Clinical and genetic features of eight Chinese autosomal-dominant optic atrophy pedigrees with six novel<i>OPA1</i>pathogenic variants

Li, Huajin; Jones, E. M.; Li, Hui; Yang, Lizhu; Sun, Zixi; Yuan, Zhisheng; Chen, Rui; Fang, Dong; Sui, Ruifang

doi:10.1080/13816810.2018.1466337

Cited by 6 publications

(3 citation statements)

References 50 publications

(46 reference statements)

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“…Missense OPA1 variant (p.Cys490Arg) in exon 14 was identified in this patient. This variant has been reported in a previous study, and hearing loss was noted in one out of two patients with this variant [34]. In addition to this variant, our patient had PARL nonsense variant, which was determined as pathogenic by ACMG classification.…”

Section: Discussionsupporting

confidence: 72%

“…Hotspots such as p.Arg445His mutations were found to be associated with sensorineural deafness and optic atrophy [ 21 , 31 , 32 , 33 ]. However, other variants have also been proposed in previous studies [ 31 , 32 , 33 , 34 ]. Some studies have hypothesized that the dominant negative effect caused by missense mutations results in the ADOA plus syndrome [ 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

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Genetic Spectrum and Characteristics of Hereditary Optic Neuropathy in Taiwan

Lin

Huang

Luo

et al. 2021

Genes

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Hereditary optic neuropathy (HON) is a group of genetically heterogeneous diseases that cause optic nerve atrophy and lead to substantial visual impairment. HON may present with optic nerve atrophy only or in association with various systemic abnormalities. Although a genetic survey is indispensable for diagnosing HON, conventional sequencing techniques could render its diagnosis challenging. In this study, we attempted to explore the genetic background of patients with HON in Taiwan through capture-based next-generation sequencing targeting 52 HON-related genes. In total, 57 patients from 48 families were recruited, with 6 patients diagnosed as having Leber hereditary optic neuropathy through initial screening for three common variants (m.3460G>A, m.11778G>A, m.14484T>C). Disease-causing genotypes were identified in 14 (33.3%) probands, and OPA1 variants were the most prevalent cause of autosomal HON. Exposure to medications such as ethambutol could trigger an attack of autosomal dominant optic atrophy. WFS1 variants were identified in three probands with variable clinical features in our cohort. Hearing impairment could occur in patients with OPA1 or WFS1 variants. This is the first comprehensive study investigating the genetic characteristics of HON in Taiwan, especially for autosomal HON. Our results could provide useful information for clinical diagnosis and genetic counseling in this field.

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Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Genetic Spectrum and Characteristics of Hereditary Optic Neuropathy in Taiwan

Lin

Huang

Luo

et al. 2021

Genes

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“…The frequency of OPA1 mutations is high in Han Chinese Patients with Optic Neuropathy (9). Here, a novel heterozygous variant, c.1444-2A>C in intron 14 of OPA1 (NM_015560), was found in a sporadic DOA patient with centrocecal scotoma and pale temporal optic disc in both eyes.…”

Section: Introductionmentioning

confidence: 82%

OPA1 haploinsufficiency due to a novel splicing variant resulting in mitochondrial dysfunction without mitochondrial DNA depletion

Sun

Bai

et al. 2020

Ophthalmic Genetics

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Background: To identify and investigate the effects of a novel splicing variant, c.1444-2A>C of OPA1, on its transcript, translation, and mitochondrial function, which was found in an 8-year-old patient with dominantly inherited optic atrophy (DOA). Materials and Methods: The clinical evaluations were performed at the Eye Center. Lymphoblast cell lines were generated from the patient, mother, and a normal control with the same haplotype of mitochondrial genome. The novel variant was confirmed by Sanger sequencing. The splicing alteration of cDNA was checked by both Sanger sequencing and agarose gel. OPA1 expression was carried out by RT-PCR and Western blotting. Transmission electron microscopy was used for mitochondrial morphology. Mitochondrial functions, including the rates of oxygen consumption, ATP generation, ROS product and membrane potential were assayed in lymphoblast cells. Results: The novel OPA1 splicing variant, c.1444-2A>C, led to a deletion of the 15th exon in mRNA transcript. Approximately 50% reduction of mRNA and protein expression was present in mutant cells as compared with controls. No marked depletion of mtDNA nor mitochondrial mass was caused by the splicing variant. However, defects that the impaired capacity of OXPHOS, reduced ATP generation, increased ROS and decreased membrane potential were observed in the mutant cells, which promoted a ubiquitin-binding mitophagy instead of apoptosis. Conclusions: The novel splicing variant, c.1444-2A>C resulted in OPA1 haploinsufficiency effect on its expression and mitochondrial function without mtDNA depletion. Our findings may provide new insights into the understanding of pathophysiology of DOA.

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