A disease-causing novel missense mutation in the ST14 gene underlies autosomal recessive ichthyosis with hypotrichosis syndrome in a consanguineous family.
A disease-causing novel missense mutation in the ST14 gene underlies autosomal recessive ichthyosis with hypotrichosis syndrome in a consanguineous family.
复制标题
DOI：
10.1684/ejd.2017.3210
复制
发表时间：
2018-04-01
期刊：
影响因子：
--
通讯作者：
Ahmad W
中科院分区：
文献类型：
--
作者：
Ahmad F;Ahmed I;Nasir A;Umair M;Shahzad S;Muhammad D;Santos-Cortez RLP;Leal SM;Ahmad W
常染色体隐性遗传性鱼鳞病伴少毛症（ARIH；MIM 602400）综合征的特点是弥漫性先天性鱼鳞病和全身性非疤痕性少毛症。 ARIH 综合征的潜在遗传原因与 ST14 基因的序列变异有关，该基因编码 II 型跨膜丝氨酸蛋白酶基质酶，定位于染色体 11q24.3。本报告旨在调查巴基斯坦血统大家族中 ARIH 综合征的临床特征和遗传原因。采用高度多态性微卫星标记的纯合性作图技术来建立家族内的连锁。对 ST14 的外显子和内含子-外显子边界进行桑格测序，以确定潜在的致病序列变异，然后对突变蛋白进行结构分析。与染色体 11q24.3 建立连锁，包含基因 ST14。序列分析导致在 ST14 基因中鉴定出一种新的纯合错义变异（c.1315G>A，p.Gly439Ser），该变异与所有受影响成员的疾病表型共分离。对ST14与野生型TMEFF1蛋白进行同源建模和分子对接分析，结果表明439位的甘氨酸对于维持正常的结构确认以及与TMEFF1蛋白的EGF结构域的相互作用至关重要。总而言之，数据强烈主张该 ST14 变异是第一个报告的巴基斯坦受影响家庭中 ARIH 综合征的潜在遗传原因。此外，本研究增加了 ST14 基因的突变谱，表明它们与 ARIH 综合征的发病机制有关。
Autosomal recessive ichthyosis with hypotrichosis (ARIH; MIM 602400) syndrome is characterized by diffused congenital ichthyosis and generalized non-scarring hypotrichosis. The underlying genetic cause of ARIH syndrome has been associated with sequence variants of the gene ST14, encoding type II transmembrane serine protease matriptase, which maps to chromosome 11q24.3. The current report aimed to investigate the clinical features and genetic cause of ARIH syndrome in a large consanguineous family of Pakistani origin. The technique of homozygosity mapping with highly polymorphic microsatellite markers was employed to establish linkage within the family. Sanger sequencing of exons and intron-exonboundaries of ST14 was performed to identify the potential pathogenic sequence variants, followed by structural analysis of the mutated protein. Linkage was established to chromosome 11q24.3, comprising the gene ST14. Sequence analysis led to the identification of a novel homozygous missense variant (c.1315G>A, p.Gly439Ser) in the ST14 gene that co-segregated with the disease phenotype in all affected members. Homology modelling and molecular docking analysis of ST14 with wild-type TMEFF1 protein was performed which revealed that glycine at position 439 is crucial for maintaining normal structural confirmation and interaction with the EGF domain of TMEFF1 protein. Taken together, the data strongly advocate this ST14 variant as the underlying genetic cause of ARIH syndrome in this first reported affected family from Pakistan. Moreover, the present study adds to the spectrum of mutations in the ST14 gene, implicating them in the pathogenesis of ARIH syndrome.