Chen W, Meyer N C, McKenna M J, Pfister M, McBride D J, Fukushima K, Thys M, Camp G V, Smith R J H
Molecular Otolaryngology Research Laboratories, Department of Otolaryngology, The University of Iowa, Iowa City, Iowa 52242, USA.
Clin Genet. 2007 May;71(5):406-14. doi: 10.1111/j.1399-0004.2007.00794.x.
Otosclerosis (MIM 166800) has a prevalence of 0.2-1% among white adults, making it the single most common cause of hearing impairment in this ethnic group. Although measles virus, hormones, human leukocyte antigen alleles and genetic factors have been implicated in the development of otosclerosis, its etiology remains unknown. In a focused effort to identify genetic factors in otosclerosis, we have mapped four disease loci (MIM 166800/605727/608244/608787); however, cloning the disease-causing genes in these intervals has not been successful. Here, we used a case-control study design to investigate the association between collagen type I genes and otosclerosis. We identified susceptibility and protective haplotypes in COL1A1 that are significantly associated with otosclerosis in the Caucasian population. These haplotypes alter reporter gene activity in an osteoblast cell line by affecting binding of transcription factors to cis-acting elements. Our data suggest that increased amounts of collagen alpha1(I) homotrimers are causally related to the development of otosclerosis. Consistent with this hypothesis, mouse mutants homozygous for a Col1a2 frameshift mutation on a C57BL/6J background that deposit only homotrimeric type I collagen have hearing loss.
耳硬化症（MIM 166800）在白人成年人中的患病率为0.2% - 1%，是该族裔听力障碍最常见的单一病因。尽管麻疹病毒、激素、人类白细胞抗原等位基因和遗传因素与耳硬化症的发生有关，但其病因仍不明。为集中精力确定耳硬化症的遗传因素，我们已定位了四个疾病位点（MIM 166800/605727/608244/608787）；然而，在这些区间克隆致病基因尚未成功。在此，我们采用病例对照研究设计来调查I型胶原基因与耳硬化症之间的关联。我们在COL1A1中鉴定出与白种人群耳硬化症显著相关的易感和保护性单倍型。这些单倍型通过影响转录因子与顺式作用元件的结合来改变成骨细胞系中的报告基因活性。我们的数据表明，I型胶原α1（I）同三聚体数量增加与耳硬化症的发生存在因果关系。与此假设一致，在C57BL/6J背景上仅沉积同三聚体I型胶原的Col1a2移码突变纯合子小鼠突变体存在听力损失。
