1 (Cyclic nucleotide-gated channel β 1) encodes the 240-kDa β subunit of the rod photoreceptor cyclic nucleotide-gated ion channel. Disease-causing sequence variants in CNGB1 lead to autosomal recessive rod-cone dystrophy/retinitis pigmentosa (RP). We herein present a comprehensive review and analysis of all previously reported CNGB1 sequence variants, and add 22 novel variants, thereby enlarging the spectrum to 84 variants in total, including 24 missense variants (two of which may also affect splicing), 21 nonsense, 19 splicing defects (7 at non-canonical positions), 10 small deletions, 1 small insertion, 1 small insertion-deletion, 7 small duplications and 1 gross deletion. According to the ACMG classification criteria, 59 variants were considered pathogenic or likely pathogenic and 25 were variants of uncertain significance. In addition, we provide further phenotypic data from 34 CNGB1-related RP cases which, overall, are in line with previous findings suggesting that this form of RP has a long-term retention of useful central vision despite the early onset of night blindness, which is valuable for patient counseling, but also has implications for it being considered a priority target for gene therapy trials. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/humu.24205DOI Listing
April 2021

Near-infrared fundus autofluorescence alterations correlate with swept-source optical coherence tomography angiography findings in patients with retinitis pigmentosa.

Sci Rep 2021 Feb 4;11(1):3180. Epub 2021 Feb 4.

Sorbonne Université, INSERM, CNRS, Institut de la Vision, 17 rue Moreau, 75012, Paris, France.

Thirty-eight patients from 37 families with retinitis pigmentosa (RP) underwent macular 6 × 6-mm swept-source optical coherence tomography angiography (SS-OCTA) and 30° near-infrared fundus autofluorescence (NIR-FAF) acquisitions in one eye. Superficial vascular complex (SVC), deep capillary complex (DCC) and choriocapillaris (CC) angiograms were registered with NIR-FAF acquisitions to comparatively assess subjects with and without central area of preserved NIR-FAF (APA). On the subset of patients showing an APA, the vessel densities for SVC and DCC and flow deficits for CC were assessed in three directions (superior, inferior and temporal) from the fovea and compared to healthy 1:1 age-matched controls. Nine patients with no APA had evidence of severe central OCTA alterations at all levels, especially in the DCC. In the other 29 subjects presenting APA, all OCTA parameters were similar to healthy eyes within the APA, where the retina preserves its structural integrity. Outside the APA, both the DCC and CC were significantly reduced in all directions. These alterations are probably related to the outer retinal atrophy outside the APA. Comparing OCTA to other imaging modalities is helpful to determine the potential interest of OCTA findings as an outcome measure for disease status and progression.
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http://dx.doi.org/10.1038/s41598-021-82757-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7862375PMC
February 2021

CHM mutation spectrum and disease: An update at the time of human therapeutic trials.

Hum Mutat 2021 Apr 19;42(4):323-341. Epub 2021 Feb 19.

Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France.

Choroideremia is an X-linked inherited retinal disorder (IRD) characterized by the degeneration of retinal pigment epithelium, photoreceptors, choriocapillaris and choroid affecting males with variable phenotypes in female carriers. Unlike other IRD, characterized by a large clinical and genetic heterogeneity, choroideremia shows a specific phenotype with causative mutations in only one gene, CHM. Ongoing gene replacement trials raise further interests in this disorder. We describe here the clinical and genetic data from a French cohort of 45 families, 25 of which carry novel variants, in the context of 822 previously reported choroideremia families. Most of the variants represent loss-of-function mutations with eleven families having large (i.e. ≥6 kb) genomic deletions, 18 small insertions, deletions or insertion deletions, six showing nonsense variants, eight splice site variants and two missense variants likely to affect splicing. Similarly, 822 previously published families carry mostly loss-of-function variants. Recurrent variants are observed worldwide, some of which linked to a common ancestor, others arisen independently in specific CHM regions prone to mutations. Since all exons of CHM may harbor variants, Sanger sequencing combined with quantitative polymerase chain reaction or multiplex ligation-dependent probe amplification experiments are efficient to achieve the molecular diagnosis in patients with typical choroideremia features.
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http://dx.doi.org/10.1002/humu.24174DOI Listing
April 2021

Retinal Phenotype of Patients With Isolated Retinal Degeneration Due to CLN3 Pathogenic Variants in a French Retinitis Pigmentosa Cohort.

JAMA Ophthalmol 2021 Mar;139(3):278-291

Sorbonne Université, INSERM, Centre national de la recherche scientifique, Institut de la Vision, Paris, France.

Importance: Biallelic variants in CLN3 lead to a spectrum of diseases, ranging from severe neurodegeneration with retinal involvement (juvenile neuronal ceroid lipofuscinosis) to retina-restricted conditions.

Objective: To provide a detailed description of the retinal phenotype of patients with isolated retinal degeneration harboring biallelic CLN3 pathogenic variants and to attempt a phenotype-genotype correlation associated with this gene defect.

Design, Setting, And Participants: This retrospective cohort study included patients carrying biallelic CLN3 variants extracted from a cohort of patients with inherited retinal disorders (IRDs) investigated at the National Reference Center for Rare Ocular Diseases of the Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts from December 2007 to August 2020. Data were analyzed from October 2019 to August 2020.

Main Outcome And Measures: Functional (best-corrected visual acuity, visual field, color vision, and full-field electroretinogram), morphological (multimodal retinal imaging), and clinical data from patients were collected and analyzed. Gene defect was identified by either next-generation sequencing or whole-exome sequencing and confirmed by Sanger sequencing, quantitative polymerase chain reaction, and cosegregation analysis.

