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

被引：32

作者：

Chanprasert, Sirisak ^{[1
]}

Wang, Jing ^{[1
]}

Weng, Shao-Wen ^{[1
,2
]}

Enns, Gregory M. ^{[8
]}

Boue, Daniel R. ^{[3
,4
]}

Wong, Brenda L. ^{[5
]}

Mendell, Jerry R. ^{[6
]}

Perry, Deborah A. ^{[7
]}

Sahenk, Zarife ^{[3
,4
]}

Craigen, William J. ^{[1
,12
]}

Climent Alcala, Francisco J. ^{[10
]}

Pascual, Juan M. ^{[9
]}

Melancon, Serge ^{[11
]}

Zhang, Victor Wei ^{[1
]}

Scaglia, Fernando ^{[1
,12
]}

Wong, Lee-Jun C. ^{[1
]}

机构：

[1] Baylor Coll Med, Houston, TX 77030 USA

[2] Chang Gung Univ, Coll Med, Kaohsiung Med Ctr, Dept Internal Med,Chang Gung Mem Hosp, Kaohsiung, Taiwan

[3] Nationwide Childrens Hosp, Res Inst, Ctr Gene Therapy, Columbus, OH USA

[4] Nationwide Childrens Hosp, Clin Neuromuscular Lab, Columbus, OH USA

[5] Cincinnati Childrens Hosp Med Ctr, Div Pediat Neurol, Cincinnati, OH 45229 USA

[6] Nationwide Childrens Hosp, Res Inst, Columbus, OH USA

[7] Childrens Hosp & Med Ctr, Dept Pathol, Omaha, NE USA

[8] Stanford Univ, Sch Med, Dept Pediat, Div Med Genet, Stanford, CA USA

[9] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA

[10] Hosp La Paz, Madrid, Spain

[11] McGill Univ, Div Med Genet, Montreal, PQ, Canada

[12] Texas Childrens Hosp, Houston, TX 77030 USA

来源：

MOLECULAR GENETICS AND METABOLISM | 2013年 / 110卷 / 1-2期

关键词：

Thymidine kinase 2 gene; Myopathic mtDNA depletion syndrome; MTDNA DEPLETION; TRIPHOSPHATE POOLS; REPLICATION; DEFICIENCY; SPECTRUM; DISEASES; DEFECT;

D O I：

10.1016/j.ymgme.2013.07.009

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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 TK2 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 TK2 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 TK2 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. (C) 2013 Elsevier Inc. All rights reserved.

引用

页码：153 / 161

页数：9

共 33 条

[1] Depletion of mtDNA: Syndromes and genes [J].