Rendtorff Nanna D, Zhu Mei, Fagerheim Toril, Antal Torben L, Jones MaryPat, Teslovich Tanya M, Gillanders Elizabeth M, Barmada Michael, Teig Erik, Trent Jeffrey M, Friderici Karen H, Stephan Dietrich A, Tranebjaerg Lisbeth
Department of Medical Biochemistry and Genetics, Wilhelm Johannsen Centre for Functional Genomics, University of Copenhagen, Copenhagen, Denmark.
Eur J Hum Genet. 2006 Oct;14(10):1097-105. doi: 10.1038/sj.ejhg.5201670. Epub 2006 Jun 14.
The gamma-actin gene (ACTG1) encodes a major cytoskeletal protein of the sensory hair cells of the cochlea. Recently, mutations in ACTG1 were found to cause autosomal dominant, progressive, sensorineural hearing impairment linked to the DFNA20/26 locus on chromosome 17q25.3 in four American families and in one Dutch family. We report here the linkage of autosomal dominant, progressive, sensorineural hearing impairment in a large Norwegian family to the DFNA20/26 locus. Sequencing of ACTG1 identified a novel missense mutation (c.1109T>C; p.V370A) segregating with the hearing loss. Functional analysis in yeast showed that the p.V370A mutation restricts cell growth at elevated temperature or under hyperosmolar stress. Molecular modelling suggested that the p.V370A mutation modestly alters a site for protein-protein interaction in gamma-actin and thereby modestly alters gamma-actin-based cytoskeletal structures. Nineteen Norwegian and Danish families with autosomal, dominant hearing impairment were analyzed for mutations in ACTG1 by sequencing, but no disease-associated mutations were identified. Finally, a long-term follow-up of the hearing loss progression associated with the p.V370A mutation in ACTG1 is provided. The present study expands our understanding of the genotype-phenotype relationship of this deafness gene and provides a sensitive and simple functional assay for missense mutations in this gene, which may assist future molecular diagnosis of autosomal-dominant hearing impairment. Finally, the present results do not indicate that mutations in ACTG1 are a frequent cause of autosomal-dominant postlingual sensorineural hearing impairment in Norway nor Denmark.
γ-肌动蛋白基因（ACTG1）编码耳蜗感觉毛细胞的一种主要细胞骨架蛋白。最近，在四个美国家庭和一个荷兰家庭中发现，ACTG1基因突变会导致与17q25.3染色体上DFNA20/26位点相关的常染色体显性、进行性、感音神经性听力障碍。我们在此报告一个挪威大家庭中常染色体显性、进行性感音神经性听力障碍与DFNA20/26位点的连锁关系。对ACTG1进行测序发现了一个新的错义突变（c.1109T>C；p.V370A），该突变与听力损失共分离。在酵母中的功能分析表明，p.V370A突变在高温或高渗应激下会限制细胞生长。分子建模表明，p.V370A突变适度改变了γ-肌动蛋白中蛋白质-蛋白质相互作用的位点，从而适度改变了基于γ-肌动蛋白的细胞骨架结构。通过测序分析了19个患有常染色体显性听力障碍的挪威和丹麦家庭的ACTG1突变，但未发现与疾病相关的突变。最后，提供了对ACTG1中p.V370A突变相关听力损失进展的长期随访。本研究扩展了我们对该耳聋基因基因型-表型关系的理解，并为该基因中的错义突变提供了一种灵敏且简单的功能检测方法，这可能有助于未来对常染色体显性听力障碍的分子诊断。最后，目前的结果并不表明ACTG1突变是挪威和丹麦常染色体显性语后感音神经性听力障碍的常见病因。