Results: Of 1533 included patients, 843 (55.0%) were women and 690 (45.0%) were men. A total of 15 cases from 11 unrelated families harboring biallelic CLN3 variants were identified. All patients presented with nonsyndromic IRD. Two distinct patterns of retinal disease could be identified: a mild rod-cone degeneration of middle-age onset (n = 6; legal blindness threshold reached by 70s) and a severe retinal degeneration with early macular atrophic changes (n = 9; legal blindness threshold reached by 40s). Eleven distinct pathogenic variants were detected, of which 4 were novel. All but 1, p.(Arg405Trp), CLN3 point variants and their genotypic associations were clearly distinct between juvenile neuronal ceroid lipofuscinosis and retina-restricted disease. Mild and severe forms of retina-restricted CLN3-linked IRDs also had different genetic background.

Conclusions And Relevance: These findings suggest CLN3 should be included in next-generation sequencing panels when investigating patients with nonsyndromic rod-cone dystrophy. These results document phenotype-genotype correlations associated with specific variants in CLN3. However, caution seems warranted regarding the potential neurological outcome if a pathogenic variant in CLN3 is detected in a case of presumed isolated IRD for the onset of neurological symptoms could be delayed.
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http://dx.doi.org/10.1001/jamaophthalmol.2020.6089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844693PMC
March 2021

Spectrum of Disease Severity in Patients With X-Linked Retinitis Pigmentosa Due to RPGR Mutations.

Invest Ophthalmol Vis Sci 2020 12;61(14):36

Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, Università degli Studi della Campania "Luigi Vanvitelli," Naples, Italy.

Purpose: The purpose of this study was to perform a detailed longitudinal phenotyping of X-linked retinitis pigmentosa (RP) caused by mutations in the RPGR gene during a long follow-up period.

Methods: An Italian cohort of 48 male patients (from 31 unrelated families) with RPGR-associated RP was clinically assessed at a single center (mean follow-up = 6.5 years), including measurements of best-corrected visual acuity (BCVA), Goldmann visual field (GVF), optical coherence tomography (OCT), fundus autofluorescence (FAF), microperimetry, and full-field electroretinography (ERG).

Results: Patients (29.6 ± 15.2 years) showed a mean BCVA of 0.6 ± 0.7 logMAR, mostly with myopic refraction (79.2%). Thirty patients (62.5%) presented a typical RP fundus, while the remaining sine pigmento RP. Over the follow-up, BCVA significantly declined at a mean rate of 0.025 logMAR/year. Typical RP and high myopia were associated with a significantly faster decline of BCVA. Blindness was driven primarily by GVF loss. ERG responses with a rod-cone pattern of dysfunction were detectable in patients (50%) that were significantly younger and more frequently presented sine pigmento RP. Thirteen patients (27.1%) had macular abnormalities without cystoid macular edema. Patients (50%) with a perimacular hyper-FAF ring were significantly younger, had a higher BCVA and a better-preserved ellipsoid zone band than those with markedly decreased FAF. Patients harboring pathogenic variants in exons 1 to 14 showed a milder phenotype compared to those with ORF15 mutations.

Conclusions: Our monocentric, longitudinal retrospective study revealed a spectrum disease progression in male patients with RPGR-associated RP. Slow disease progression correlated with sine pigmento RP, absence of high myopia, and mutations in RPGR exons 1 to 14.
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http://dx.doi.org/10.1167/iovs.61.14.36DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774109PMC
December 2020

WDR34, a candidate gene for non-syndromic rod-cone dystrophy.

Clin Genet 2021 Feb 9;99(2):298-302. Epub 2020 Nov 9.

Department of Genetics, Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France.

Rod-cone dystrophy (RCD), also called retinitis pigmentosa, is characterized by rod followed by cone photoreceptor degeneration, leading to gradual visual loss. Mutations in over 65 genes have been associated with non-syndromic RCD explaining 60% to 70% of cases, with novel gene defects possibly accounting for the unsolved cases. Homozygosity mapping and whole-exome sequencing applied to a case of autosomal recessive non-syndromic RCD from a consanguineous union identified a homozygous variant in WDR34. Mutations in WDR34 have been previously associated with severe ciliopathy syndromes possibly associated with a retinal dystrophy. This is the first report of a homozygous mutation in WDR34 associated with non-syndromic RCD.
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http://dx.doi.org/10.1111/cge.13872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049445PMC
February 2021

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

Peripapillary Sparing With Near Infrared Autofluorescence Correlates With Electroretinographic Findings in Patients With Stargardt Disease.

Invest Ophthalmol Vis Sci 2019 12;60(15):4951-4957

Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientfique, Institut de la Vision, Paris, France.

Purpose: To evaluate the correlation between the quantification of peripapillary sparing and electroretinogram (ERG) outcomes in autosomal recessive Stargardt disease (STGD1).

Methods: Near infrared fundus autofluorescence (NIR-FAF) images of 101 eyes of 101 patients were retrospectively reviewed. Peripapillary sparing was assessed both qualitatively and quantitatively. The area of spared tissue (AST) was calculated in a 1-mm-wide ring around the optic disc after binarization of the 55° NIR-FAF. These measurements were correlated with the presence of normal ERG (group I), abnormal photopic responses (group II), or abnormal photopic and scotopic responses (group III).

Results: AST showed significant correlations with ERG groups (R = -0.802, P < 0.001). While qualitative assessment of peripapillary sparing (i.e., present or not) also showed a significant correlation with ERG groups (R = -0.435, P < 0.001), it was weaker than by AST quantification. The ordinal regression analysis showed that the increase in AST was associated with a decrease in the odds of belonging to ERG groups II and III, with an odds ratio of 0.82 (95% confidence interval [CI] 0.78-0.87), P < 0.001.

