Usher I syndrome: unravelling the mechanisms that underlie the cohesion of the growing hair bundle in inner ear sensory cells
Usher I syndrome: unravelling the mechanisms that underlie the cohesion of the growing hair bundle in inner ear sensory cells
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DOI：
10.1242/jcs.02636
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发表时间：
2005-10-15
影响因子：
4
通讯作者：
Petit, C
中科院分区：
文献类型：
--
作者：
El-Amraoui, A;Petit, C
肌球蛋白VIIa、含PDZ结构域的蛋白harmonin、钙粘蛋白23和原钙粘蛋白15（两种具有大细胞外区域的钙粘蛋白）以及推定的支架蛋白Sans的缺陷是I型Usher综合征（USH 1）的五种遗传形式的基础，USH 1是人类遗传性失明的最常见原因。所有USH 1蛋白都位于生长中的静纤毛和/或动纤毛内，这些动纤毛构成了发育中的听觉毛束，这是一种接受声音刺激的机械敏感结构。钙粘蛋白23已被证明是一个纤维连接的成分，连接生长中的静纤毛以及动纤毛和最近的高静纤毛。预期原钙粘蛋白15具有类似的功能。USH 1蛋白之间的多种直接相互作用已被证明。特别是，harmonin B可以结合到钙粘蛋白23和原钙粘蛋白15的细胞质区域，并结合到F-肌动蛋白，因此可能将这些钙粘蛋白锚定到填充静纤毛的肌动蛋白丝。肌球蛋白VIIa和Sans均参与harmonin B对静纤毛的分选和/或靶向。总之，这表明在缺乏USH 1蛋白直系同源物的小鼠突变体中观察到的毛束的解体可能是由于毛束连接介导的粘附力的缺陷。此外，最近的一些证据表明，Usher 11型综合征中的一些基因缺陷也编码静纤毛间的链接，从而桥接USH 1和USH 2听力障碍的致病途径。从这些小鼠中观察到的其他表型异常中可以明显看出USH 1蛋白在内耳和视网膜中的其他功能。特别是，肌球蛋白VIIa可以在微管和肌动蛋白为基础的运输之间的接口。
Defects in myosin VIIa, the PDZ-domain-containing protein harmonin, cadherin 23 and protocadherin 15 (two cadherins with large extracellular regions), and the putative scaffolding protein Sans underlie five genetic forms of Usher syndrome type I (USH1), the most frequent cause of hereditary deafness-blindness in humans. All USH1 proteins are localised within growing stereocilia and/or the kinocilium that make up the developing auditory hair bundle, the mechanosensitive structure receptive to sound stimulation. Cadherin 23 has been shown to be a component of fibrous links interconnecting the growing stereocilia as well as the kinocilium and the nearest tall stereocilia. A similar function is anticipated for protocadherin 15. Multiple direct interactions between USH1 proteins have been demonstrated. In particular, harmonin b can bind to the cytoplasmic regions of cadherin 23 and protocadherin 15, and to F-actin, and thus probably anchors these cadherins to the actin filaments filling the stereocilia. Myosin VIIa and Sans are both involved in the sorting and/or targeting of harmonin b to the stereocilia. Together, this suggests that the disorganisation of the hair bundles observed in mice mutants lacking orthologues of USH1 proteins may result from a defect of hair-bundle-link-mediated adhesion forces. Moreover, several recent evidences suggest that some genes defective in Usher type 11 syndrome also encode interstereocilia links, thus bridging the pathogenic pathways of USH1 and USH2 hearing impairment. Additional functions of USH1 proteins in the inner ear and the retina are evident from other phenotypic abnormalities observed in these mice. In particular, myosin VIIa could act at the interface between microtubule- and actin-based transport.