Diversity of the Genes Implicated in Algerian Patients Affected by Usher Syndrome
Diversity of the Genes Implicated in Algerian Patients Affected by Usher Syndrome
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DOI：
10.1371/journal.pone.0161893
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发表时间：
2016-09-01
期刊：
影响因子：
3.7
通讯作者：
Petit, Christine
中科院分区：
文献类型：
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作者：
Abdi, Samia;Bahloul, Amel;Petit, Christine
Usher综合征（USH）是一种常染色体隐性遗传疾病，其特征是影响听力和视力的双重感觉障碍。USH是临床和遗传异质性。已经报道了10种不同的致病基因。我们通过靶向外显子组测序研究了18名无关阿尔及利亚患者的分子基础，并确定了所有患者的致病双等位基因突变：16名患者携带纯合状态的突变和2名复合杂合状态的突变。在MYO 7A（5种突变中的1种）、CDH 23（7种突变中的4种）、PCDH 15（1种突变）、USH 1C（1种突变）、USH 1G（1种突变）和USH 2A（2种突变中的1种）中检测到的17种不同突变中的9种先前未报告。分别从cadherin-23的胞外钙粘蛋白（EC）结构域和USH 1G/sans的无菌α基序（SAM）结构域的三维结构预测了CDH 23（p.Asp1501Asn）错义突变和USH 1G（p.Ala397del）框内单密码子缺失对相应蛋白质的有害后果。此外，我们能够证明USH 1G突变可能影响SAM结构域和USH 1C/harmonin之间的结合界面。这应该刺激使用3D结构，不仅是分离的蛋白质结构域，而且是蛋白质-蛋白质相互作用界面，以预测USH基因中检测到的突变的功能影响。
Usher syndrome (USH) is an autosomal recessive disorder characterized by a dual sensory impairment affecting hearing and vision. USH is clinically and genetically heterogeneous. Ten different causal genes have been reported. We studied the molecular bases of the disease in 18 unrelated Algerian patients by targeted-exome sequencing, and identified the causal biallelic mutations in all of them: 16 patients carried the mutations at the homozygous state and 2 at the compound heterozygous state. Nine of the 17 different mutations detected in MYO7A (1 of 5 mutations), CDH23 (4 of 7 mutations), PCDH15 (1 mutation), USH1C (1 mutation), USH1G (1 mutation), and USH2A (1 of 2 mutations), had not been previously reported. The deleterious consequences of a missense mutation of CDH23 (p. Asp1501Asn) and the in-frame single codon deletion in USH1G (p. Ala397del) on the corresponding proteins were predicted from the solved 3D-structures of extracellular cadherin (EC) domains of cadherin-23 and the sterile alpha motif (SAM) domain of USH1G/sans, respectively. In addition, we were able to show that the USH1G mutation is likely to affect the binding interface between the SAM domain and USH1C/harmonin. This should spur the use of 3D-structures, not only of isolated protein domains, but also of protein-protein interaction interfaces, to predict the functional impact of mutations detected in the USH genes.