Gibson Shelley, Azamian Mahshid S, Lalani Seema R, Yen Kimberly G, Sutton V Reid, Scott Daryl A
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Texas Children's Hospital, Houston, Texas, USA.
Am J Med Genet A. 2020 Aug;182(8):1960-1966. doi: 10.1002/ajmg.a.61634. Epub 2020 May 25.
The mitochondrial aconitase gene (ACO2) encodes an enzyme that catalyzes the conversion of citrate to isocitrate in the tricarboxylic acid cycle. Biallelic variants in ACO2 are purported to cause two distinct disorders: infantile cerebellar-retinal degeneration (ICRD) which is characterized by CNS abnormalities, neurodevelopmental phenotypes, optic atrophy and retinal degeneration; and optic atrophy 9 (OPA9), characterized by isolated ophthalmologic phenotypes including optic atrophy and low vision. However, some doubt remains as to whether biallelic ACO2 variants can cause isolated ophthalmologic phenotypes. A review of the literature revealed five individuals from three families who carry biallelic ACO2 variants whose phenotypes are consistent with OPA9. Here, we describe a brother and sister with OPA9 who are compound heterozygous for novel missense variants in ACO2; c.[487G>T];[1894G>A], p.[(Val163Leu)];[(Val632Met)]. A review of pathogenic ACO2 variants revealed that those associated with OPA9 are distinct from those associated with ICRD. Missense variants associated with either OPA9 or ICRD do not cluster in distinct ACO2 domains, making it difficult to predict the severity of a variant based on position alone. We conclude that biallelic variants in ACO2 can cause the milder OPA9 phenotype, and that the OPA9-related ACO2 variants identified to date are distinct from those that cause ICRD.
线粒体乌头酸酶基因（ACO2）编码一种在三羧酸循环中催化柠檬酸转化为异柠檬酸的酶。据称，ACO2的双等位基因变异会导致两种不同的疾病：婴儿小脑视网膜变性（ICRD），其特征为中枢神经系统异常、神经发育表型、视神经萎缩和视网膜变性；以及视神经萎缩9型（OPA9），其特征为包括视神经萎缩和视力低下在内的孤立眼科表型。然而，关于双等位基因ACO2变异是否会导致孤立眼科表型仍存在一些疑问。文献综述发现，来自三个家族的五名个体携带双等位基因ACO2变异，其表型与OPA9一致。在此，我们描述了一对患有OPA9的兄妹，他们是ACO2中新型错义变异的复合杂合子；c.[487G>T]；[1894G>A]，p.[(Val163Leu)]；[(Val632Met)]。对致病性ACO2变异的综述表明，与OPA9相关的变异与与ICRD相关的变异不同。与OPA9或ICRD相关的错义变异并不聚集在ACO2的不同结构域中，因此仅根据位置很难预测变异的严重程度。我们得出结论，ACO2中的双等位基因变异可导致较轻的OPA9表型，并且迄今为止鉴定出的与OPA9相关的ACO2变异与导致ICRD的变异不同。
