Mutations in TUBB4B Cause a Distinctive Sensorineural Disease
Mutations in TUBB4B Cause a Distinctive Sensorineural Disease
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DOI：
10.1016/j.ajhg.2017.10.010
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发表时间：
2017-12-07
影响因子：
9.8
通讯作者：
Perrault, Isabelle
中科院分区：
文献类型：
--
作者：
Luscan, Romain;Mechaussier, Sabrina;Perrault, Isabelle
Leber先天性黑蒙（LCA）是一种感光细胞的神经退行性疾病，在生命的第一年内导致失明。它偶尔发生在综合征代谢疾病和多系统纤毛病。使用外显子组测序在一个多重家庭和三个单一的情况下，一个非典型的LCA与早发性听力损失的关联，我们确定了两个杂合突变影响Arg 391 β-微管蛋白4 B同种型编码（TUBB 4 B）。微管（MT）原丝的原子结构的检查表明，β-微管蛋白Arg 391残基有助于与纵向相邻的α β-异源二聚体中所含的α-微管蛋白相互作用的结合口袋，与维持MT稳定性的作用一致。在培养的过表达FLAG标记的野生型或突变体TUBB 4 B的细胞中以及在原代皮肤来源的成纤维细胞中的功能分析显示，突变体TUBB 4 B能够折叠，形成α β-异二聚体，并共组装成内源性MT晶格。然而，不断增长的MT的动力学不断改变，表明突变对正常MT生长有显着的抑制作用。我们的研究结果提供了一个链接之间的感觉神经疾病和异常的MT行为，并描述了一个综合征LCA无关的睫状体功能障碍。
Leber congenital amaurosis (LCA) is a neurodegenerative disease of photoreceptor cells that causes blindness within the first year of life. It occasionally occurs in syndromic metabolic diseases and plurisystemic ciliopathies. Using exome sequencing in a multiplex family and three simplex case subjects with an atypical association of LCA with early-onset hearing loss, we identified two heterozygous mutations affecting Arg391 in beta-tubulin 4B isotype-encoding (TUBB4B). Inspection of the atomic structure of the microtubule (MT) protofilament reveals that the beta-tubulin Arg391 residue contributes to a binding pocket that interacts with alpha-tubulin contained in the longitudinally adjacent alpha beta-heterodimer, consistent with a role in maintaining MT stability. Functional analysis in cultured cells over-expressing FLAG-tagged wild-type or mutant TUBB4B as well as in primary skin-derived fibroblasts showed that the mutant TUBB4B is able to fold, form alpha beta-heterodimers, and co-assemble into the endogenous MT lattice. However, the dynamics of growing MTs were consistently altered, showing that the mutations have a significant dampening impact on normal MT growth. Our findings provide a link between sensorineural disease and anomalies in MT behavior and describe a syndromic LCA unrelated to ciliary dysfunction.