Stewart J D, Tennant S, Powell H, Pyle A, Blakely E L, He L, Hudson G, Roberts M, du Plessis D, Gow D, Mewasingh L D, Hanna M G, Omer S, Morris A A, Roxburgh R, Livingston J H, McFarland R, Turnbull D M, Chinnery P F, Taylor R W
Mitochondrial Research Group, The Medical School, Newcastle University, Framlington Place, Newcastle upon Tyne, NE2 4HH, UK.
J Med Genet. 2009 Mar;46(3):209-14. doi: 10.1136/jmg.2008.058180.
The POLG1 gene encodes the catalytic subunit of DNA polymerase gamma, essential for mitochondrial DNA replication and repair. Mutations in POLG1 have been linked to a spectrum of clinical phenotypes, and may account for up to 25% of all adult presentations of mitochondrial disease.
We present 14 patients, with characteristic features of mitochondrial disease including progressive external ophthalmoplegia (PEO) and Alpers-Huttenlocher syndrome and laboratory findings indicative of mitochondrial dysfunction, including cytochrome c oxidase (COX) deficiency and multiple deletions or depletion of the mitochondrial DNA. Four novel POLG1 missense substitutions (p.R597W, p.L605R, p.G746S, p.A862T), are described, together with the first adult patient with a recently described polymerase domain mutation (p.R1047W). All novel changes were rare in a control population and affected highly conserved amino acids.
The addition of these substitutions-including the first report of a dinucleotide mutation (c.1814_1815TT>GC)-to the growing list of defects further confirms the importance of POLG1 mutations as the underlying abnormality in a range of neurological presentations.
POLG1基因编码DNA聚合酶γ的催化亚基，这对于线粒体DNA复制和修复至关重要。POLG1基因突变与一系列临床表型相关，可能占所有成人线粒体疾病病例的25%。
我们报告了14例患者，他们具有线粒体疾病的特征性表现，包括进行性眼外肌麻痹（PEO）和阿尔珀斯-许滕洛赫尔综合征，实验室检查结果提示线粒体功能障碍，包括细胞色素c氧化酶（COX）缺乏以及线粒体DNA的多处缺失或耗竭。本文描述了4种新的POLG1错义替代突变（p.R597W、p.L605R、p.G746S、p.A862T），以及首例患有最近描述的聚合酶结构域突变（p.R1047W）的成年患者。所有新发现的突变在对照人群中均很罕见，且影响高度保守的氨基酸。
这些替代突变的发现——包括首例二核苷酸突变（c.1814_1815TT>GC）的报告——进一步证实了POLG1突变作为一系列神经学表现潜在异常的重要性。 新增的这些突变，使得POLG1突变导致相关疾病的案例列表不断增加，从而进一步证明了POLG1突变在一系列神经学症状中作为潜在异常的重要性。