Conclusions: The AST around the optic disc in eyes with STGD1 correlates with the impairment of photoreceptors as shown in the ERG. If replicated in future longitudinal studies, the quantification of peripapillary sparing may prove to be a useful parameter for evaluating the visual prognosis of these eyes.
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http://dx.doi.org/10.1167/iovs.19-27100DOI Listing
December 2019

Generation of human induced pluripotent stem cell lines from a patient with ITM2B-related retinal dystrophy and a non mutated brother.

Stem Cell Res 2019 12 5;41:101625. Epub 2019 Nov 5.

INSERM, CNRS, Institut de la Vision, Sorbonne Université, 17 rue Moreau, Paris, F-75012, France; CHNO des Quinze-Vingts, INSERM-DGOS CIC 1423, 28 rue de Charenton, Paris, F-75012, France. Electronic address:

Human induced pluripotent stem cell (iPSC) lines were generated from fibroblasts of a patient affected with an autosomal dominant retinal dystrophy carrying the mutation c.782A>C, p.Glu261Ala in ITM2B and from an unaffected brother. Three different iPSC lines were generated and characterized from primary dermal fibroblasts of the affected subject and two from the unaffected brother. All iPSC lines expressed the pluripotency markers, were able to differentiate into the three germ layers and presented normal karyotypes. This cellular model will provide a powerful tool to study this retinal dystrophy and better understand the role of ITM2B.
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http://dx.doi.org/10.1016/j.scr.2019.101625DOI Listing
December 2019

Prevalence of Deep-Intronic Variants and Related Phenotype in An Unsolved "One-Hit" Cohort with Stargardt Disease.

Int J Mol Sci 2019 Oct 11;20(20). Epub 2019 Oct 11.

Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012 Paris, France.

We investigated the prevalence of reported deep-intronic variants in a French cohort of 70 patients with Stargardt disease harboring a monoallelic pathogenic variant on the exonic regions of . Direct Sanger sequencing of selected intronic regions of ABCA4 was conducted. Complete phenotypic analysis and correlation with the genotype was performed in case a known intronic pathogenic variant was identified. All other variants found on the analyzed sequences were queried for minor allele frequency and possible pathogenicity by in silico predictions. The second mutated allele was found in 14 (20%) subjects. The three known deep-intronic variants found were c.5196+1137G>A in intron 36 (6 subjects), c.4539+2064C>T in intron 30 (4 subjects) and c.4253+43G>A in intron 28 (4 subjects). Even though the phenotype depends on the compound effect of the biallelic variants, a genotype-phenotype correlation suggests that the c.5196+1137G>A was mostly associated with a mild phenotype and the c.4539+2064C>T with a more severe one. A variable effect was instead associated with the variant c.4253+43G>A. In addition, two novel variants, c.768+508A>G and c.859-245_859-243delinsTGA never associated with Stargardt disease before, were identified and a possible splice defect was predicted in silico. Our study calls for a larger cohort analysis including targeted locus sequencing and 3D protein modeling to better understand phenotype-genotype correlations associated with deep-intronic changes and patients' selection for clinical trials.
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http://dx.doi.org/10.3390/ijms20205053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829239PMC
October 2019

Phenotype Analysis of Retinal Dystrophies in Light of the Underlying Genetic Defects: Application to Cone and Cone-Rod Dystrophies.

Int J Mol Sci 2019 Sep 30;20(19). Epub 2019 Sep 30.

Institut de la Vision, Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, 17 rue Moreau, 75012 Paris, France.

Phenotypes observed in a large cohort of patients with cone and cone-rod dystrophies (COD/CORDs) are described based on multimodal retinal imaging features in order to help in analyzing massive next-generation sequencing data. Structural abnormalities of 58 subjects with molecular diagnosis of COD/CORDs were analyzed through specific retinal imaging including spectral-domain optical coherence tomography (SD-OCT) and fundus autofluorescence (BAF/IRAF). Findings were analyzed with the underlying genetic defects. A ring of increased autofluorescence was mainly observed in patients with and mutations (33% and 22% of cases respectively). "Speckled" autofluorescence was observed with mutations in three different genes ( 64%; and , 18% each). Peripapillary sparing was only found in association with mutations in , although only present in 40% of such genotypes. Regarding SD-OCT, specific outer retinal abnormalities were more commonly observed in particular genotypes: focal retrofoveal interruption and mutations (50%), foveal sparing and mutations (50%), and outer retinal atrophy associated with hyperreflective dots and mutations (69%). This study outlines the phenotypic heterogeneity of COD/CORDs hampering statistical correlations. A larger study correlating retinal imaging with genetic results is necessary to identify specific clinical features that may help in selecting pathogenic variants generated by high-throughput sequencing.
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http://dx.doi.org/10.3390/ijms20194854DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6801687PMC
September 2019

PHENOTYPIC CHARACTERISTICS OF ROD-CONE DYSTROPHY ASSOCIATED WITH MYO7A MUTATIONS IN A LARGE FRENCH COHORT.

Retina 2020 Aug;40(8):1603-1615

Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France.

Purpose: To document the rod-cone dystrophy phenotype of patients with Usher syndrome type 1 (USH1) harboring MYO7A mutations.

Methods: Retrospective cohort study of 53 patients (42 families) with biallelic MYO7A mutations who underwent comprehensive examination, including functional visual tests and multimodal retinal imaging. Genetic analysis was performed either using a multiplex amplicon panel or through direct sequencing. Data were analyzed with IBM SPSS Statistics software v. 21.0.

