A Missense Mutation in OPA1 Causes Dominant Optic Atrophy in a Chinese Family

Abstract

Background To investigate the genetic causes and clinical characteristics of dominant optic atrophy (DOA) in a Chinese family. Methods A 5-generation pedigree of 35 family members including 12 individuals affected with DOA was recruited from Shenzhen Eye Hospital, China. Four affected family members and one unaffected family member were selected for whole exome sequencing. Sanger sequencing was used to confirm and screen the identified mutation in 18 members of the family. The disease-causing mutation was identified by bioinformatics analysis and confirmed by segregation analysis. The clinical characteristics of the family members were analyzed. Results A heterozygous missense mutation (c.1313A>G, p.D438G) in optic atrophy 1 (OPA1) was identified in 10 individuals affected with DOA in this family. None of the unaffected family members had the mutation. Patients in this family had vision loss since they were children or adolescence. The visual acuity decreased progressively to hand movement, except for one patient (IV-12) who had relatively good vision of 20/30 and 20/28. The fundus typically manifested as optic disc pallor. The visual fields, optical coherence tomography, and visual evoked potential suggested variable degree of abnormality in patients. Patients who had a history of cigarette smoking and alcohol drinking had more severe clinical manifestations. Conclusions Our results suggest that the p.D438G mutation in OPA1 causes optic atrophy in this family. The patients who carried the mutation demonstrated heterogeneous clinical manifestations in this family. This is the first report on the c.1313A>G (p.D438G) mutation of OPA1 in a Chinese family affected with DOA.

Findings from a Genotyping Study of over 1000 People with Inherited Retinal Disorders in Ireland

“…IRDs are typically caused by improper development or death of photoreceptor cells and have a substantial effect on both the quality of life of those affected and health economics. Inheritance patterns include autosomal recessive, autosomal dominant and X-linked, as well as rarer mitochondrial and digenic forms [1,2].…”

Mutations at a split codon in the GTPase-encoding domain of OPA1 cause dominant optic atrophy through different molecular mechanisms

“…All three possible variants affecting the second position of the codon (i.e. the first nucleotide of exon 14) have been identified in patients with DOA, namely c.1313A > C, p.(D438A) ( 26 ), c.1313A > G, p.(D438G) ( 27 , 28 ), and c.1313A > T, p.(D438V) ( 29 ). Variants affecting the first position of codon 438 (i.e.…”

Dynamic properties of mitochondria during human corticogenesis

“…In fact, mitochondrial diseases, which are linked to mutations that impair OXPHOS, affect about 1 in 5000 live births ( Schaefer et al, 2004 ). In addition, perturbations in genes involved in the maintenance of mitochondrial morphology and cristae dynamics also have devastating effects on human brain development ( Table 1 ) ( Amati-Bonneau et al, 2008 ; Assia Batzir et al, 2019 ; Bartsakoulia et al, 2018 ; Benincá et al, 2020 ; Fahrner et al, 2016 ; Gerber et al, 2017 ; Gödiker et al, 2018 ; Hogarth et al, 2018 ; Koch et al, 2016 ; Ladds et al, 2018 ; Mei et al, 2019 ; Nasca et al, 2018 ; Panda et al, 2020 ; Ryan et al, 2018 ; Schmid et al, 2019 ; Shamseldin et al, 2012 ; Sheffer et al, 2016 ; Shimizu et al, 2003 ; Tarailo-Graovac et al, 2019 ; Vanstone et al, 2016 ; Verrigni et al, 2019 ; von Spiczak et al, 2017 ; Waterham et al, 2007 ; Whitley et al, 2018 ; Zeharia et al, 2016 ). Although animal models have been pivotal for elucidating some phenotypes associated with dysfunctional mitochondria, human psychiatric and neurological conditions have developmental origins that cannot be fully understood using animal models ( Molnár et al, 2019 ; O'Rahilly and Müller, 2008 ).…”

“…Mitochondrial homeostasis is maintained through the concerted execution of mitochondrial dynamics (fusion and fission), cristae dynamics, motility and mitophagy ( Barnhart, 2016 ; Chen and Dorn, 2013 ; Cogliati et al, 2013 ; Frank et al, 2001 ; Giacomello et al, 2020 ; Schwarz, 2013 ; Scorrano et al, 2002 ; Ziviani et al, 2010 ). As evidence of the importance of these dynamic properties in the modulation of brain development, rare mutations in proteins involved in their regulation cause phenotypically heterogeneous and severe neurodevelopmental diseases ( Table 1 ) ( Amati-Bonneau et al, 2008 ; Assia Batzir et al, 2019 ; Bartsakoulia et al, 2018 ; Benincá et al, 2020 ; Fahrner et al, 2016 ; Gerber et al, 2017 ; Gödiker et al, 2018 ; Hogarth et al, 2018 ; Koch et al, 2016 ; Ladds et al, 2018 ; Mei et al, 2019 ; Nasca et al, 2018 ; Panda et al, 2020 ; Ryan et al, 2018 ; Schmid et al, 2019 ; Shamseldin et al, 2012 ; Sheffer et al, 2016 ; Shimizu et al, 2003 ; Tarailo-Graovac et al, 2019 ; Vanstone et al, 2016 ; Verrigni et al, 2019 ; von Spiczak et al, 2017 ; Waterham et al, 2007 ; Whitley et al, 2018 ; Zeharia et al, 2016 ). Emerging studies have highlighted the crosstalk between the mitochondrial dynamics machinery, the mitochondrial contact site and the cristae organizing system (MICOS), as well as motility and mitophagy machinery at the mitochondria ( Kageyama et al, 2014 ; Morciano et al, 2016 ; Fu et al, 2019 ; Picard et al, 2016 ).…”