Usher syndrome type I G (USH1G) is caused by mutations in the gene encoding SANS, a protein that associates with the USH1C protein, harmonin.
Usher syndrome type I G (USH1G) is caused by mutations in the gene encoding SANS, a protein that associates with the USH1C protein, harmonin.
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DOI：
10.1093/hmg/ddg051
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发表时间：
2003-03
影响因子：
3.5
通讯作者：
D. Weil;A. El-Amraoui;S. Masmoudi;M. Mustapha;Y. Kikkawa;Sophie Lainé;S. Delmaghani;A. Adato
中科院分区：
文献类型：
--
作者：
D. Weil;A. El-Amraoui;S. Masmoudi;M. Mustapha;Y. Kikkawa;Sophie Lainé;S. Delmaghani;A. Adato
Usher综合征I型（USH 1）是人类遗传性眼盲的最常见原因。到目前为止，7个遗传基因座（USH 1A-G）与这种疾病有关，其中4个相应的基因已被鉴定：USH 1B，C，D和F。我们对USH 1G（染色体17 q24 -25）进行了精细定位，将该基因的位置限制在2.6 Mb的区间内，然后筛选该区间内存在的突变基因。筛选的基因包括Sans基因的直向同源物，该基因在杰克逊震聋突变体中有缺陷，并映射到小鼠的同线区。在两个血缘关系USH 1G影响的家庭，我们检测到两个不同的移码突变的SANS基因。来自一个德国USH 1G家族的两个兄弟被发现是移码和错义突变的复合杂合子。这些结果表明SANS是USH 1G的基础。SANS蛋白含有三个锚蛋白结构域和一个无菌α基序，其C-末端三肽呈现I类PDZ结合基序。我们通过共转染实验表明，SANS与harmonin（一种负责USH 1C的含PDZ结构域的蛋白质）相关。在杰克逊震鼠中，内耳感觉细胞的机械感受结构--毛束是紊乱的。基于USH 1B（肌球蛋白VIIa），USH 1C（harmonin）和USH 1D（钙粘蛋白23）蛋白之间的相互作用和本研究中获得的结果，我们认为USH 1B，C，D和G蛋白形成的功能网络负责毛束的正确凝聚力。
Usher syndrome type I (USH1) is the most frequent cause of hereditary deaf-blindness in humans. Seven genetic loci (USH1A-G) have been implicated in this disease to date, and four of the corresponding genes have been identified: USH1B, C, D and F. We carried out fine mapping of USH1G (chromosome 17q24-25), restricting the location of this gene to an interval of 2.6 Mb and then screened genes present within this interval for mutations. The genes screened included the orthologue of the Sans gene, which is defective in the Jackson shaker deaf mutant and maps to the syntenic region in mice. In two consanguineous USH1G-affected families, we detected two different frameshift mutations in the SANS gene. Two brothers from a German family affected with USH1G were found to be compound heterozygotes for a frameshift and a missense mutation. These results demonstrate that SANS underlies USH1G. The SANS protein contains three ankyrin domains and a sterile alpha motif, and its C-terminal tripeptide presents a class I PDZ-binding motif. We showed, by means of co-transfection experiments, that SANS associates with harmonin, a PDZ domain-containing protein responsible for USH1C. In Jackson shaker mice the hair bundles, the mechanoreceptive structures of inner ear sensory cells, are disorganized. Based on the known interaction between USH1B (myosin VIIa), USH1C (harmonin) and USH1D (cadherin 23) proteins and the results obtained in this study, we suggest that a functional network formed by the USH1B, C, D and G proteins is responsible for the correct cohesion of the hair bundle.