NCOA3 identified as a new candidate to explain autosomal dominant progressive hearing loss.
NCOA3 identified as a new candidate to explain autosomal dominant progressive hearing loss.
复制标题
DOI：
10.1093/hmg/ddaa240
复制
发表时间：
2021-01-21
影响因子：
3.5
通讯作者：
Mingroni-Netto RC
中科院分区：
文献类型：
--
作者：
Salazar-Silva R;Dantas VLG;Alves LU;Batissoco AC;Oiticica J;Lawrence EA;Kawafi A;Yang Y;Nicastro FS;Novaes BC;Hammond C;Kague E;Mingroni-Netto RC
听力损失是人类常见的感觉障碍，遗传因素在病例中所占比例较高。我们调查了一个五代人的大家庭，有15个报告的个体表现为非综合征、感觉神经性、双侧和进行性听力损失，分离为常染色体显性疾病。利用SNP阵列和选定的微卫星进行连锁分析，确定20号染色体上近13 cM的区域是容纳致病突变的最佳候选区域。经过外显子组测序和变异筛选，只有一个预测的NCOA3基因的有害变异(NM_181659，C.2810C >； G；p.Ser937Cys)符合我们的连锁数据。RT-PCR、免疫染色和原位杂交显示，ncoa3基因在小鼠内耳和斑马鱼中均有表达。我们利用CRISPR/Cas9系统获得了一个稳定的纯合斑马鱼突变系。NCoA-3−/−在耳部未见明显的形态异常，但黄斑前部毛细胞方向改变。令人惊讶的是，在ncoa3−/−中，形成耳软骨的软骨细胞表现出异常行为，脱离它们的位置，侵入耳道并堵塞眉骨。成年突变体表现出更密集的物质堆积，包裹着Ncoa3−/−的耳石，并增加了骨密度。斑马鱼游泳行为的改变证实了ncoa3在听力损失中的潜在作用。总之，我们确定了一个潜在的候选基因来解释遗传性听力损失，我们的功能分析表明，微妙和异常的骨骼行为是进行性感觉功能障碍的发病机制。
Hearing loss is a frequent sensory impairment in humans and genetic factors account for an elevated fraction of the cases. We have investigated a large family of five generations, with 15 reported individuals presenting non-syndromic, sensorineural, bilateral and progressive hearing loss, segregating as an autosomal dominant condition. Linkage analysis, using SNP-array and selected microsatellites, identified a region of near 13 cM in chromosome 20 as the best candidate to harbour the causative mutation. After exome sequencing and filtering of variants, only one predicted deleterious variant in the NCOA3 gene (NM_181659, c.2810C > G; p.Ser937Cys) fit in with our linkage data. RT-PCR, immunostaining and in situ hybridization showed expression of ncoa3 in the inner ear of mice and zebrafish. We generated a stable homozygous zebrafish mutant line using the CRISPR/Cas9 system. ncoa3−/− did not display any major morphological abnormalities in the ear, however, anterior macular hair cells showed altered orientation. Surprisingly, chondrocytes forming the ear cartilage showed abnormal behaviour in ncoa3−/−, detaching from their location, invading the ear canal and blocking the cristae. Adult mutants displayed accumulation of denser material wrapping the otoliths of ncoa3−/− and increased bone mineral density. Altered zebrafish swimming behaviour corroborates a potential role of ncoa3 in hearing loss. In conclusion, we identified a potential candidate gene to explain hereditary hearing loss, and our functional analyses suggest subtle and abnormal skeletal behaviour as mechanisms involved in the pathogenesis of progressive sensory function impairment.
登录
查看更多内容
DOI：
10.1073/pnas.0808207105
发表时间：
2008-11-04
影响因子：
11.1
作者：
Coste, Agnes;Louet, Jean-Francois;Auwerx, Johan
通讯作者：
Auwerx, Johan
microRNA-17 和 microRNA-20b 表达的减少通过上调 NCOA3 促进乳腺癌对紫杉醇治疗的耐药性。
影响因子：
9
作者：
Ao X;Nie P;Wu B;Xu W;Zhang T;Wang S;Chang H;Zou Z
通讯作者：
Zou Z
影响因子：
10.5
作者：
Dasgupta S;Lonard DM;O'Malley BW
通讯作者：
O'Malley BW
DOI：
10.1038/s41436-018-0285-0
发表时间：
2019-04
期刊：
Genetics in medicine : official journal of the American College of Medical Genetics
影响因子：
--
作者：
Booth KT;Askew JW;Talebizadeh Z;Huygen PLM;Eudy J;Kenyon J;Hoover D;Hildebrand MS;Smith KR;Bahlo M;Kimberling WJ;Smith RJH;Azaiez H;Smith SD
通讯作者：
Smith SD
影响因子：
2.9
作者：
Asik, Mehmet Dogan;Gursoy, Safa;Bozkurt, Murat
通讯作者：
Bozkurt, Murat