A novel mutation in MERTK for rod-cone dystrophy in a North Indian family

Bhatia, Sofia; Kaur, Navdeep; Singh, Indu; Vanita, Vanita

doi:10.1016/j.jcjo.2018.02.008

Cited by 8 publications

(9 citation statements)

References 24 publications

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“…RD may be inherited as an autosomal dominant (AD), autosomal recessive (AR), X-linked (XL), or mitochondrial traits. Rare forms of RP have also been reported before, such as X-linked dominant inheritance, digenic diallelic, and triallelic mutations [3]. Different genes are associated with similar clinical phenotypes being obstacles to targeted genetic analyses.…”

Section: Introductionmentioning

confidence: 95%

High-Throughput Sequencing to Identify Mutations Associated with Retinal Dystrophies

Song

Owczarek‐Lipska

Ahmels

et al. 2021

Genes

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Retinal dystrophies (RD) are clinically and genetically heterogenous disorders showing mutations in over 270 disease-associated genes. Several millions of people worldwide are affected with different types of RD. Studying the relevance of disease-associated sequence alterations will assist in understanding disorders and may lead to the development of therapeutic approaches. Here, we established a whole exome sequencing (WES) pipeline to rapidly identify disease-associated mutations in patients. Sanger sequencing was applied to identify deep-intronic variants and to verify the co-segregation of WES results within families. We analyzed 26 unrelated patients with different syndromic and non-syndromic clinical manifestations of RD. All patients underwent ophthalmic examinations. We identified nine novel disease-associated sequence variants among 37 variants identified in total. The sequence variants located to 17 different genes. Interestingly, two cases presenting with Stargardt disease carried deep-intronic variants in ABCA4. We have classified 21 variants as pathogenic variants, 4 as benign/likely benign variants, and 12 as variants of uncertain significance. This study highlights the importance of WES-based mutation analyses in RD patients supporting clinical decisions, broadly based genetic diagnosis and support genetic counselling. It is essential for any genetic therapy to expand the mutation spectrum, understand the genes’ function, and correlate phenotypes with genotypes.

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Section: Introductionmentioning

confidence: 95%

High-Throughput Sequencing to Identify Mutations Associated with Retinal Dystrophies

Song

Owczarek‐Lipska

Ahmels

et al. 2021

Genes

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“…encode proteins with yet-unknown function [5]. In addition, genetic abnormalities expressed in various organs other than the eyes cause syndromic RP such as Usher syndrome [6]. In relation to these diverse functions of causative genes, considerable ethnic and regional differences are expected in its genetic landscape [7,8].…”

Section: Patientsmentioning

confidence: 99%

“…Diverse functions of RP causative genes involve various pathways, i.e., phototransduction, vitamin A metabolism, signaling, cell–cell interaction, and protein synthesis, i.e., structural or cytoskeletal proteins, synaptic interaction proteins, mRNA intron-splicing factors, trafficking of intracellular proteins, maintenance of cilia/ciliated cells, phagocytosis, pH regulator and a few encode proteins with yet-unknown function [ 5 ]. In addition, genetic abnormalities expressed in various organs other than the eyes cause syndromic RP such as Usher syndrome [ 6 ]. In relation to these diverse functions of causative genes, considerable ethnic and regional differences are expected in its genetic landscape [ 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

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Diverse Genetic Landscape of Suspected Retinitis Pigmentosa in a Large Korean Cohort