Results: Fifty different genetic variations including 4 novel were identified. Most patients showed a typical rod-cone dystrophy phenotype, with best-corrected visual acuity and central visual field deteriorating linearly with age. At age 29, binocular visual field demonstrated an average preservation of 50 central degrees, constricting by 50% within 5 years. Structural changes based on spectral domain optical coherence tomography, short wavelength autofluorescence, and near-infrared autofluorescence measurements did not however correlate with age. Our study revealed a higher percentage of epiretinal membranes and cystoid macular edema in patients with MYO7A mutations compared with rod-cone dystrophy patients with other mutations. Subgroup analyses did not reveal substantial genotype-phenotype correlations.

Conclusion: To the best of our knowledge, this is the largest French cohort of patients with MYO7A mutations reported to date. Functional visual characteristics of this subset of patients followed a linear decline as in other typical rod-cone dystrophy, but structural changes were variable indicating the need for a case-by-case evaluation for prognostic prediction and choice of potential therapies.
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http://dx.doi.org/10.1097/IAE.0000000000002636DOI Listing
August 2020

Outer Retinal Alterations Associated With Visual Outcomes in Best Vitelliform Macular Dystrophy.

Am J Ophthalmol 2019 12 26;208:429-437. Epub 2019 Aug 26.

Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, Centre de Maladies Rares "dystrophies rétiniennes d'origine génétique," Département hospitalo-universitaire Sight Restore, Institut National de la Santé et de la Recherche Médicale, DHOS Centre d'Investigation Clinique 1423, Paris, France; Sorbonne Université, Institut National de la Santé et de la Recherche Médicale, Centre National de la Recherche Scientifique, Institut de la Vision, Paris, France.

Purpose: To describe outer retinal structure in patients with Best vitelliform macular dystrophy (BVMD) using spectral-domain optical coherence tomography (OCT) and correlate these results with best-corrected visual acuity (BCVA) and patient age.

Design: Retrospective cross-sectional study.

Methods: Patients with molecularly confirmed BVMD were compared with normal control subjects (NCs). A complete clinical evaluation was performed, including BCVA, fundus photography, spectral-domain OCT, and fundus autofluorescence. Spectral-domain OCT images were analyzed to determine the stage of the lesion, the central macular thickness (CMT), the foveal outer nuclear layer (ONL) thickness, and tomographic structural changes.

Results: Forty-two patients with BVMD (42 eyes) with a molecular diagnosis and 42 NCs (42 eyes) were included. Clinical stages (Gass clinical classification) were distributed as follows: 4.8% for stage 1, 23.8% for stage 2, 16.6% for stage 3, 45.2% for stage 4, and 9.5% for stage 5. The presence of subretinal fluid and vitelliform material was noted in 76% and 79% of the BVMD eyes examined, respectively, and was not associated with BCVA modification (P = .758 and P = .968, respectively). The median ONL thickness was significantly lower compared with the NCs (P < .001). BCVA was significantly correlated with stage (R = 0.710; P < .01), age (R = 0.448; P < .01), CMT (R = -0.411; P < .01), and ONL thickness (R = -0.620; P < .01). The disruption of the external limiting membrane and the ellipsoid zone was associated with a decreased BCVA (P < .001 for both). Among the 32 eyes with subretinal detachment, photoreceptor outer segment length was significantly correlated with BCVA (R = -0.467; P < .01) and ONL thickness (R = 0.444; P = < .01).

Conclusion: This study shows the correlation between BCVA, age, and spectral-domain OCT features in patients with BVMD. ONL thickness as well as photoreceptor outer segment length are relevant functional correlates and outcome measures to follow photoreceptor impairments and disease progression.
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http://dx.doi.org/10.1016/j.ajo.2019.08.011DOI Listing
December 2019

Mutation profile of glaucoma candidate genes in Mauritanian families with primary congenital glaucoma.

Mol Vis 2019 13;25:373-381. Epub 2019 Jul 13.

Unité de Recherche sur les Biomarqueurs dans la Population Mauritanienne, Université des Sciences de Technologies et de médecine (USTM), Nouakchott, Mauritanie.

Purpose: Intraocular pressure leading to glaucoma is a major cause of childhood blindness in developing countries. In this study, we sought to identify gene variants potentially associated with primary congenital glaucoma (PCG) in the Mauritanian population.

Methods: Using next-generation sequencing (NGS), a panel of PCG candidate genes was screened in a search for DNA mutations in four families with multiple occurrences of PCG.

Results: Targeted exome sequencing analysis revealed predicted pathogenic mutations in four genes: (c.217_218delTC, p.Ser73Valfs*150), (878C>A, p.T293K), (c.601T>G, p.Cys201Gly), and (c.2078A>G, p.Asn693Ser), each carried by a different family.

Conclusions: Genetic variation associated with PCG in this study reflects the ethnic heterogeneity of the Mauritanian population. However, a larger cohort is needed to identify additional families carrying these mutations and confirm their biologic role.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639433PMC
April 2020

Longitudinal Clinical Follow-up and Genetic Spectrum of Patients With Rod-Cone Dystrophy Associated With Mutations in PDE6A and PDE6B.

JAMA Ophthalmol 2019 06;137(6):669-679

Sorbonne Université, Institut national de la santé et de la recherche médicale, Centre national de la recherche scientifique, Institut de la Vision, Paris, France.

Importance: A precise phenotypic characterization of retinal dystrophies is needed for disease modeling as a basis for future therapeutic interventions.

Objective: To compare genotype, phenotype, and structural changes in patients with rod-cone dystrophy (RCD) associated with mutations in PDE6A or PDE6B.

Design, Setting, And Participants: In a retrospective cohort study conducted in Paris, France, from January 2007 to September 2017, 54 patients from a cohort of 1095 index patients with RCD underwent clinical examination, including personal and familial history, best-corrected visual acuity (BCVA), color vision, slitlamp examination, full-field electroretinography, kinetic visual fields (VFs), retinophotography, optical coherence tomography, near-infrared fundus autofluorescence, and short-wavelength fundus autofluorescence imaging. Genotyping was performed using microarray analysis, targeted next-generation sequencing, and Sanger sequencing validation with familial segregation when possible. Data were analyzed from September 1, 2017, to February 1, 2018. Clinical variables were subsequently analyzed in 2018.

