Cell-based analysis of CLIC5A and SLC12A2 variants associated with hearing impairment in two African families.
Cell-based analysis of CLIC5A and SLC12A2 variants associated with hearing impairment in two African families.
复制标题
DOI：
10.3389/fgene.2022.924904
复制
发表时间：
2022
影响因子：
3.7
通讯作者：
Wonkam, Ambroise
中科院分区：
文献类型：
--
作者：
Adadey, Samuel Mawuli;Wonkam-Tingang, Edmond;de Souza Rios, Leonardo Alves;Aboagye, Elvis Twumasi;Esoh, Kevin;Manyisa, Noluthando;De Kock, Carmen;Awandare, Gordon A.;Mowla, Shaheen;Wonkam, Ambroise
我们之前已经报道了来自喀麦隆和加纳的两个家系中的CLIC5A和SLC12a2变异，分离了非综合征性听力障碍(NSHI)。在这项研究中，通过生物学检测进一步研究了CLIC5[c.224T>；C；p.(L75P)]和SCL12A2[c.2935G>；A：p.(E979K)]变异体的致病性。细胞模型中蛋白质的异位表达表明，与野生型相比，CLIC5A和SLC12a2变异体都过度表达。突变的CLIC5A蛋白呈聚集的核周小体，而野生型蛋白均匀分布在细胞质中。此外，转染野生型CLIC5A的细胞形成了薄膜丝状突起，这在表达CLIC5A突变体的细胞和对照细胞中是不存在的。另一方面，野生型SLc12a2表达细胞具有突变型表达细胞和对照细胞所没有的轴突形态。网络分析显示，CLIC5A可以与立体纤毛底部的至少8种蛋白质相互作用。这项研究产生了与在两个非洲家庭中发现的CLIC5A和SLC12a2目标变异的致病性相关的新的生物学数据，从而扩大了我们对它们在听力障碍中的病理生物学的理解。
We have previously reported CLIC5A and SLC12A2 variants in two families from Cameroon and Ghana, segregating non-syndromic hearing impairment (NSHI). In this study, biological assays were performed to further functionally investigate the pathogenicity of CLIC5 [c.224T>C; p.(L75P)] and SCL12A2 [c.2935G>A: p.(E979K)] variants. Ectopic expression of the proteins in a cell model shows that compared to wild-type, both the CLIC5A and SLC12A2 variants were overexpressed. The mutant CLIC5A protein appears as aggregated perinuclear bodies while the wild-type protein was evenly distributed in the cytoplasm. Furthermore, cells transfected with the wild-type CLIC5A formed thin membrane filopodia-like protrusions which were absent in the CLIC5A mutant expressing and control cells. On the other hand, the wild-type SLC12A2 expressing cells had an axon-like morphology which was not observed in the mutant expressing and control cells. A network analysis revealed that CLIC5A can interact with at least eight proteins at the base of the stereocilia. This study has generated novel biological data associated with the pathogenicity of targeted variants in CLIC5A and SLC12A2, found in two African families, and therefore expands our understanding of their pathobiology in hearing impairment.
登录
查看更多内容
DOI：
10.1111/febs.15531
发表时间：
2021-05
期刊：
The FEBS journal
影响因子：
--
作者：
Pizzagalli MD;Bensimon A;Superti-Furga G
通讯作者：
Superti-Furga G
DOI：
10.1083/jcb.143.7.1883
发表时间：
1998-12-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Johnston JA;Ward CL;Kopito RR
通讯作者：
Kopito RR
影响因子：
4.8
作者：
Harrop, SJ;DeMaere, MZ;Curmi, PMG
通讯作者：
Curmi, PMG
影响因子：
5.3
作者：
Gagnon, Leona H.;Longo-Guess, Chantal M.;Johnson, Kenneth R.
通讯作者：
Johnson, Kenneth R.
影响因子：
14.9
作者：
Franceschini A;Szklarczyk D;Frankild S;Kuhn M;Simonovic M;Roth A;Lin J;Minguez P;Bork P;von Mering C;Jensen LJ
通讯作者：
Jensen LJ