Shah Khadim, Ali Raja Hussain, Ansar Muhammad, Lee Kwanghyuk, Chishti Muhammad Salman, Abbe Izoduwa, Li Biao, Smith Joshua D, Nickerson Deborah A, Shendure Jay, Coucke Paul J, Steyaert Wouter, Bamshad Michael J, Santos-Cortez Regie Lyn P, Leal Suzanne M, Ahmad Wasim
Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, 45320, Pakistan.
Center for Medical Genetics, Ghent University Hospital, 9000, Ghent, Belgium.
BMC Med Genet. 2016 Feb 16;17:13. doi: 10.1186/s12881-016-0275-5.
Nonphotosensitive trichothiodystrophy (TTDN) is a rare autosomal recessive disorder of neuroectodermal origin. The condition is marked by hair abnormalities, intellectual impairment, nail dystrophies and susceptibility to infections but with no UV sensitivity.
We identified three consanguineous Pakistani families with varied TTDN features and used homozygosity mapping, linkage analysis, and Sanger and exome sequencing in order to identify pathogenic variants. Haplotype analysis was performed and haplotype age estimated. A splicing assay was used to validate the effect of the MPLKIP splice variant on expression.
Affected individuals from all families exhibit several TTDN features along with a heart-specific feature, i.e. mitral regurgitation. Exome sequencing in the probands from families ED168 and ED241 identified a homozygous splice mutation c.339 + 1G > A within MPLKIP. The same splice variant co-segregates with TTDN in a third family ED210. The MPLKIP splice variant was not found in public databases, e.g. the Exome Aggregation Consortium, and in unrelated Pakistani controls. Functional analysis of the splice variant confirmed intron retention, which leads to protein truncation and loss of a phosphorylation site. Haplotype analysis identified a 585.1-kb haplotype which includes the MPLKIP variant, supporting the existence of a founder haplotype that is estimated to be 25,900 years old.
This study extends the allelic and phenotypic spectra of MPLKIP-related TTDN, to include a splice variant that causes cardiomyopathy as part of the TTDN phenotype.
非光敏性毛发硫营养不良（TTDN）是一种罕见的神经外胚层起源的常染色体隐性疾病。该病症的特征为毛发异常、智力障碍、指甲营养不良以及易感染，但对紫外线不敏感。
我们鉴定了三个具有不同TTDN特征的巴基斯坦近亲家庭，并使用纯合性定位、连锁分析、桑格测序和外显子组测序来鉴定致病变异。进行了单倍型分析并估计了单倍型年龄。使用剪接试验来验证MPLKIP剪接变异体对表达的影响。
所有家庭的受影响个体均表现出多种TTDN特征以及一种心脏特异性特征，即二尖瓣反流。对ED168和ED241家庭的先证者进行外显子组测序，在MPLKIP基因内鉴定出一个纯合剪接突变c.339 + 1G > A。相同的剪接变异体在第三个家庭ED210中与TTDN共分离。在公共数据库（如外显子组聚合联盟）和无关的巴基斯坦对照中未发现MPLKIP剪接变异体。对该剪接变异体的功能分析证实了内含子保留，这导致蛋白质截短并失去一个磷酸化位点。单倍型分析鉴定出一个585.1 kb的单倍型，其中包括MPLKIP变异体，支持存在一个估计有25900年历史的奠基者单倍型。
本研究扩展了与MPLKIP相关的TTDN的等位基因和表型谱，将一种导致心肌病的剪接变异体纳入TTDN表型。
