Formin-1维持人类和小鼠听力所需的耳蜗微管结构

文献信息

中文摘要

Formin蛋白参与多种哺乳动物器官系统的细胞骨架组织。Formin基因的遗传缺陷可导致神经、肾脏、生殖和心脏疾病，但尚未描述过FMN1（编码form-1，即首个被鉴定的formin）突变的人类表型。在一个巴勒斯坦大家系中，常染色体隐性先天性听力损失被证实是由于FMN1 c.2162-2A>G纯合突变所致，该突变导致异常剪接、无义介导的衰变以及检测不到formin-1蛋白。听力损失为双侧、中度且稳定，伴有浅色头发，无其他异常。Fmn1敲除小鼠Fmn1Pro/Pro（曾用于最初的formin-1表征）模拟了该人类家系的听力损失。对Fmn1Pro/Pro小鼠耳蜗的成像显示，支持细胞Deiters细胞和柱细胞显著结构紊乱，其特征是紧密成束的微管结构丧失。这些异常在出生后早期出现并随年龄持续存在。微管组织破坏伴有听神经活动降低（通过ABR波I振幅降低揭示）以及听神经纤维数量减少。总之，这些观察结果确定FMN1是听觉功能所需的基因，并支持一种机制：formin-1缺失破坏耳蜗支持细胞中的微管组织和细胞骨架结构，从而损害Corti器的力学功能。受影响个体的银灰色头发和轻度较浅的皮肤可能是由于不同机制：formin-1-spire-1-myosin-5a复合物在黑素体从微管转运至黑素细胞表面的作用。FMN1为哺乳动物听力所必需的200多个基因增添了新的一员。

英文摘要

Formin proteins contribute to the cytoskeletal organization of multiple mammalian organ systems. Genetic defects in formins lead to neurologic, renal, reproductive, and cardiac disorders, but no human phenotype has been described for mutation of FMN1, encoding formin-1, the first-identified formin. In an extended Palestinian kindred, autosomal recessive congenital hearing loss proved due to homozygosity for FMN1 c.2162-2A>G, which leads to aberrant splicing, nonsense mediated decay, and absence of detectable formin-1 protein. The hearing loss is bilateral, moderate, and stable, and accompanied by light hair with no other anomalies. The Fmn1 knockout mouse Fmn1Pro/Pro, which contributed to the original formin-1 characterization, models the hearing loss of the human family. Imaging the cochlea of Fmn1Pro/Pro mice revealed significant disorganization of supporting Deiters' and pillar cells, characterized by loss of tightly bundled microtubule architecture. These abnormalities emerged early postnatally and persisted with age. Disruption of microtubule organization was accompanied by reduced activity of the auditory nerve, revealed by reduced ABR wave I amplitudes, and by reduced numbers of auditory nerve fibers. Together these observations identify FMN1 as a gene required for auditory function and support a mechanism in which formin-1 loss disrupts microtubule organization and cytoskeletal architecture in cochlear supporting cells, compromising organ of Corti mechanics. Silvery-gray hair and mildly lighter skin of the affected individuals may be due to a different mechanism: the role of the formin-1-spire-1-myosin-5a complex in transport of melanosomes from microtubules to the surface of melanocytes. FMN1 adds another gene to the more than 200 essential for mammalian hearing.