Mitochondrial DNA polymerase-γ and human disease

被引:161
作者
Hudson, Gavin
Chinnery, Patrick F.
机构
[1] Newcastle Univ, Sch Med, Mitochondrial Res Grp, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England
[2] Newcastle Univ, Sch Med, Inst Human Genet, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England
关键词
PROGRESSIVE EXTERNAL OPHTHALMOPLEGIA; POLG MUTATIONS; ALPERS-SYNDROME; MTDNA MAINTENANCE; MALE-INFERTILITY; NEUROGASTROINTESTINAL ENCEPHALOMYOPATHY; TRANSCRIPTION FACTOR; ACCESSORY SUBUNIT; POINT MUTATIONS; COPY NUMBER;
D O I
10.1093/hmg/ddl233
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The maintenance of mitochondrial DNA (mtDNA) is critically dependent upon polymerase-gamma (pol-gamma), encoded by the nuclear gene POLG. Over the last 5 years, it has become clear that mutations of POLG are a major cause of human disease. Secondary mtDNA defects characterize these disorders, with mtDNA depletion, multiple mtDNA deletions or multiple point mutations of mtDNA in clinically affected tissues. The secondary mtDNA defects cause cell and tissue-specific deficiencies of mitochondrial oxidative phosphorylation, leading to organ dysfunction and human disease. Functional genetic variants of POLG are present in up to similar to 0.5% of the general population, and pathogenic mutations have been described in most exons of the gene. Clinically, POLG mutations can present from early neonatal life to late middle age, with a spectrum of phenotypes that includes common neurological disorders such as migraine, epilepsy and Parkinsonism. Transgenic mice and biochemical studies of recombinant mutated proteins are helping to unravel mechanisms of pathogenesis, and patterns are beginning to emerge relating genotype to phenotype.
引用
收藏
页码:R244 / R252
页数:9
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