期刊
AMERICAN JOURNAL OF HUMAN GENETICS
卷 95, 期 3, 页码 294-300出版社
CELL PRESS
DOI: 10.1016/j.ajhg.2014.07.013
关键词
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资金
- Ministry of Education, Science, Sports and Culture of Japan [25461537, 25860842, 25129701]
- Global Center of Excellence program of the Japan Society for the Promotion of Science, Formation of an International Network for Education and Research of Molecular Epidemiology
- Grants-in-Aid for Scientific Research [24592441, 25860842, 25461537, 25670087, 25870074, 25293041, 24590400] Funding Source: KAKEN
Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy characterized by clinical and genetic heterogeneity. Although more than 30 loci harboring CMT-causing mutations have been identified, many other genes still remain to be discovered for many affected individuals. For two consanguineous families with CMT (axonal and mixed phenotypes), a parametric linkage analysis using genome-wide SNP chip identified a 4.3 Mb region on 12q24 showing a maximum multipoint LOD score of 4.23. Subsequent whole-genome sequencing study in one of the probands, followed by mutation screening in the two families, revealed a disease-specific 5 bp deletion (c.247-10_247-6de1CACTC) in a splicing element (pyrimidine tract) of intron 2 adjacent to the third exon of cytochrome c oxidase subunit VIa polypeptide 1 (COX6A1), which is a component of mitochondrial respiratory complex IV (cytochrome c oxidase [COX]), within the autozygous linkage region. Functional analysis showed that expression of COX6A1 in peripheral white blood cells from the affected individuals and COX activity in their EB-virus-transformed lymphoblastoid cell lines were significantly reduced. In addition, Cox6a1-null mice showed significantly reduced COX activity and neurogenic muscular atrophy leading to a difficulty in walking. Those data indicated that COX6A1 mutation causes the autosomal-recessive axonal or mixed CMT.
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