TY - JOUR
T1 - A Mutation of COX6A1 causes a recessive axonal or mixed form of charcot-marie-tooth disease
AU - Tamiy, Gen
AU - Makino, Satoshi
AU - Hayashi, Makiko
AU - Abe, Akiko
AU - Numakura, Chikahiko
AU - Ueki, Masao
AU - Tanaka, Atsushi
AU - Ito, Chizuru
AU - Toshimori, Kiyotaka
AU - Ogawa, Nobuhiro
AU - Terashima, Tomoya
AU - Maegawa, Hiroshi
AU - Yanagisawa, Daijiro
AU - Tooyama, Ikuo
AU - Tada, Masayoshi
AU - Onodera, Osamu
AU - Hayasaka, Kiyoshi
N1 - Funding Information:
We would like to thank Kaoru Honaga, Michiyuki Kawakami, Akio Kimura, and Keiko Murayama for clinical information. This work was supported by Grant-in-Aid for Scientific Research from the Ministry of Education, Science, Sports and Culture of Japan to K.H. (grant number 25461537), A.A. (grant number 25860842), and G.T. (grant number 25129701) and Grant-in-Aid from the 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.”
Publisher Copyright:
© 2014 by The American Society of Human Genetics. All rights reserved.
PY - 2014
Y1 - 2014
N2 - 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.247102476delCACTC) 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.
AB - 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.247102476delCACTC) 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.
UR - http://www.scopus.com/inward/record.url?scp=84908238090&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84908238090&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2014.07.013
DO - 10.1016/j.ajhg.2014.07.013
M3 - Article
C2 - 25152455
AN - SCOPUS:84908238090
VL - 95
SP - 294
EP - 300
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 3
ER -