Alpha-tectorin involvement in hearing disabilities: one gene two phenotypes
Alpha-tectorin involvement in hearing disabilities: one gene two phenotypes
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DOI：
10.1007/s004390051091
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发表时间：
1999-09-01
期刊：
影响因子：
5.3
通讯作者：
Jazin, EE
中科院分区：
文献类型：
--
作者：
Balciuniene, J;Dahl, N;Jazin, EE
最近克隆了人α-tectorin（TECTA）基因，并提出其与两个与DFNA 12基因座相关的家族中的常染色体显性非综合征性听力损伤（NSHI）有关。我们研究了一个瑞典家系常染色体显性NSHI与可能的双基因遗传的疾病，涉及基因座DFNA 12在染色体11和基因座DFNA 2在染色体1。在这个家庭的TECTA基因的突变分析已确定8个核苷酸取代，表明TECTA是高度多态性。其中一个变化导致TECTA的zonadhesin结构域中的半胱氨酸变为丝氨酸（C1057 S）突变;这与11号染色体上的疾病单倍型分离，并且不存在于对照人群中。该突变导致蛋白质的zonadhesin/Von Willebrand结构域的重复序列之一中的半胱氨酸被替换，并且可能引起多肽交联的变化。这些发现增加了支持TECTA参与听力残疾。然而，携带不同TECTA突变的三个家族也显示出表型差异：听力损失从语前到晚发性进行性。对不同表型的解释和关于TECTA功能的一些线索可能在于蛋白质的不同模块中的突变的定位。另一种可能性是，瑞典家族的表型是两个缺陷基因的结果。
The human alpha-tectorin (TECTA) gene has recently been cloned and proposed to be involved in autosomal dominant non-syndromic hearing impairment (NSHI) in two families linked to the DFNA12 locus. We have studied a Swedish pedigree with autosomal dominant NSHI with possible digenic inheritance of the disease, involving locus DFNA12 in chromosome 11 and locus DFNA2 in chromosome 1. Mutation analysis of the TECTA gene in this family has identified eight nucleotide substitutions indicating that TECTA is highly polymorphic. One of the changes results in a cysteine to serine (C1057 S) mutation, in the zonadhesin domain of TECTA; this segregates with the disease haplotype on chromosome 11 and is not present in a control population. The mutation results in the replacement of a cysteine in one of the repeats of the zonadhesin/Von Willebrand domain of the protein and might cause a chang in the crosslinking of the polypeptide. These findings add support to the involvement of TECTA in hearing disabilities. However, the three families carrying different TECTA mutations also show phenotypic differences: the hearing loss ranges from prelingual to progressive with late onset. The explanation for the different phenotypes and some clues regarding the functions of TECTA may lie in the localization of the mutations in the different modules of the protein. Another possibility is that the phenotype in the Swedish family is the result of two defective genes.