Ikezono Tetsuo, Shindo Susumu, Li Lishu, Omori Akira, Ichinose Sachiyo, Watanabe Atsushi, Kobayashi Toshimitsu, Pawankar Ruby, Yagi Toshiaki
Department of Otorhinolaryngology, Nippon Medical School, Tokyo, Japan.
Biochem Biophys Res Commun. 2004 Feb 6;314(2):440-6. doi: 10.1016/j.bbrc.2003.12.106.
The COCH gene mutated in DFNA9, an autosomal dominant hereditary sensorineural hearing loss and vestibular disorder, encodes Cochlin. Previously, we reported three bovine Cochlin isoforms, p63s, p44s, and p40s, which exhibit significant molecular heterogeneity in vivo. Here we have characterized Cochlin isoforms by generating four isoform-specific anti-Cochlin antibodies. The same three Cochlin isoforms, p63s, p44s, and p40s, were detected in human and cow inner ear tissue; however, p44s and p40s were not detected in perilymph. We identified a novel short 16kDa isoform in human perilymph and a 18-23kDa isoform in cow perilymph, named Cochlin-tomoprotein (CTP), corresponding to the N-terminus of full-length Cochlin (p63s) and the LCCL domain. Notably, CTP contains all of the known mutation sites associated with DFNA9. The pathogenesis of DFNA9 is not fully clarified as yet, and this novel perilymph-associated CTP isoform might provide mechanistic clues to how mutations in the COCH gene damage the inner ear function.
DFNA9是一种常染色体显性遗传性感觉神经性听力损失和前庭疾病，其相关的COCH基因发生突变，该基因编码耳蜗蛋白（Cochlin）。此前，我们报道了三种牛耳蜗蛋白异构体，即p63s、p44s和p40s，它们在体内表现出显著的分子异质性。在此，我们通过制备四种异构体特异性抗耳蜗蛋白抗体对耳蜗蛋白异构体进行了表征。在人和牛的内耳组织中检测到了相同的三种耳蜗蛋白异构体，即p63s、p44s和p40s；然而，在外淋巴中未检测到p44s和p40s。我们在人外淋巴中鉴定出一种新的16kDa短异构体，在牛外淋巴中鉴定出一种18 - 23kDa异构体，命名为耳蜗蛋白截短蛋白（CTP），它对应于全长耳蜗蛋白（p63s）的N端和LCCL结构域。值得注意的是，CTP包含所有与DFNA9相关的已知突变位点。DFNA9的发病机制尚未完全阐明，这种新的与外淋巴相关的CTP异构体可能为COCH基因突变如何损害内耳功能提供机制线索。
