FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing
FAM65B is a membrane-associated protein of hair cell stereocilia required for hearing
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DOI：
10.1073/pnas.1401950111
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发表时间：
2014-07-08
影响因子：
11.1
通讯作者：
Tekin, Mustafa
中科院分区：
文献类型：
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作者：
Diaz-Horta, Oscar;Subasioglu-Uzak, Asli;Tekin, Mustafa
在一个患有隐性非综合征性、语前性、深度听力损失的大型土耳其近亲亲属中，我们在基因 FAM65B (MIM611410) 中发现了一个与该家族表型完美共分离的剪接位点突变 (c.102-1G>A)。该突变导致外显子跳跃和 PX 膜定位结构域 52 个氨基酸残基的缺失。已知 FAM65B 参与肌管形成以及细胞粘附、极化和迁移的调节。我们发现野生型 Fam65b 在小鼠耳蜗的胚胎和出生后发育阶段表达，并且该蛋白定位于内耳内毛细胞和外毛细胞静纤毛的质膜。野生型蛋白靶向质膜，而突变型蛋白在细胞质包涵体中积累并且不到达膜。在斑马鱼中，fam65b 的敲低会导致囊状毛细胞和神经丘数量显着减少，并导致听力损失。我们得出的结论是，FAM65B 是毛细胞静纤毛的质膜相关蛋白，对听力至关重要。
In a large consanguineous Turkish kindred with recessive nonsyndromic, prelingual, profound hearing loss, we identified in the gene FAM65B (MIM611410) a splice site mutation (c.102-1G>A) that perfectly cosegregates with the phenotype in the family. The mutation leads to exon skipping and deletion of 52-amino acid residues of a PX membrane localization domain. FAM65B is known to be involved in myotube formation and in regulation of cell adhesion, polarization, and migration. We show that wild-type Fam65b is expressed during embryonic and postnatal development stages in murine cochlea, and that the protein localizes to the plasma membranes of the stereocilia of inner and outer hair cells of the inner ear. The wild-type protein targets the plasma membrane, whereas the mutant protein accumulates in cytoplasmic inclusion bodies and does not reach the membrane. In zebrafish, knockdown of fam65b leads to significant reduction of numbers of saccular hair cells and neuromasts and to hearing loss. We conclude that FAM65B is a plasma membrane-associated protein of hair cell stereocilia that is essential for hearing.