Identification of rare PTCH1 nonsense variant causing orofacial cleft in a Chinese family and an up-to-date genotype-phenotype analysis.
Identification of rare PTCH1 nonsense variant causing orofacial cleft in a Chinese family and an up-to-date genotype-phenotype analysis.
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中国家庭中引起口颌裂的罕见 PTCH1 无义变异的鉴定及最新基因型-表型分析
DOI：
10.1016/j.gendis.2019.12.010
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发表时间：
2021-09
期刊：
影响因子：
6.8
通讯作者：
Lin J
中科院分区：
文献类型：
--
作者：
Zhong W;Zhao H;Huang W;Zhang M;Zhang Q;Zhang Y;Chen C;Nueraihemaiti Z;Tuerhong D;Huang H;Maimaitili G;Chen F;Lin J
Patched 1（PTCH 1）基因编码一种参与Hedgehog（Hh）信号通路的膜受体，其异常状态可能导致先天性缺陷或人类肿瘤。在本研究中，我们对一个三代中国人的口面裂家系进行了全外显子组测序。PTCH 1基因中的一种罕见杂合变异（c.2833C > T p.R945X）被鉴定为疾病相关突变。结构建模揭示了从PTCH 1蛋白的第二胞外结构域的中间开始的截短。这可能损害其配体识别和固醇转运能力，从而影响Hh信号通路。生化分析表明，R945X蛋白在体外的稳定性降低相比，野生型。此外，我们还回顾了PTCH 1变异体在具有分裂表型的个体中的位置和突变类型，并分析了PTCH 1内的分裂和变异体的位置或类型之间的关联。我们的研究结果提供了进一步的证据，PTCH 1变异导致口面裂，并有助于遗传咨询和临床监测，在这个家庭。
The Patched 1 (PTCH1) gene encodes a membrane receptor involved in the Hedgehog (Hh) signaling pathway, an abnormal state of which may result in congenital defects or human tumors. In this study, we conducted whole-exome sequencing on a three-generation Chinese family characterized with variable penetrance of orofacial clefts. A rare heterozygous variant in the PTCH1 gene (c.2833C > T p.R945X) was identified as a disease-associated mutation. Structural modeling revealed a truncation starting from the middle of the second extracellular domain of PTCH1 protein. This may damage its ligand recognition and sterol transportation abilities, thereby affecting the Hh signaling pathway. Biochemical assays indicated that the R945X protein had reduced stability compared to the wild-type in vitro. In addition, we reviewed the locations and mutation types of PTCH1 variants in individuals with clefting phenotypes, and analyzed the associations between clefts and locations or types of variants within PTCH1. Our findings provide further evidence that PTCH1 variants result in orofacial clefts, and contributed to genetic counseling and clinical surveillance in this family.
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