An integrated genetic and functional analysis of the role of type II transmembrane serine proteases (TMPRSSs) in hearing loss
An integrated genetic and functional analysis of the role of type II transmembrane serine proteases (TMPRSSs) in hearing loss
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DOI：
10.1002/humu.20617
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发表时间：
2008-01-01
期刊：
影响因子：
3.9
通讯作者：
Scott, Hamish S.
中科院分区：
文献类型：
--
作者：
Guipponi, Michel;Toh, Min-Yen;Scott, Hamish S.
基于我们发现跨膜丝氨酸蛋白酶TMPRSS 3的突变会导致非综合征性耳聋，我们研究了其他TWRSS家族成员对听觉功能的贡献。为了鉴定16个已知的TMPRSS基因中的哪一个具有参与听力功能的强烈可能性，检查了三种类型的生物学证据：1）在内耳组织中的表达; 2）在含有尚未鉴定的耳聋基因的基因组间隔中的位置;以及3）评估任何可用的Tmprss敲除小鼠品系的听力状态。这项分析表明，除了TMPRSS 3，另一个TMPRSS基因对听力至关重要，事实上，Hepsin（Hpn）缺陷的小鼠（也称为Tmprss 1）表现出严重的听力损失。此外，TMPRSS 2、TAVRSS 5和CORIN（也称为TMPRSS 10）基于它们的内耳表达和分别在耳聋基因座PKSR 7、DFNB 24和DFNB 25内的定位而显示出参与的强烈可能性。然后在DFNB 24和DFNB 25耳聋家族的受影响成员以及362例散发性耳聋病例的队列中筛选这四个TMPRSS基因的突变。这种大的突变筛选揭示了许多新的序列变异，包括TMPRSS 5基因中的三个潜在致病突变。TMPRSS 5的突变形式显示蛋白水解活性降低或不存在。随后，TMPRSS基因参与耳聋的证据进行了进一步表征，并确定其表达的网站。在螺旋神经节神经元中检测到Tmprss 1、3和5蛋白。Tmprss 3也存在于Corti器中。TMPRSS 1和3蛋白稳定锚定在内质网膜，而TMPRSS 5也检测到质膜。总的来说，这些结果提供了证据，TMPRSS 1和TMPRSS 3发挥和TMPRSS 5可能发挥重要和具体的作用，在听力。
Building on our discovery that mutations in the transmembrane serine protease, TMPRSS3, cause nonsyndromic deafness, we have investigated the contribution of other TWRSS family members to the auditory function. To identify which of the 16 known TMPRSS genes had a strong likelihood of involvement in hearing function, three types of biological evidence were examined: 1) expression in inner ear tissues; 2) location in a genomic interval that contains a yet unidentified gene for deafness; and 3) evaluation of hearing status of any available Tmprss knockout mouse strains. This analysis demonstrated that, besides TMPRSS3, another TMPRSS gene was essential for hearing and, indeed, mice deficient for Hepsin (Hpn) also known as Tmprss1 exhibited profound hearing loss. In addition, TMPRSS2, TAVRSS5, and CORIN, also named TMPRSS10, showed strong likelihood of involvement based on their inner ear expression and mapping position within deafness loci PKSR7, DFNB24, and DFNB25, respectively. These four TMPRSS genes were then screened for mutations in affected members of the DFNB24 and DFNB25 deafness families, and in a cohort of 362 sporadic deaf cases. This large mutation screen revealed numerous novel sequence variations including three potential pathogenic mutations in the TMPRSS5 gene. The mutant forms of TMPRSS5 showed reduced or absent proteolytic activity. Subsequently, TMPRSS genes with evidence of involvement in deafness were further characterized, and their sites of expression were determined. Tmprss1, 3, and 5 proteins were detected in spiral ganglion neurons. Tmprss3 was also present in the organ of Corti. TMPRSS1 and 3 proteins appeared stably anchored to the endoplasmic reticulum membranes, whereas TMPRSS5 was also detected at the plasma membrane. Collectively, these results provide evidence that TMPRSS1 and TMPRSS3 play and TMPRSS5 may play important and specific roles in hearing.