Main Outcomes And Measures: Phenotype and genotype comparison of patients carrying mutations in PDE6A or PDE6B.

Results: Of the 54 patients included in the study, 19 patients of 17 families (11 women [58%]; mean [SD] age at diagnosis, 14.83 [10.63] years) carried pathogenic mutations in PDE6A, and 35 patients of 26 families (17 women [49%]; mean [SD] age at diagnosis, 21.10 [11.56] years) had mutations in PDE6B, accounting for prevalences of 1.6% and 2.4%, respectively. Among 49 identified genetic variants, 14 in PDE6A and 15 in PDE6B were novel. Overall, phenotypic analysis revealed no substantial differences between the 2 groups except for night blindness as a presenting symptom that was noted to be more prevalent in the PDE6A than PDE6B group (80% vs 37%, respectively; P = .005). The mean binocular BCVA and VF decrease over time (measured as mean individual slopes coefficients) was comparable between patients with PDE6A and PDE6B mutations: 0.04 (0.12) vs 0.02 (0.05) for BCVA (P = .89) and 14.33 (7.12) vs 13.27 (6.77) for VF (P = .48).

Conclusions And Relevance: Mutations in PDE6A and PDE6B accounted for 1.6% and 2.4%, respectively, in a cohort of French patients with RCD. The functional and structural findings reported may constitute the basis of disease modeling that might be used for better prognostic estimation and candidate selection for photoreceptor therapeutic rescue.
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http://dx.doi.org/10.1001/jamaophthalmol.2018.6367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567841PMC
June 2019

Where are the missing gene defects in inherited retinal disorders? Intronic and synonymous variants contribute at least to 4% of CACNA1F-mediated inherited retinal disorders.

Hum Mutat 2019 06 28;40(6):765-787. Epub 2019 Mar 28.

Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.

Inherited retinal disorders (IRD) represent clinically and genetically heterogeneous diseases. To date, pathogenic variants have been identified in ~260 genes. Albeit that many genes are implicated in IRD, for 30-50% of the cases, the gene defect is unknown. These cases may be explained by novel gene defects, by overlooked structural variants, by variants in intronic, promoter or more distant regulatory regions, and represent synonymous variants of known genes contributing to the dysfunction of the respective proteins. Patients with one subgroup of IRD, namely incomplete congenital stationary night blindness (icCSNB), show a very specific phenotype. The major cause of this condition is the presence of a hemizygous pathogenic variant in CACNA1F. A comprehensive study applying direct Sanger sequencing of the gene-coding regions, exome and genome sequencing applied to a large cohort of patients with a clinical diagnosis of icCSNB revealed indeed that seven of the 189 CACNA1F-related cases have intronic and synonymous disease-causing variants leading to missplicing as validated by minigene approaches. These findings highlight that gene-locus sequencing may be a very efficient method in detecting disease-causing variants in clinically well-characterized patients with a diagnosis of IRD, like icCSNB.
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http://dx.doi.org/10.1002/humu.23735DOI Listing
June 2019

Novel Missense Mutations in Are Associated with Bestrophinopathies in Lebanese Patients.

Genes (Basel) 2019 02 18;10(2). Epub 2019 Feb 18.

Rammal Hassan Rammal Research Laboratory, PhyToxE research group, Department of Life and Earth Sciences, Faculty of Sciences, Lebanese University, Nabatieh 1700, Lebanon.

To identify () causative mutations in six Lebanese patients from three families, of whom four had a presumed clinical diagnosis of autosomal recessive bestrophinopathy (ARB) and two showed a phenotype with a single vitelliform lesion, patients were subjected to standard ophthalmic examinations. In addition, exons and their flanking regions were amplified and sequenced by Sanger sequencing. Co-segregation and detailed bio-informatic analyses were performed. Clinical examination results were consistent with ARB diagnosis for all index patients showing multifocal vitelliform lesions and a markedly reduced light peak in the electrooculogram, including the two patients with a single vitelliform lesion. In all cases, most likely disease-causing mutations co-segregated with the phenotype. The ARB cases showed homozygous missense variants (M1, c.209A>G, p.(Asp70Gly) in exon 3, M2, c.1403C>T; p.(Pro468Leu) in exon 10 and M3, c.830C>T, p.(Thr277Met) in exon 7), while the two patients with a single vitelliform lesion were compound heterozygous for M1 and M2. To our knowledge, this is the first study describing mutations in Lebanese patients with bestrophinopathy, where novel biallelic mutations associated with two phenotypes were identified. Homozygous mutations were associated with multifocal lesions, subretinal fluid, and intraretinal cysts, whereas compound heterozygous ones were responsible for a single macular vitelliform lesion.
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http://dx.doi.org/10.3390/genes10020151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6409913PMC
February 2019

The E3 Ubiquitin Ligases TRIM17 and TRIM41 Modulate α-Synuclein Expression by Regulating ZSCAN21.

Cell Rep 2018 11;25(9):2484-2496.e9

Institut de Génétique Moléculaire de Montpellier, University of Montpellier, CNRS, Montpellier, France.

