ABSTRACT

Background

Autosomal Dominant Optic Atrophy (ADOA) is caused by mutations in the Optic Atrophy 1 Gene which disrupts the OPA1 protein. This disruption affects the normal function of the protein; impairs fusion of the mitochondrial inner membrane; and prevents normal OPA1 protein degradation. These events cause damage in retinal ganglion cells that could affect the patients with symptoms ranging from none to legally blind.

Materials and methods

Our study identifies a missense variant mutation, c.1024 A > G (p.K342E), in OPA1 gene causing ADOA. Diagnosed clinically in three family members and the presence of this mutation was confirmed in two members by genetic testing. Pathogenic variants in OPA1 impact the secondary protein structure and function by causing non-conservative amino acid substitutions. We also modeled this mutation and compared it to the wild type using statistical mechanics.

Results and conclusions

The proband’s pathogenic variant, c.1024 A > G (p.K342E), is located in the GTPase domain of OPA1 and causes changes in the protein structure by affecting the oligomerization pattern thus resulting in ADOA. Identifying the pathogenic potential of the missense mutations in the OPA1 gene using neoteric protein modeling techniques would help in the early detection of ADOA in patients who have family history of blindness. This action would help in providing early follow up, possible treatment in the future, and genetic counseling.

Abbreviations: ADOA: Autosomal Dominant Optic Atrophy; CYCS: Caspase Activator Cytochrome C; OPA1: Optic Atrophy Gene 1; RGC: Retinal Ganglion Cells; VUS: Variant of Uncertain Significance

中文翻译：

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基因组学结合蛋白质信息学平台，评估常染色体显性视神经萎缩患者OPA1中的新型致病变异c.1024 A> G（p.K342E）。

摘要

背景

常染色体显性视神经萎缩（ADOA）是由视神经萎缩1基因突变引起的，该基因破坏了OPA1蛋白。这种破坏影响蛋白质的正常功能。损害线粒体内膜的融合；并防止正常的OPA1蛋白降解。这些事件会导致视网膜神经节细胞受损，从而影响患者的症状，从无症状到合法失明。

材料和方法

我们的研究在引起ADOA的OPA1基因中鉴定出一个错义变异体，突变c.1024 A> G（p.K342E）。临床上有3个家庭成员进行了诊断，通过基因测试证实了2个成员中存在此突变。OPA1中的致病变体通过引起非保守氨基酸取代，影响二级蛋白质的结构和功能。我们还对该突变进行了建模，并使用统计机制将其与野生型进行了比较。

结果与结论

先证者的致病变异体c.1024 A> G（p.K342E）位于OPA1的GTPase域中，并通过影响寡聚化模式而导致蛋白质结构发生变化，从而导致ADOA。使用新型蛋白质建模技术鉴定OPA1基因中错义突变的致病潜力，将有助于早期发现患有失明家族史的患者的ADOA。该行动将有助于提供早期随访，将来可能的治疗以及遗传咨询。

缩写： ADOA：常染色体显性视神经萎缩；CYCS：胱天蛋白酶激活剂细胞色素C；OPA1：视神经萎缩基因1；RGC：视网膜神经节细胞；VUS：不确定意义的变体