Mutations in LOXHD1, an Evolutionarily Conserved Stereociliary Protein, Disrupt Hair Cell Function in Mice and Cause Progressive Hearing Loss in Humans
Mutations in LOXHD1, an Evolutionarily Conserved Stereociliary Protein, Disrupt Hair Cell Function in Mice and Cause Progressive Hearing Loss in Humans
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DOI：
10.1016/j.ajhg.2009.07.017
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发表时间：
2009-09-11
影响因子：
9.8
通讯作者：
Mueller, Ulrich
中科院分区：
文献类型：
--
作者：
Grillet, Nicolas;Schwander, Martin;Mueller, Ulrich
听力损失是人类最常见的感觉障碍形式，并且通常是进行性的。在这里，我们将一个以前未表征的基因与小鼠和人类的听力障碍联系起来。我们发现乙基亚硝基脲 (ENU) 诱导的桑巴小鼠系的听力损失是由 Loxhd1 突变引起的。 LOXHD1 完全由 PLAT（多囊蛋白/脂氧合酶/α-毒素）结构域组成，并沿着成熟毛细胞静纤毛的膜表达。桑巴小鼠的立体纤毛发育不受影响，但毛细胞功能受到干扰，毛细胞最终退化。基于对小鼠的研究，我们筛选了分离耳聋的人类家族的 DNA，并发现了 LOXHD1 的突变，该突变会导致 DFNB77，这是一种进行性形式的常染色体隐性非综合征性听力损失 (ARNSHL)。 LOXHD1、MYO3a 和 PJVK 是迄今为止唯一与进行性 ARNSHL 相关的人类基因。这三个基因是毛细胞功能所必需的，表明年龄依赖性毛细胞衰竭是进行性 ARNSHL 的常见机制。
Hearing loss is the most common form of sensory impairment in humans and is frequently progressive in nature. Here we link a previously uncharacterized gene to hearing impairment in mice and humans. We show that hearing loss in the ethylnitrosourea (ENU)-induced samba mouse line is caused by a mutation in Loxhd1. LOXHD1 consists entirely of PLAT (polycystin/lipoxygenase/alpha-toxin) domains and is expressed along the membrane of mature hair cell stereocilia. Stereociliary development is unaffected in samba mice, but hair cell function is perturbed and hair cells eventually degenerate. Based on the studies in mice, we screened DNA from human families segregating deafness and identified a mutation in LOXHD1, which causes DFNB77, a progressive form of autosomal-recessive nonsyndromic hearing loss (ARNSHL). LOXHD1, MYO3a, and PJVK are the only human genes to date linked to progressive ARNSHL. These three genes are required for hair cell function, suggesting that age-dependent hair cell failure is a common mechanism for progressive ARNSHL.