Institute of Medical Biology, A STAR, Singapore.
J Clin Invest. 2013 Feb;123(2):740-50. doi: 10.1172/JCI66911. Epub 2013 Jan 25.
Hereditary hearing loss is the most common sensory deficit. We determined that progressive high-frequency hearing loss in 2 families of Iraqi Jewish ancestry was due to homozygosity for the protein truncating mutation SYNE4 c.228delAT. SYNE4, a gene not previously associated with hearing loss, encodes nesprin-4 (NESP4), an outer nuclear membrane (ONM) protein expressed in the hair cells of the inner ear. The truncated NESP4 encoded by the families' mutation did not localize to the ONM. NESP4 and SUN domain-containing protein 1 (SUN1), which localizes to the inner nuclear membrane (INM), are part of the linker of nucleoskeleton and cytoskeleton (LINC) complex in the nuclear envelope. Mice lacking either Nesp4 or Sun1 were evaluated for hair cell defects and hearing loss. In both Nesp4-/- and Sun1-/- mice, OHCs formed normally, but degenerated as hearing matured, leading to progressive hearing loss. The nuclei of OHCs from mutant mice failed to maintain their basal localization, potentially affecting cell motility and hence the response to sound. These results demonstrate that the LINC complex is essential for viability and normal morphology of OHCs and suggest that the position of the nucleus in sensory epithelial cells is critical for maintenance of normal hearing.
遗传性听力损失是最常见的感觉缺陷。我们发现，2 个具有伊拉克犹太血统的家族中出现的进行性高频听力损失是由于 SYNE4 蛋白截断突变 c.228delAT 的纯合性所致。SYNE4 是一个以前与听力损失无关的基因，它编码核膜外膜（ONM）蛋白 nesprin-4（NESP4），该蛋白在内耳毛细胞中表达。该家族突变编码的截断 NESP4 不能定位于 ONM。NESP4 和 SUN 结构域蛋白 1（SUN1），它定位于核内膜（INM），是核膜中核骨架和细胞骨架连接体（LINC）复合物的一部分。缺乏 Nesp4 或 Sun1 的小鼠被评估了毛细胞缺陷和听力损失。在 Nesp4-/-和 Sun1-/-小鼠中，OHC 正常形成，但随着听力成熟而退化，导致进行性听力损失。突变小鼠的 OHC 细胞核未能保持其基底定位，这可能影响细胞的运动性，从而影响对声音的反应。这些结果表明 LINC 复合物对于 OHC 的存活和正常形态至关重要，并表明感觉上皮细胞中细胞核的位置对于维持正常听力至关重要。