Kim

Yoon

et al. 2021

Genes

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We conducted targeted next-generation sequencing (TGS) and/or whole exome sequencing (WES) to assess the genetic profiles of clinically suspected retinitis pigmentosa (RP) in the Korean population. A cohort of 279 unrelated Korean patients with clinically diagnosed RP and available family members underwent molecular analyses using TGS consisting of 88 RP-causing genes and/or WES with clinical variant interpretation. The combined genetic tests (TGS and/or WES) found a mutation in the 44 RP-causing genes and seven inherited retinal disease (IRD)-causing genes, and the total mutation detection rate was 57%. The mutation detection rate was higher in patients who experienced visual deterioration at a younger age (75.4%, age of symptom onset under 10 years) and who had a family history of RP (70.7%). The most common causative genes were EYS (8.2%), USH2A (6.8%), and PDE6B (4.7%), but mutations were dispersed among the 51 RP/IRD genes generally. Meanwhile, the PDE6B mutation was the most common in patients experiencing initial symptoms in their first decade, EYS in their second to third decades, and USH2A in their fifth decades and older. Of note, WES revealed some unexpected genotypes: ABCC6, CHM, CYP4V2, RS1, TGFBI, VPS13B, and WDR19, which were verified by ophthalmological re-phenotyping.

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“…Nowadays, around 90 genes were identified to be associated with non-syndromic RP (https://sph.uth.tmc.edu/retnet/). The proteins encoded by RP-associated genes exert different roles in transcription, retina phototransduction, transport processes via the photoreceptor connecting cilium, cell growth, cellular structure, and metabolism of vitamin A (Collin et al, 2011;Bhatia et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Autosomal Recessive Rod-Cone Dystrophy Associated With Compound Heterozygous Variants in ARL3 Gene

Yao

et al. 2021

Front. Cell Dev. Biol.

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Purpose:ARL3 (ADP-ribosylation factor-like 3) variants cause autosomal dominant retinitis pigmentosa (RP) or autosomal recessive Joubert syndrome. We found a family with rod-cone dystrophy (RCD) and verified it was associated with compound heterozygous variants in ARL3 gene.Methods: Ophthalmic examinations including optical coherence tomography and electroretinogram (ERG) were performed. Targeted next generation sequencing (NGS) was performed for the proband using a custom designed panel. Sanger sequencing and co-segregation were conducted in the family members. Changes of protein structure mediated by the variants were studied in vitro. ARL3 protein stability and its interaction with RP2 protein were assessed by cycloheximide chase assay and co-immunoprecipitation (Co-IP) assay.Results: Visual acuity of the 18-year-old male proband was 0.25 in the right and 0.20 in the left eye, while his non-consanguineous parents and sister was normal. The proband showed signs of RCD, including nyctalopia, peripheral field loss, bone-spicule deposits in the retina, and reduced ERG responses. The father, aged 50 years old, showed visual acuity of 1.0 in both eyes. Unlike the proband, he presented late onset and mild cone-rod dystrophy (CRD), including macular atrophy, central scotomata, moderate reduction in photopic ERG responses. None of all the family members had hearing abnormality, mental dysplasia or gait instability. We identified two novel compound heterozygous variants (c.91A>G, p.T31A; c.353G>T, p.C118F) in ARL3 in the proband, while his father only had variant c.91A>G. Bioinformatics analysis indicated amino acid positions of the two variants are highly conserved among species. The in silico tools predicted the variants to be harmful. Protein structure analysis showed the two variants had potential to alter the protein structure. Based on the ACMG guidelines, the two variants were likely pathogenic. In addition, the ARL3 mutations destabilized ARL3 protein, and the mutation c.353G>T disrupted the interaction between ARL3 and RP2 in HEK293T cells.Conclusions: We showed novel compound heterozygous variants in ARL3 were associated with early onset of autosomal recessive RCD, while c.91A>G along may be associated with a late onset of dominant CRD. The two variants in ARL3 could be causative by destabilizing ARL3 protein and impairing its interaction with RP2 protein.

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A novel mutation in MERTK for rod-cone dystrophy in a North Indian family

Cited by 8 publications

References 24 publications

High-Throughput Sequencing to Identify Mutations Associated with Retinal Dystrophies

High-Throughput Sequencing to Identify Mutations Associated with Retinal Dystrophies

Diverse Genetic Landscape of Suspected Retinitis Pigmentosa in a Large Korean Cohort

Autosomal Recessive Rod-Cone Dystrophy Associated With Compound Heterozygous Variants in ARL3 Gene

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