Although accumulating data indicate that increased α-synuclein expression is crucial for Parkinson disease (PD), mechanisms regulating the transcription of its gene, SNCA, are largely unknown. Here, we describe a pathway regulating α-synuclein expression. Our data show that ZSCAN21 stimulates SNCA transcription in neuronal cells and that TRIM41 is an E3 ubiquitin ligase for ZSCAN21. In contrast, TRIM17 decreases the TRIM41-mediated degradation of ZSCAN21. Silencing of ZSCAN21 and TRIM17 consistently reduces SNCA expression, whereas TRIM41 knockdown increases it. The mRNA levels of TRIM17, ZSCAN21, and SNCA are simultaneously increased in the midbrains of mice following MPTP treatment. In addition, rare genetic variants in ZSCAN21, TRIM17, and TRIM41 genes occur in patients with familial forms of PD. Expression of variants in ZSCAN21 and TRIM41 genes results in the stabilization of the ZSCAN21 protein. Our data thus suggest that deregulation of the TRIM17/TRIM41/ZSCAN21 pathway may be involved in the pathogenesis of PD.
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http://dx.doi.org/10.1016/j.celrep.2018.11.002DOI Listing
November 2018

A novel missense mutation of causes congenital cataract in a large Mauritanian family.

Eur J Ophthalmol 2019 Nov 29;29(6):621-628. Epub 2018 Oct 29.

Unité de Recherche sur les Biomarqueurs dans la Population Mauritanienne, Université des Sciences de Technologies et de médecine (USTM), Nouakchott, Mauritanie.

Objective Of The Study: Inborn lens opacity is the most frequent cause of childhood blindness. In this study, we aimed to define the presumed genetic cause of a congenital cataract present in a Mauritanian family over the last nine generations.

Methods: A family history of the disease and eye examination were carried out for the family members. Next-generation sequencing using a panel of 116 cataract underlying genes was selectively conducted on the proband's DNA. Nucleotide and amino acid changes and their impact on the phenotype were evaluated using various data analyzing software.

Results: Congenital nuclear cataract, with autosomal dominant mode, was observed in the family. All patients had consequences on their vision in the first 2 years of life. Genetic screening revealed a new mutation c.166A>C (p.Thr56Pro) in , encoding the Cx50 α-connexin protein. This mutation co-segregated in all patients and was not observed in the unaffected family members and controls. The predicted secondary structure impacted by p.Thr56Pro revealed a localized disruption, in the first extra membrane loop of the wild-type sheet, which is replaced in the mutant protein by a turn then a coil. This conformational change was functionally predicted as probably damaging.

Conclusion: A (c.166A>C) in Its segregation with the phenotype might be useful as a predicting marker of the disease.
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http://dx.doi.org/10.1177/1120672118804757DOI Listing
November 2019

Whole exome sequencing resolves complex phenotype and identifies CC2D2A mutations underlying non-syndromic rod-cone dystrophy.

Clin Genet 2019 02 4;95(2):329-333. Epub 2018 Nov 4.

Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France.

Genetic investigations were performed in three brothers from a consanguineous union, the two oldest diagnosed with rod-cone dystrophy (RCD), the youngest with early-onset cone-rod dystrophy and the two youngest with nephrotic-range proteinuria. Targeted next-generation sequencing did not identify homozygous pathogenic variant in the oldest brother. Whole exome sequencing (WES) applied to the family identified compound heterozygous variants in CC2D2A (c.2774G>C p.(Arg925Pro); c.4730_4731delinsTGTATA p.(Ala1577Valfs*5)) in the three brothers with a homozygous deletion in CNGA3 (c.1235_1236del p.(Glu412Valfs*6)) in the youngest correcting his diagnosis to achromatopsia plus RCD. None of the three subjects had cerebral abnormalities or learning disabilities inconsistent with Meckel-Gruber and Joubert syndromes, usually associated with CC2D2A mutations. Interestingly, an African woman with RCD shared the CC2D2A missense variant (c.2774G>C p.(Arg925Pro); with c.3182+355_3825del p.(?)). The two youngest also carried compound heterozygous variants in CUBN (c.7906C>T rs137998687 p.(Arg2636*); c.10344C>G p.(Cys3448Trp)) that may explain their nephrotic-range proteinuria. Our study identifies for the first time CC2D2A mutations in isolated RCD and underlines the power of WES to decipher complex phenotypes.
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http://dx.doi.org/10.1111/cge.13453DOI Listing
February 2019

Expanding the Mutation Spectrum in : Sixty Novel Disease Causing Variants and Their Associated Phenotype in a Large French Stargardt Cohort.

Int J Mol Sci 2018 Jul 27;19(8). Epub 2018 Jul 27.

Sorbonne Université, INSERM, CNRS, Institut de la Vision, F-75012 Paris, France.

Here we report novel mutations in with the underlying phenotype in a large French cohort with autosomal recessive Stargardt disease. The DNA samples of 397 index subjects were analyzed in exons and flanking intronic regions of (NM_000350.2) by microarray analysis and direct Sanger sequencing. At the end of the screening, at least two likely pathogenic mutations were found in 302 patients (76.1%) while 95 remained unsolved: 40 (10.1%) with no variants identified, 52 (13.1%) with one heterozygous mutation, and 3 (0.7%) with at least one variant of uncertain significance (VUS). Sixty-three novel variants were identified in the cohort. Three of them were variants of uncertain significance. The other 60 mutations were classified as likely pathogenic or pathogenic, and were identified in 61 patients (15.4%). The majority of those were missense (55%) followed by frameshift and nonsense (30%), intronic (11.7%) variants, and in-frame deletions (3.3%). Only patients with variants never reported in literature were further analyzed herein. Recruited subjects underwent complete ophthalmic examination including best corrected visual acuity, kinetic and static perimetry, color vision test, full-field and multifocal electroretinography, color fundus photography, short-wavelength and near-infrared fundus autofluorescence imaging, and spectral domain optical coherence tomography. Clinical evaluation of each subject confirms the tendency that truncating mutations lead to a more severe phenotype with electroretinogram (ERG) impairment ( = 0.002) and an earlier age of onset ( = 0.037). Our study further expands the mutation spectrum in the exonic and flanking regions of underlying Stargardt disease.
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http://dx.doi.org/10.3390/ijms19082196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121640PMC
July 2018

MERTK mutation update in inherited retinal diseases.

