Molecular and clinical characterization of the myopathic form of mitochondrial DNA depletion syndrome caused by mutations in the thymidine kinase (TK2) gene

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• 作者：Sirisak Chanprasert ; Jing Wang ; Shao-Wen Weng ; Gregory M. Enns ; Daniel R. Bou¨¦ ; Brenda L. Wong ; Jerry R. Mendell ; Deborah A. Perry ; Zarife Sahenk ; William J. Craigen ; Francisco J. Climent Alcala ; Juan M. Pascual ; Serge Melancon ; Victor Wei Zhang ; Fern ; o Scaglia ; Lee-Jun C. Wong
• 关键词：Thymidine kinase 2 gene ; Myopathic mtDNA depletion syndrome
• 刊名：Molecular Genetics and Metabolism
• 出版年：2013
• 出版时间：September-October, 2013
• 年：2013
• 卷：110
• 期：1-2
• 页码：153-161
• 全文大小：1224 K

文摘

Mitochondrial DNA (mtDNA) depletion syndromes (MDSs) are a clinically and molecularly heterogeneous group of mitochondrial cytopathies characterized by severe mtDNA copy number reduction in affected tissues. Clinically, MDSs are mainly categorized as myopathic, encephalomyopathic, hepatocerebral, or multi-systemic forms. To date, the myopathic form of MDS is mainly caused by mutations in the m>TK2m> gene, which encodes thymidine kinase 2, the first and rate limiting step enzyme in the phosphorylation of pyrimidine nucleosides. We analyzed 9 unrelated families with 11 affected subjects exhibiting the myopathic form of MDS, by sequencing the m>TK2m> gene. Twelve mutations including 4 novel mutations were detected in 9 families. Skeletal muscle specimens were available from 7 out of 11 subjects. Respiratory chain enzymatic activities in skeletal muscle were measured in 6 subjects, and enzymatic activities were reduced in 3 subjects. Quantitative analysis of mtDNA content in skeletal muscle was performed in 5 subjects, and marked mtDNA content reduction was observed in each. In addition, we outline the molecular and clinical characteristics of this syndrome in a total of 52 patients including those previously reported, and a total of 36 m>TK2m> mutations are summarized. Clinically, hypotonia and proximal muscle weakness are the major phenotypes present in all subjects. In summary, our study expands the molecular and clinical spectrum associated with TK2 deficiency.