New role of LRP5, associated with nonsyndromic autosomal-recessive hereditary hearing loss
New role of LRP5, associated with nonsyndromic autosomal-recessive hereditary hearing loss
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LRP5 的新作用与非综合征性常染色体隐性遗传性听力损失相关
DOI：
10.1002/humu.23285
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发表时间：
2017
期刊：
影响因子：
3.9
通讯作者：
Ma Duan
中科院分区：
文献类型：
--
作者：
Xia Wenjun;Hu Jiongjiong;Liu Fei;Ma Jing;Sun Shaoyang;Zhang Jin;Jin Kaiyue;Huang Jianbo;Jiang Nan;Wang Xu;Li Wen;Ma Zhaoxin;Ma Duan
人类听力损失是一种常见的神经感觉障碍，许多基础研究和临床相关问题尚未解决。至少 50% 的听力损失是由遗传病因造成的。尽管已报道了数百个基因，但仍有数百个相关的耳聋基因有待发现。我们进行了临床、遗传和功能研究，以确定一个患有舌后非综合征性感音神经性听力损失的独特中国家庭的致病突变。全外显子组测序 (WES) 鉴定出脂蛋白受体相关蛋白 5 (LRP5)（低密度脂蛋白受体家族的成员）是该家族的致病基因。在斑马鱼模型中，使用吗啉代的lrp5下调导致斑马鱼内耳和侧线神经丘的显着异常，并在一定程度上导致听力和平衡障碍。救援实验表明，LRP5突变与听力损失有关。与野生型斑马鱼相比，敲低斑马鱼中的 lrp5 会导致与 Wnt 信号通路相关的多个基因的表达减少，并减少细胞增殖。总之，LRP5突变通过Wnt信号通路影响细胞增殖，从而减少支持细胞和毛细胞的数量，导致该中国家族的非综合征性听力损失。
Human hearing loss is a common neurosensory disorder about which many basic research and clinically relevant questions are unresolved. At least 50% of hearing loss are due to a genetic etiology. Although hundreds of genes have been reported, there are still hundreds of related deafness genes to be found. Clinical, genetic, and functional investigations were performed to identify the causative mutation in a distinctive Chinese family with postlingual nonsyndromic sensorineural hearing loss. Whole‐exome sequencing (WES) identified lipoprotein receptor‐related protein 5 (LRP5), a member of the low‐density lipoprotein receptor family, as the causative gene in this family. In the zebrafish model,lrp5downregulation using morpholinos led to significant abnormalities in zebrafish inner ear and lateral line neuromasts and contributed, to some extent, to disabilities in hearing and balance. Rescue experiments showed thatLRP5mutation is associated with hearing loss. Knocking downlrp5in zebrafish results in reduced expression of several genes linked to Wnt signaling pathway and decreased cell proliferation when compared with those in wild‐type zebrafish. In conclusion, theLRP5mutation influences cell proliferation through the Wnt signaling pathway, thereby reducing the number of supporting cells and hair cells and leading to nonsyndromic hearing loss in this Chinese family.