Usami Shin-ichi, Takahashi Kentaro, Yuge Isamu, Ohtsuka Akihiro, Namba Atsushi, Abe Satoko, Fransen Erik, Patthy Laszlo, Otting Gottfried, Van Camp Guy
Department of Otorhinolaryngology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
Eur J Hum Genet. 2003 Oct;11(10):744-8. doi: 10.1038/sj.ejhg.5201043.
The COCH gene is the only gene identified in man that causes autosomal dominantly inherited hearing loss associated with vestibular dysfunction. The condition is rare and only five mutations have been reported worldwide. All affected families showed a similar progressive hearing loss and vestibular dysfunction. Since Meniere's disease-like symptoms have also been described in some families, it was suggested that COCH mutations might be present in some patients diagnosed with Meniere's disease. In this study, using a Japanese population, we performed a COCH mutation analysis in 23 patients from independent families with autosomal dominant hearing impairment, four of whom reported vestibular symptoms, and also in 20 Meniere's patients. While a new point mutation, A119 T, was found in a patient with autosomal dominant hearing loss and vestibular symptoms, no mutations were found in the Meniere's patients. Like all other previously identified COCH mutations, the mutation identified here is a missense mutation located in the FCH domain of the protein. The current mutation is located in close spatial proximity to W117, in which a mutation (W117R) had previously been associated with autosomal dominant hearing loss. Model building suggests that, like the W117R mutation, the A119 T mutation does not affect the structural integrity of the FCH domain, but may interfere with the interaction with a yet unknown binding partner. We conclude that mutations in the COCH gene are responsible for a significant fraction of patients with autosomal dominantly inherited hearing loss accompanied by vestibular symptoms, but not for dominant hearing loss without vestibular dysfunction, or sporadic Meniere's disease.
COCH基因是人类中唯一被鉴定出可导致与前庭功能障碍相关的常染色体显性遗传性听力损失的基因。这种病症很罕见，全球仅报道了五个突变。所有受影响的家族都表现出类似的进行性听力损失和前庭功能障碍。由于在一些家族中也描述过类似梅尼埃病的症状，因此有人提出，一些被诊断为梅尼埃病的患者可能存在COCH突变。在本研究中，我们以日本人群为对象，对来自独立家族的23例常染色体显性听力障碍患者（其中4例报告有前庭症状）以及20例梅尼埃病患者进行了COCH突变分析。虽然在一名患有常染色体显性听力损失和前庭症状的患者中发现了一个新的点突变A119T，但在梅尼埃病患者中未发现突变。与所有其他先前鉴定出的COCH突变一样，此处鉴定出的突变是位于该蛋白质FCH结构域的错义突变。当前的突变位于与W117在空间上接近的位置，此前在W117处的一个突变（W117R）与常染色体显性听力损失相关。模型构建表明，与W117R突变一样，A119T突变不会影响FCH结构域的结构完整性，但可能会干扰与一个未知结合伴侣的相互作用。我们得出结论，COCH基因突变是导致相当一部分伴有前庭症状的常染色体显性遗传性听力损失患者发病的原因，但不是导致无前庭功能障碍的显性听力损失或散发性梅尼埃病的原因。
