Dataset Information

Clinical and genetic features of eight Chinese autosomal-dominant optic atrophy pedigrees with six novel OPA1 pathogenic variants.

ABSTRACT:

Background

Autosomal-dominant optic atrophy (ADOA) is one of the most common types of inherited optic atrophy. We identify OPA1 pathogenic variants and assess the clinical features of a cohort of Chinese ADOA patients Materials and Methods: Detailed clinical evaluations were performed and genomic DNA was extracted from peripheral blood for all the participants. Sanger sequencing was used to analyze all exons and exon/intron junctions of OPA1 for eight pedigrees. Target exome capture plus next-generation sequencing (NGS) were applied for one atypical family with photophobia. Reverse transcription polymerase chain reaction was carried out to further characterize the mRNA change of selected splicing alteration.

Results

All 17 patients had impaired vision and optic-disk pallor; however, the clinical severity varied markedly. Two patients complicated with hearing loss. Six novel and two reported pathogenic variants in OPA1 (GenBank Accession No. NM_130837.2) were identified including four nonsynonymous variants (c.2400T > G, c.1468T > C, c.1567A > G and c.1466T > C), two splicing variants (c.2984-1_2986delGAGA and c.2983 + 5G > A), one small deletion (c.2960_2968delGCGTTCAAC), and one small insertion (c.3009_3010insA). RNA analysis revealed the splicing variant c.2984-1_2986delGAGA caused small deletion of mRNA (r.2983_2988del).

Conclusions

ADOA patients presented variable clinical manifestations. Novel OPA1 pathogenic variants are the main genetic defect for Chinese ADOA cases. NGS may be a useful molecular testing tool for atypical ADOA.

SUBMITTER: Li H

PROVIDER: S-EPMC6239416 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Publications

Clinical and genetic features of eight Chinese autosomal-dominant optic atrophy pedigrees with six novel OPA1 pathogenic variants.

Li Huajin H Jones Evan M EM Li Hui H Yang Lizhu L Sun Zixi Z Yuan Zhisheng Z Chen Rui R Dong Fangtian F Sui Ruifang R

Ophthalmic genetics 20180628 5

<h4>Background</h4>Autosomal-dominant optic atrophy (ADOA) is one of the most common types of inherited optic atrophy. We identify OPA1 pathogenic variants and assess the clinical features of a cohort of Chinese ADOA patients Materials and Methods: Detailed clinical evaluations were performed and genomic DNA was extracted from peripheral blood for all the participants. Sanger sequencing was used to analyze all exons and exon/intron junctions of OPA1 for eight pedigrees. Target exome capture plus ...[more]

PMID: 29952689

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Project description:Autosomal dominant optic atrophy (DOA) is the most common inherited optic neuropathy, characterized by the preferential loss of retinal ganglion cells (RGCs), resulting in optic nerve degeneration and progressive bilateral central vision loss. More than 60% of genetically confirmed patients with DOA carry variants in the nuclear OPA1 gene, which encodes for a ubiquitously expressed, mitochondrial GTPase protein. OPA1 has diverse functions within the mitochondrial network, facilitating inner membrane fusion and cristae modelling, regulating mitochondrial DNA maintenance and coordinating mitochondrial bioenergetics. There are currently no licensed disease-modifying therapies for DOA and the disease mechanisms driving RGC degeneration are poorly understood. Here, we describe the generation of isogenic, heterozygous OPA1 null induced pluripotent stem cell (iPSC) (OPA1+/-) through clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing of a control cell line, in conjunction with the generation of DOA patient-derived iPSC carrying OPA1 variants, namely, the c.2708_2711delTTAG variant (DOA iPSC), and previously reported missense variant iPSC line (c.1334G>A, DOA plus [DOA]+ iPSC) and CRISPR/Cas9 corrected controls. A two-dimensional (2D) differentiation protocol was used to study the effect of OPA1 variants on iPSC-RGC differentiation and mitochondrial function. OPA1+/-, DOA and DOA+ iPSC showed no differentiation deficit compared to control iPSC lines, exhibiting comparable expression of all relevant markers at each stage of differentiation. OPA1+/- and OPA1 variant iPSC-RGCs exhibited impaired mitochondrial homeostasis, with reduced bioenergetic output and compromised mitochondrial DNA maintenance. These data highlight mitochondrial deficits associated with OPA1 dysfunction in human iPSC-RGCs, and establish a platform to study disease mechanisms that contribute to RGC loss in DOA, as well as potential therapeutic interventions.

Dataset Information

Clinical and genetic features of eight Chinese autosomal-dominant optic atrophy pedigrees with six novel OPA1 pathogenic variants.

Background

Results

Conclusions

Publications

Clinical and genetic features of eight Chinese autosomal-dominant optic atrophy pedigrees with six novel OPA1 pathogenic variants.

Similar Datasets

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