Publications by authors named "Cécile Méjécase"

19 Publications

  • Page 1 of 1

The Genetic and Clinical Features of -Related Blepharophimosis, Ptosis and Epicanthus Inversus Syndrome.

Genes (Basel) 2021 Mar 4;12(3). Epub 2021 Mar 4.

Kings College Hospital NHS Foundation Trust, London SE5 9RS, UK.

Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a craniofacial disorder caused by heterozygous variants of the forkhead box L2 () gene. It shows autosomal dominant inheritance but can also occur sporadically. Depending on the mutation, two phenotypic subtypes have been described, both involving the same craniofacial features: type I, which is associated with premature ovarian failure (POF), and type II, which has no systemic features. The genotype-phenotype correlation is not fully understood, but it has been hypothesised that type I BPES involves more severe loss of function variants spanning the whole gene. Type II BPES has been linked to frameshift mutations that result in elongation of the protein rather than complete loss of function. A mutational hotspot has been identified within the poly-alanine domain, although the exact function of this region is still unknown. However, the BPES subtype cannot be determined genetically, necessitating informed genetic counselling and careful discussion of family planning advice in view of the associated POF particularly as the patient may still be a child. Following puberty, female patients should be referred for ovarian reserve and response assessment. Oculofacial features can be managed with surgical intervention and regular monitoring to prevent amblyopia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes12030364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998575PMC
March 2021

Ocular Phenotype Associated with Variants.

Genes (Basel) 2021 Feb 5;12(2). Epub 2021 Feb 5.

UCL Institute of Ophthalmology, London EC1V E9L, UK.

Dual-specificity tyrosine phosphorylation-regulated kinase 1A or contributes to central nervous system development in a dose-sensitive manner. Triallelic is implicated in the neuropathology of Down syndrome, whereas haploinsufficiency causes the rare -related intellectual disability syndrome (also known as mental retardation 7). It is characterised by intellectual disability, autism spectrum disorder and microcephaly with a typical facial gestalt. Preclinical studies elucidate a role for in eye development and case studies have reported associated ocular pathology. In this study families of the DYRK1A Syndrome International Association were asked to self-report any co-existing ocular abnormalities. Twenty-six patients responded but only 14 had molecular confirmation of a pathogenic variant. A further nineteen patients from the UK Genomics England 100,000 Genomes Project were identified and combined with 112 patients reported in the literature for further analysis. Ninety out of 145 patients (62.1%) with heterozygous variants revealed ocular features, these ranged from optic nerve hypoplasia (13%, 12/90), refractive error (35.6%, 32/90) and strabismus (21.1%, 19/90). Patients with variants should be referred to ophthalmology as part of their management care pathway to prevent amblyopia in children and reduce visual comorbidity, which may further impact on learning, behaviour, and quality of life.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes12020234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7915179PMC
February 2021

Generation of human iPSC line (UCLi013-A) from a patient with microphthalmia and aniridia, carrying a heterozygous missense mutation c.372C>A p.(Asn124Lys) in PAX6.

Stem Cell Res 2021 Mar 18;51:102184. Epub 2021 Jan 18.

UCL Institute of Ophthalmology, London, UK; The Francis Crick Institute, London, UK; Moorfields Eye Hospital NHS Foundation Trust, London, UK; Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. Electronic address:

A human induced pluripotent stem cell (hiPSC) line (UCLi013-A) was generated from fibroblast cells of a 34-year-old donor with multiple ocular conditions including severe microphthalmia and aniridia. The patient had a heterozygous missense mutation in PAX6 c.372C>A, p.(Asn124Lys), validated in the fibroblasts through Sanger sequencing. Fibroblasts derived from a skin biopsy were reprogrammed using integration free episomal reprogramming. The established iPSC line was found to express pluripotency markers, exhibit differentiation potential in vitro and display a normal karyotype. This cell line will act as a tool for disease modelling of microphthalmia and aniridia, identification of therapeutic targets and drug screening.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.scr.2021.102184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957338PMC
March 2021

A Novel Splice-Site Variant in Causes a Phenotype Synonymous with Åland Island Eye Disease and Incomplete Congenital Stationary Night Blindness.

Genes (Basel) 2021 Jan 27;12(2). Epub 2021 Jan 27.

Moorfields Eye Hospital UAE, Abu Dhabi 62807, United Arab Emirates.

Background: -related disorders encompass progressive and non-progressive disorders, including Åland island eye disease and incomplete congenital stationary night blindness. These two X-linked disorders are characterized by nystagmus, color vision defect, myopia, and electroretinography (ERG) abnormalities. Ocular hypopigmentation and iris transillumination are reported only in patients with Åland island eye disease. Around 260 variants were reported to be associated with these two non-progressive disorders, with 19 specific to Åland island eye disease and 14 associated with both Åland island eye disease and incomplete congenital stationary night blindness. variants spread on the gene and further analysis are needed to reveal phenotype-genotype correlation.

Case Report: A complete ocular exam and genetic testing were performed on a 13-year-old boy. A novel splice-site variant, c.4294-11C>G in intron 36 in , was identified at hemizygous state in the patient and at heterozygous state in his asymptomatic mother and explained the phenotype synonymous with Åland island eye disease and incomplete congenital stationary night blindness observed in the patient.

Conclusion: We present a novel variant in the gene causing phenotypic and electrophysiologic findings indistinguishable from those of AIED/CSNB2A disease. This finding further expands the mutational spectrum and our knowledge of -related disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes12020171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911795PMC
January 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaophthalmol.2020.6089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7844693PMC
March 2021

Generation of two human control iPS cell lines (UCLi016-A and UCLi017-A) from healthy donors with no known ocular conditions.

