A Mutation of COX6A1 Causes a Recessive Axonal or Mixed Form of Charcot-Marie-Tooth Disease

作者：Tamiya Gen^*; Makino Satoshi; Hayashi Makiko; Abe Akiko; Numakura Chikahiko; Ueki Masao; Tanaka Atsushi; Ito Chizuru; Toshimori Kiyotaka; Ogawa Nobuhiro; Terashima Tomoya; Maegawa Hiroshi; Yanagisawa Daijiro; Tooyama Ikuo; Tada Masayoshi; Onodera Osamu; Hayasaka Kiyoshi

来源：American Journal of Human Genetics, 2014, 95(3): 294-300.

DOI：10.1016/j.ajhg.2014.07.013

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.

• 出版日期2014-9-4
• 单位河北医科大学