Hum Mutat 2018 07 23;39(7):887-913. Epub 2018 May 23.

Sorbonne Université, INSERM, CNRS, Institut de la Vision, Paris, France.

MER tyrosine kinase (MERTK) encodes a surface receptor localized at the apical membrane of the retinal pigment epithelium. It plays a critical role in photoreceptor outer segment internalization prior to phagocytosis. Mutations in MERTK have been associated with severe autosomal recessive retinal dystrophies in the RCS rat and in humans. We present here a comprehensive review of all reported MERTK disease causing variants with the associated phenotype. In addition, we provide further data and insights of a large cohort of 1,195 inherited retinal dystrophies (IRD) index cases applying state-of-the-art genotyping techniques and summarize current knowledge. A total of 79 variants have now been identified underlying rod-cone dystrophy and cone-rod dystrophy including 11 novel variants reported here. The mutation spectrum in MERTK includes 33 missense, 12 nonsense, 12 splice defects, 12 small deletions, two small insertion-deletions, three small duplications, and two exonic and three gross deletions. Altogether, mutations in MERTK account for ∼2% of IRD cases with a severe retinal phenotype. These data are important for current and future therapeutic trials including gene replacement therapy or cell-based therapy.
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http://dx.doi.org/10.1002/humu.23431DOI Listing
July 2018

AUTOSOMAL DOMINANT VITREORETINOCHOROIDOPATHY: When Molecular Genetic Testing Helps Clinical Diagnosis.

Retina 2019 May;39(5):867-878

Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, DHUSight Restore, INSERM-DGOS CIC 1423, Paris, France.

Purpose: Autosomal dominant vitreoretinochoroidopathy is an extremely rare disease, which belongs to the BEST1-related disease spectrum.

Methods: Report of five patients with an initial diagnosis of atypical rod-cone dystrophy, for whom autosomal dominant vitreoretinochoroidopathy was retrospectively diagnosed on genetic results using targeted next-generation sequencing. Each patient had a comprehensive ophthalmic examination including multimodal retinal imaging and functional evaluation.

Results: Visual acuity ranged from <20/800 to 20/25. Two patients had narrowed angle with history of acute angle-closure glaucoma for one patient. Full-field electroretinogram showed severe reduction of both scotopic and photopic responses for 3/5 patients. Electrooculogram could be performed for one of the two patients with moderate alterations of full-field electroretinogram. It revealed severe light rise abnormalities with decreased Arden ratio (125% right eye, 145% left eye) in keeping with generalized severe dysfunction of the retinal pigment epithelium. On fundoscopy, the pathognomonic circumferential hyperpigmented band of the peripheral retina was totally absent in two patients.

Conclusion: This report highlights the high phenotypic variability of autosomal dominant vitreoretinochoroidopathy, which may be misdiagnosed, especially in advanced forms with severe generalized photoreceptor dysfunction mimicking retinitis pigmentosa. Targeted next-generation sequencing can contribute to the proper clinical diagnosis, especially in case of atypical phenotypic features of autosomal dominant vitreoretinochoroidopathy.
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http://dx.doi.org/10.1097/IAE.0000000000002041DOI Listing
May 2019

Further Insights into the Ciliary Gene and Protein KIZ and Its Murine Ortholog PLK1S1 Mutated in Rod-Cone Dystrophy.

Genes (Basel) 2017 Oct 18;8(10). Epub 2017 Oct 18.

Sorbonne Universités, UPMC University Paris 06, INSERM U968, CNRS UMR 7210, Institut de la Vision, 75012 Paris, France.

We identified herein additional patients with rod-cone dystrophy (RCD) displaying mutations in , encoding the ciliary centrosomal protein kizuna and performed functional characterization of the respective protein in human fibroblasts and of its mouse ortholog PLK1S1 in the retina. Mutation screening was done by targeted next generation sequencing and subsequent Sanger sequencing validation. mRNA levels were assessed on blood and serum-deprived human fibroblasts from a control individual and a patient, compound heterozygous for the c.52G>T (p.Glu18*) and c.119_122del (p.Lys40Ilefs*14) mutations in . KIZ localization, documentation of cilium length and immunoblotting were performed in these two fibroblast cell lines. In addition, PLK1S1 immunolocalization was conducted in mouse retinal cryosections and isolated rod photoreceptors. Analyses of additional RCD patients enabled the identification of two homozygous mutations in , the known c.226C>T (p.Arg76*) mutation and a novel variant, the c.3G>A (p.Met1?) mutation. Albeit the expression levels of were three-times lower in the patient than controls in whole blood cells, further analyses in control- and mutant patient-derived fibroblasts unexpectedly revealed no significant difference between the two genotypes. Furthermore, the averaged monocilia length in the two fibroblast cell lines was similar, consistent with the preserved immunolocalization of KIZ at the basal body of the primary cilia. Analyses in mouse retina and isolated rod photoreceptors showed PLK1S1 localization at the base of the photoreceptor connecting cilium. In conclusion, two additional patients with mutations in were identified, further supporting that defects in KIZ/PLK1S1, detected at the basal body of the primary cilia in fibroblasts, and the photoreceptor connecting cilium in mouse, respectively, are involved in RCD. However, albeit the mutations were predicted to lead to nonsense mediated mRNA decay, we could not detect changes upon expression levels, protein localization or cilia length in -mutated fibroblast cells. Together, our findings unveil the limitations of fibroblasts as a cellular model for RCD and call for other models such as induced pluripotent stem cells to shed light on retinal pathogenic mechanisms of mutations.
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http://dx.doi.org/10.3390/genes8100277DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5664127PMC
October 2017

Identification of a Novel Homozygous Nonsense Mutation Confirms the Implication of GNAT1 in Rod-Cone Dystrophy.

