Zhu M, Yang T, Wei S, DeWan A T, Morell R J, Elfenbein J L, Fisher R A, Leal S M, Smith R J H, Friderici K H
Department of Microbiology & Molecular Genetics, Michigan State University, East Lansing, MI 48824, USA.
Am J Hum Genet. 2003 Nov;73(5):1082-91. doi: 10.1086/379286. Epub 2003 Sep 16.
Age-related hearing loss (presbycusis) is a significant problem in the population. The genetic contribution to age-related hearing loss is estimated to be 40%-50%. Gene mutations that cause nonsyndromic progressive hearing loss with early onset may provide insight into the etiology of presbycusis. We have identified four families segregating an autosomal dominant, progressive, sensorineural hearing loss phenotype that has been linked to chromosome 17q25.3. The critical interval containing the causative gene was narrowed to approximately 2 million bp between markers D17S914 and D17S668. Cochlear-expressed genes were sequenced in affected family members. Sequence analysis of the gamma-actin gene (ACTG1) revealed missense mutations in highly conserved actin domains in all four families. These mutations change amino acids that are conserved in all actins, from protozoa to mammals, and were not found in >100 chromosomes from normal hearing individuals. Much of the specialized ultrastructural organization of the cells in the cochlea is based on the actin cytoskeleton. Many of the mutations known to cause either syndromic or nonsyndromic deafness occur in genes that interact with actin (e.g., the myosins, espin, and harmonin). The mutations we have identified are in various binding domains of actin and are predicted to mildly interfere with bundling, gelation, polymerization, or myosin movement and may cause hearing loss by hindering the repair or stability of cochlear cell structures damaged by noise or aging. This is the first description of a mutation in cytoskeletal, or nonmuscle, actin.
年龄相关性听力损失（老年性聋）是人群中的一个重要问题。据估计，遗传因素对年龄相关性听力损失的贡献率为40%-50%。导致早发性非综合征性进行性听力损失的基因突变可能有助于深入了解老年性聋的病因。我们已经确定了四个家系，这些家系中存在一种常染色体显性、进行性、感音神经性听力损失表型，该表型与17号染色体q25.3区域相关联。包含致病基因的关键区间在标记物D17S914和D17S668之间被缩小至约200万碱基对。对受影响家系成员的耳蜗表达基因进行了测序。γ-肌动蛋白基因（ACTG1）的序列分析显示，所有四个家系中高度保守的肌动蛋白结构域均存在错义突变。这些突变改变了从原生动物到哺乳动物所有肌动蛋白中保守的氨基酸，在100多条听力正常个体的染色体中未发现。耳蜗中细胞的许多特殊超微结构组织都基于肌动蛋白细胞骨架。许多已知导致综合征性或非综合征性耳聋的突变发生在与肌动蛋白相互作用的基因中（例如，肌球蛋白、espin和harmonin）。我们鉴定出的突变位于肌动蛋白的不同结合结构域，预计会轻微干扰肌动蛋白束形成、凝胶化、聚合或肌球蛋白运动，并可能通过阻碍因噪声或衰老而受损的耳蜗细胞结构的修复或稳定性而导致听力损失。这是首次对细胞骨架肌动蛋白或非肌肉肌动蛋白突变的描述。
