A novel PTCH1 mutation underlies nonsyndromic cleft lip and/or palate in a Han Chinese family.
A novel PTCH1 mutation underlies nonsyndromic cleft lip and/or palate in a Han Chinese family.
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DOI：
10.1111/odi.12915
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发表时间：
2018-07
期刊：
影响因子：
3.8
通讯作者：
Huaxiang Zhao;Wenjie Zhong;Chuntao Leng;Jieni Zhang;Mengqi Zhang;Wen-Zhi Huang;Yunfan Zhang;
中科院分区：
文献类型：
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作者：
Huaxiang Zhao;Wenjie Zhong;Chuntao Leng;Jieni Zhang;Mengqi Zhang;Wen-Zhi Huang;Yunfan Zhang;
唇腭裂（Cleft lip and/or palate，CL/P）是颅颌面部最常见的先天性疾病，其病因复杂。本研究的目的是确定一个中国汉族家庭与CL/P的致病基因突变。对象和方法进行全外显子组测序的先证者和她的母亲，谁表现出相同的表型。采用孟德尔显性遗传模型、等位基因频率、突变区域、功能预测和文献复习等方法筛选变异体。通过桑格测序验证候选物。进行了保守性分析和同源性建模。结果在PTCH 1基因中发现了一个杂合错义突变c.1175C>T，预测p.Ala392Val。该变体尚未报道，预计是有害的。桑格测序证实了该变异和家系中的显性遗传模式。错义改变影响在PTCH 1蛋白的第一胞外环中进化上保守的氨基酸。根据同源性建模，突变蛋白的局部结构被显著改变。结论PTCH 1（NM_000264）基因c.1175C>T突变可能是该家系的致病突变。我们的研究结果增加了PTCH 1变异体在口面裂发病机制中发挥作用的证据。
OBJECTIVES Cleft lip and/or palate (CL/P) is the most common craniofacial congenital disease, and it has a complex aetiology. This study aimed to identify the causative gene mutation of a Han Chinese family with CL/P. SUBJECTS AND METHODS Whole exome sequencing was conducted on the proband and her mother, who exhibited the same phenotype. A Mendelian dominant inheritance model, allele frequency, mutation regions, functional prediction and literature review were used to screen and filter the variants. The candidate was validated by Sanger sequencing. Conservation analysis and homology modelling were conducted. RESULTS A heterozygous missense mutation c.1175C>T in the PTCH1 gene predicting p.Ala392Val was identified. This variant has not been reported and was predicted to be deleterious. Sanger sequencing verified the variant and the dominant inheritance model in the family. The missense alteration affects an amino acid that is evolutionarily conserved in the first extracellular loop of the PTCH1 protein. The local structure of the mutant protein was significantly altered according to homology modelling. CONCLUSIONS Our findings suggest that c.1175C>T in PTCH1 (NM_000264) may be the causative mutation of this pedigree. Our results add to the evidence that PTCH1 variants play a role in the pathogenesis of orofacial clefts.