Masuda Masatsugu, Mutai Hideki, Arimoto Yukiko, Nakano Atsuko, Matsunaga Tatsuo
Laboratory of Auditory Disorders, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka Meguro-ku, Tokyo 152-8902, Japan; Department of Otolaryngology, School of Medicine, Kyorin University, 6-20-2 Shinkawa, Mitaka-shi, Tokyo 181-8611, Japan.
Laboratory of Auditory Disorders, National Institute of Sensory Organs, National Hospital Organization Tokyo Medical Center, 2-5-1 Higashigaoka Meguro-ku, Tokyo 152-8902, Japan.
Biochem Biophys Res Commun. 2016 Jan 8;469(2):270-4. doi: 10.1016/j.bbrc.2015.11.106. Epub 2015 Nov 26.
COCH (coagulation factor C homology) encodes cochlin, and certain mutations of COCH cause autosomal dominant nonsyndromic deafness 9 (DFNA9). Hearing loss due to COCH mutation begins in adulthood, and 17 missense mutations and two in-frame mutations have been reported. Studies with animal and cellular models have suggested that the underlying biological mechanism of DFNA9 is the dominant-negative effect of mutated COCH and not haploinsufficiency. However, no human cases of DFNA9 that support this hypothesis have been reported. The proband of the present case was an 18-year-old male with congenital or infantile hearing loss. Targeted next-generation sequencing analysis detected a heterozygous novel frameshift mutation of COCH (c.146dupT, p.C50LfsX8) in the proband, whose hearing loss began earlier than what is typical for DFNA9. His mother also carried the mutation but had normal hearing. Consequently, the mutation was not considered to be the cause of the proband's hearing loss. This family is the first case of a truncating COCH variant and supports the hypothesis that COCH haploinsufficiency is not the cause of hearing loss in humans.
COCH（凝血因子C同源结构域）编码耳蜗素，COCH的某些突变会导致常染色体显性非综合征性耳聋9型（DFNA9）。由COCH突变引起的听力损失始于成年期，已报道了17种错义突变和两种框内突变。对动物和细胞模型的研究表明，DFNA9潜在的生物学机制是突变型COCH的显性负效应，而非单倍体不足。然而，尚无支持这一假说的DFNA9人类病例报道。本病例的先证者是一名患有先天性或婴儿期听力损失的18岁男性。靶向二代测序分析在该先证者中检测到一种新的COCH杂合移码突变（c.146dupT，p.C50LfsX8），其听力损失比DFNA9的典型情况出现得更早。他的母亲也携带该突变，但听力正常。因此，该突变不被认为是先证者听力损失的原因。这个家系是首例截短型COCH变异的病例，支持了COCH单倍体不足并非人类听力损失原因这一假说。
