GJB4 and GJC3 variants in non-syndromic hearing impairment in Ghana
GJB4 and GJC3 variants in non-syndromic hearing impairment in Ghana
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DOI：
10.1177/1535370220931035
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发表时间：
2020-06-11
影响因子：
3.2
通讯作者：
Wonkam, Ambroise
中科院分区：
文献类型：
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作者：
Adadey, Samuel M.;Esoh, Kevin K.;Wonkam, Ambroise
在非洲，GJB4和GJC3基因变异对听力障碍的贡献尚未被研究。在这里，我们调查了这些基因在加纳儿童常染色体隐性遗传性非综合征性听力障碍中的作用。来自加纳11所聋人学校的141个单一家庭和59个多家庭的听力障碍儿童入学。对GJB4和GJC3的编码区进行了扩增、测序，并对先前发现GJB2和GJB6变异体为阴性的研究参与者进行了分析。共鉴定出7个GJB4和1个GJC3变异。在七个GJB4变异中，有一个被归类为可能的致病基因，而其他的要么是良性的，要么是同义的。可能的致病变异(p.Asn119Thr/rs190460237)被预测可能与听力障碍有关。我们对该突变体(p.Asn119Thr)的野生型和突变型蛋白进行了建模，以评估突变对蛋白质结构和配体结合特性的影响。突变体而不是野生型有可能与N-乙基-5-修饰剂字母Prime-Carboxamido腺苷(DB03719)结合，这是因为观察到了轻微的结构变化。在GJC3基因中没有发现与临床相关的变异。我们首次报告了一种可能的致病基因GJB4变异，它可能与加纳的非综合征性听力障碍有关；这一发现将增加GJB4对世界各地听力障碍病例的贡献的证据。虽然已知连接蛋白是与HI相关的主要遗传因素，但只有几项研究调查了听力受损患者中的GJB4和GJC3变异。这项研究首次报道了来自非洲HI队列的GJB4和GJC3变异。我们已经证明，GJB4和GJC3基因可能对加纳的HI没有显著贡献，因此不应考虑将这些基因用于加纳的常规临床筛查。然而，重要的是要研究更大的人群，以确定GJB4和GJC3变异与HI的关联。
The contribution ofGJB4andGJC3gene variants to hearing impairment in Africa has not yet been studied. Here, we investigated the contribution of these genes to autosomal recessive non-syndromic hearing impairment in Ghanaian children. Hearing-impaired children from 141 simplex and 59 multiplex families were enrolled from 11 schools for the deaf in Ghana. The coding regions ofGJB4andGJC3were amplified, sequenced, and analyzed for the study participants previously found to be negative forGJB2andGJB6variants. SevenGJB4and oneGJC3variants were identified. One out of the sevenGJB4variants was classified as likely pathogenic, while the others were either benign or synonymous. The likely pathogenic variant (p.Asn119Thr/rs190460237) was predicted to be likely associated with hearing impairment. We modeled the wild-type and mutant proteins of this variant (p.Asn119Thr) to evaluate the effect of the mutation on protein structure and ligand-binding properties. The mutant and not the wild type had the potential to bind N-Ethyl-5MODIFIER LETTER PRIME-Carboxamido Adenosine (DB03719) which was due to a slight structural change that was observed. No clinically relevant variant was identified in theGJC3gene. We report for the first time a likely pathogenicGJB4variant that may be associated with non-syndromic hearing impairment in Ghana; the finding will add to the body of evidence of the contribution ofGJB4to hearing impairment cases around the world. Impact statement Although connexins are known to be the major genetic factors associated with HI, only a few studies have investigatedGJB4andGJC3variants among hearing-impaired patients. This study is the first to reportGJB4andGJC3variants from an African HI cohort. We have demonstrated thatGJB4andGJC3genes may not contribute significantly to HI in Ghana, hence these genes should not be considered for routine clinical screening in Ghana. However, it is important to study a larger population to determine the association ofGJB4andGJC3variants with HI.