PLoS One 2016 15;11(12):e0168271. Epub 2016 Dec 15.

Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Institut de la Vision, Paris, France.

GNAT1, encoding the transducin subunit Gα, is an important element of the phototransduction cascade. Mutations in this gene have been associated with autosomal dominant and autosomal recessive congenital stationary night blindness. Recently, a homozygous truncating GNAT1 mutation was identified in a patient with late-onset rod-cone dystrophy. After exclusion of mutations in genes underlying progressive inherited retinal disorders, by targeted next generation sequencing, a 32 year-old male sporadic case with severe rod-cone dystrophy and his unaffected parents were investigated by whole exome sequencing. This led to the identification of a homozygous nonsense variant, c.963C>A p.(Cys321*) in GNAT1, which was confirmed by Sanger sequencing. The mother was heterozygous for this variant whereas the variant was absent in the father. c.963C>A p.(Cys321*) is predicted to produce a shorter protein that lacks critical sites for the phototransduction cascade. Our work confirms that the phenotype and the mode of inheritance associated with GNAT1 variants can vary from autosomal dominant, autosomal recessive congenital stationary night blindness to autosomal recessive rod-cone dystrophy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168271PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5158031PMC
July 2017

Loss-of-function mutations in RAB39B are associated with typical early-onset Parkinson disease.

Neurol Genet 2015 Jun 18;1(1):e9. Epub 2015 Jun 18.

Institut du Cerveau et de la Moelle épinière, ICM, Inserm U 1127, CNRS, UMR 7225, Sorbonne Universités, UPMC University Paris 06 UMR S 1127 (S.L., F.C.-D., C.C., A.N., A.B.), Paris, France; Centre d'Investigation Clinique Pitié Neurosciences CIC-1422 (F.C.-D.); AP-HP, Hôpital de la Salpêtrière (A.B.), Department of Genetics and Cytogenetics, Paris, France; Department of Molecular Neuroscience (J.B., L.D., R.G., M.F., N.W., J.H.), UCL Institute of Neurology, London, United Kingdom; Laboratory of Neurogenetics (E.M., M.F., A.S.), National Institute on Aging, Bethesda, MD; Hertie Institute for Clinical Brain Research (P.H., T.G.), University of Tübingen and DZNE (P.H., T.G.), German Center for Neurodegenerative Diseases, Tübingen, Germany; and Institut des Maladies Neurodégénératives (F.T.), Université de Bordeaux et CHU de Bordeaux, Bordeaux, France.

Rab proteins are small molecular weight guanosine triphosphatases involved in the regulation of vesicular trafficking.(1) Three of 4 X-linked RAB genes are specific to the brain, including RAB39B. Recently, Wilson et al.(2) reported that mutations in RAB39B cause X-linked intellectual disability (ID) and pathologically confirmed Parkinson disease (PD). They identified a ∼45-kb deletion resulting in the complete loss of RAB39B in an Australian kindred and a missense mutation in a large Wisconsin kindred. Here, we report an additional affected man with typical PD and mild mental retardation harboring a new truncating mutation in RAB39B.
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http://dx.doi.org/10.1212/NXG.0000000000000009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4821081PMC
June 2015

Biallelic Mutations in GNB3 Cause a Unique Form of Autosomal-Recessive Congenital Stationary Night Blindness.

Am J Hum Genet 2016 05 7;98(5):1011-1019. Epub 2016 Apr 7.

Department of Ophthalmology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada; Department of Ophthalmology, University of Toronto, 340 College Street, Toronto, ON M5T 3A9, Canada. Electronic address:

Congenital stationary night blindness (CSNB) is a heterogeneous group of non-progressive inherited retinal disorders with characteristic electroretinogram (ERG) abnormalities. Riggs and Schubert-Bornschein are subtypes of CSNB and demonstrate distinct ERG features. Riggs CSNB demonstrates selective rod photoreceptor dysfunction and occurs due to mutations in genes encoding proteins involved in rod phototransduction cascade; night blindness is the only symptom and eye examination is otherwise normal. Schubert-Bornschein CSNB is a consequence of impaired signal transmission between the photoreceptors and bipolar cells. Schubert-Bornschein CSNB is subdivided into complete CSNB with an ON bipolar signaling defect and incomplete CSNB with both ON and OFF pathway involvement. Both subtypes are associated with variable degrees of night blindness or photophobia, reduced visual acuity, high myopia, and nystagmus. Whole-exome sequencing of a family screened negative for mutations in genes associated with CSNB identified biallelic mutations in the guanine nucleotide-binding protein subunit beta-3 gene (GNB3). Two siblings were compound heterozygous for a deletion (c.170_172delAGA [p.Lys57del]) and a nonsense mutation (c.1017G>A [p.Trp339(∗)]). The maternal aunt was homozygous for the nonsense mutation (c.1017G>A [p.Trp339(∗)]). Mutational analysis of GNB3 in a cohort of 58 subjects with CSNB identified a sporadic case individual with a homozygous GNB3 mutation (c.200C>T [p.Ser67Phe]). GNB3 encodes the β subunit of G protein heterotrimer (Gαβγ) and is known to modulate ON bipolar cell signaling and cone transducin function in mice. Affected human subjects showed an unusual CSNB phenotype with variable degrees of ON bipolar dysfunction and reduced cone sensitivity. This unique retinal disorder with dual anomaly in visual processing expands our knowledge about retinal signaling.
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http://dx.doi.org/10.1016/j.ajhg.2016.03.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867910PMC
May 2016