Mutations in TOP2B cause autosomal-dominant hereditary hearing loss via inhibition of the PI3K-Akt signalling pathway
Mutations in TOP2B cause autosomal-dominant hereditary hearing loss via inhibition of the PI3K-Akt signalling pathway
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TOP2B 突变通过抑制 PI3K-Akt 信号通路导致常染色体显性遗传性听力损失
DOI：
10.1002/1873-3468.13482
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发表时间：
2019
期刊：
影响因子：
3.5
通讯作者：
Ma Zhaoxin
中科院分区：
文献类型：
--
作者：
Xia Wenjun;Hu Jiongjiong;Ma Jing;Huang Jianbo;Jing Tianrui;Deng Lisha;Zhang Jin;Jiang Nan;Ma Duan;Ma Zhaoxin
遗传性听力障碍是一种临床和遗传异质性疾病。对一个中国常染色体显性遗传性非综合征性听力损失大家族的7名受累成员和6名未受累成员进行全外显子组测序。在该谱系中，编码人类拓扑异构酶IIβ的基因的致病性变体TOP 2B（c.G4837C：p.D1613H）与听力损失共分离，并且在66名散发性听力损失患者中检测到另外两种TOP 2B变体。top 2b基因敲低导致斑马鱼内耳明显缺陷，并导致fakt下调，从而导致PI 3 K-Akt信号传导失活。因此，通过抑制PI 3 K-Akt通路，支持细胞和毛细胞数量减少。数据库研究中的全外显子组序列数据可在Sequence Read Archive数据库（NCBI）中获得，登录号为SRR 9050868、SRR 9050867、SRR 90508676、SRR 90508675、SRR 90508674、SRR 90508676、SRR 90508677、SRR 90 SRR90508673、SRR90508672、SRR90508671、SRR90508679、SRR90508670、SRR9050859。SRR 9050858和SRR 9050857。
Hereditary hearing impairment is a clinically and genetically heterogeneous disease. Whole‐exome sequencing was performed on seven affected and six unaffected members in a large Chinese family with autosomal‐dominant nonsyndromic hearing loss. The pathogenic variant of the gene encoding human topoisomerase IIβTOP2B(c.G4837C:p.D1613H) was cosegregated with hearing loss in this pedigree and another two variants ofTOP2Bwere detected in 66 sporadic patients with hearing loss.top2bknockdown led to significant defects in zebrafish inner ears and caused downregulation ofaktwhich resulted in inactivation of PI3K‐Akt signalling. As a result, supporting cell and hair cell numbers were reduced through inhibition of the PI3K‐Akt pathway. Therefore, we hypothesized that mutations inTOP2Bcan cause autosomal‐dominant nonsyndromic hearing impairment through inhibition of the PI3K‐Akt signalling pathway.DatabaseThe whole‐exome sequence data in the study are available at the Sequence Read Archive database (NCBI) under the accession numbers SRR9050868, SRR9050867, SRR90508676, SRR90508675, SRR90508674, SRR90508673, SRR90508672, SRR90508671, SRR90508679, SRR90508670, SRR9050859. SRR9050858 and SRR9050857, respectively.