Stem Cell Res 2020 12 8;49:102113. Epub 2020 Dec 8.

UCL Institute of Ophthalmology, London, UK; The Francis Crick Institute, London, UK; Moorfields Eye Hospital NHS Foundation Trust, London, UK; Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. Electronic address:

Two human induced pluripotent stem cell (hiPSC) lines (UCLi016-A and UCLi017-A) were generated from fibroblast cells of 23- and 34-year-old healthy male donors with no known ocular conditions. Fibroblast cells were derived from skin biopsies and reprogrammed using integration free episomal reprogramming. The established iPSC lines were found to express pluripotency markers, exhibit differentiation potential in vitro and display a normal karyotype. These cell lines will act as a control lines for researchers studying ocular diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.scr.2020.102113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7768179PMC
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/cge.13872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049445PMC
February 2021

Practical guide to genetic screening for inherited eye diseases.

Ther Adv Ophthalmol 2020 Jan-Dec;12:2515841420954592. Epub 2020 Sep 22.

Professor, Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK.

Genetic eye diseases affect around one in 1000 people worldwide for which the molecular aetiology remains unknown in the majority. The identification of disease-causing gene variant(s) allows a better understanding of the disorder and its inheritance. There is now an approved retinal gene therapy for autosomal recessive retinopathy, and numerous ocular gene/mutation-targeted clinical trials underway, highlighting the importance of establishing a genetic diagnosis so patients can fully access the latest research developments and treatment options. In this review, we will provide a practical guide to managing patients with these conditions including an overview of inheritance patterns, required pre- and post-test genetic counselling, different types of cytogenetic and genetic testing available, with a focus on next generation sequencing using targeted gene panels, whole exome and genome sequencing. We will expand on the pros and cons of each modality, variant interpretation and options for family planning for the patient and their family. With the advent of genomic medicine, genetic screening will soon become mainstream within all ophthalmology subspecialties for prevention of disease and provision of precision therapeutics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2515841420954592DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7513416PMC
September 2020

The genetic landscape of inherited eye disorders in 74 consecutive families from the United Arab Emirates.

Am J Med Genet C Semin Med Genet 2020 09 11;184(3):762-772. Epub 2020 Aug 11.

Institute of Ophthalmology, University College London, London, UK.

Genetic eye diseases are phenotypically and genetically heterogeneous, affecting 1 in 1,000 people worldwide. This prevalence can increase in populations where endogamy is a social preference, such as in Arab populations. A retrospective consecutive cohort of 91 patients from 74 unrelated families affected with non-syndromic and syndromic inherited eye disease presenting to the ocular genetics service at Moorfields Eye Hospitals United Arab Emirates (UAE) between 2017 and 2019, underwent clinically accredited genetic testing using targeted gene panels. The mean ± SD age of probands was 27.4 ± 16.2 years, and 45% were female (41/91). The UAE has a diverse and dynamic population, and the main ethnicity of families in this cohort was 74% Arab (n = 55), 8% Indian (n = 6) and 7% Pakistani (n = 5). Fifty-six families (90.3%) were genetically solved, with 69 disease-causing variants in 40 genes. Fourteen novel variants were detected with large deletions in CDHR1 and TTLL5, a multiexon (1-8) duplication in TEAD1 and 11 single nucleotides variants in 9 further genes. ABCA4-retinopathy was the most frequent cause accounting for 21% of cases, with the confirmed UAE founder mutation c.5882G>A p.(Gly1961Glu)/c.2570T>C p.(Leu857Pro) in 25%. High diagnostic yield for UAE patients can guide prognosis, family decision-making, access to clinical trials and approved treatments.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.c.31824DOI Listing
September 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20205053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829239PMC
October 2019

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaophthalmol.2018.6367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567841PMC
June 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms19082196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121640PMC
July 2018

A Novel Heterozygous Missense Mutation in Leads to Autosomal Dominant Riggs Type of Congenital Stationary Night Blindness.

Biomed Res Int 2018 23;2018:7694801. Epub 2018 Apr 23.

Department of Ophthalmology and Byers Eye Institute, Stanford University School of Medicine, Palo Alto, CA, USA.

Autosomal dominant congenital stationary night blindness (adCSNB) is rare and results from altered phototransduction giving a Riggs type of electroretinogram (ERG) with loss of the rod a-wave and small b-waves. These patients usually have normal vision in light. Only few mutations in genes coding for proteins of the phototransduction cascade lead to this condition; most of these gene defects cause progressive rod-cone dystrophy. Mutation analysis of an adCSNB family with a Riggs-type ERG revealed a novel variant (c.155T>A p.Ile52Asn) in coding for the -subunit of transducin, cosegregating with the phenotype. Domain predictions and 3D-modelling suggest that the variant does not affect the GTP-binding site as other adCSNB mutations do. It affects a predicted nuclear localization signal and a part of the first -helix, which is distant from the GTP-binding site. The subcellular protein localization of this and other mutant GNAT1 proteins implicated in CSNB are unaltered in mammalian GNAT1 overexpressing cells. Our findings add a third mutation causing adCSNB and suggest that different pathogenic mechanisms may cause this condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2018/7694801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5937575PMC
October 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/humu.23431DOI Listing
July 2018

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0168271PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5158031PMC
July 2017