Zabalza Ramón, Nurminen Anssi, Kaguni Laurie S, Garesse Rafael, Gallardo M Esther, Bornstein Belén
Departamento de Bioquímica, Facultad de Medicina, Instituto de Investigaciones Biomédicas "Alberto Sols" UAM-CSIC and Centro de Investigación Biomédica en Red (CIBERER), Madrid, Spain.
BMC Res Notes. 2014 Dec 8;7:883. doi: 10.1186/1756-0500-7-883.
Mitochondrial DNA maintenance disorders are an important cause of hereditary ataxia syndrome, and the majority are associated with mutations in the gene encoding the catalytic subunit of the mitochondrial DNA polymerase (DNA polymerase gamma), POLG. Mutations resulting in the amino acid substitutions A467T and W748S are the most common genetic causes of inherited cerebellar ataxia in Europe.
We report here a POLG mutational screening in a family with a mitochondrial ataxia phenotype. To evaluate the likely pathogenicity of each of the identified changes, a 3D structural analysis of the PolG protein was carried out, using the Alpers mutation clustering tool reported previously.
Three novel nucleotide changes and the p.Q1236H polymorphism have been identified in the affected members of the pedigree. Computational analysis suggests that the p.K601E mutation is likely the major contributing factor to the pathogenic phenotype.
Computational analysis of the PolG protein suggests that the p.K601E mutation is likely the most significant contributing factor to a pathogenic phenotype. However, the co-occurrence of multiple POLG alleles may be necessary in the development an adult-onset mitochondrial ataxia phenotype.
线粒体DNA维持障碍是遗传性共济失调综合征的重要病因，大多数与线粒体DNA聚合酶（DNA聚合酶γ）催化亚基编码基因POLG的突变有关。导致氨基酸替换A467T和W748S的突变是欧洲遗传性小脑共济失调最常见的遗传病因。
我们在此报告一个具有线粒体共济失调表型的家系的POLG突变筛查。为评估每个已鉴定变化的可能致病性，使用先前报道的阿尔珀斯突变聚类工具对PolG蛋白进行了三维结构分析。
在家系的受累成员中鉴定出三个新的核苷酸变化和p.Q1236H多态性。计算分析表明，p.K601E突变可能是致病表型的主要促成因素。
对PolG蛋白的计算分析表明，p.K601E突变可能是致病表型最重要的促成因素。然而，在成人发病的线粒体共济失调表型的发生过程中，多个POLG等位基因的共同出现可能是必要的。
