Institute of Biochemistry, University of Balochistan, Quetta, Pakistan.
Department of Biotechnology & Genetic Engineering, Kohat University of Science & Technology, Kohat, Khyber Pakhtunkhwa, Pakistan.
Int J Dermatol. 2019 Aug;58(8):946-952. doi: 10.1111/ijd.14480. Epub 2019 May 11.
Autosomal recessive wooly hair/hypotrichosis is an inherited disorder of hair characterized by less dense, short, and tightly curled hair on the scalp and sometimes less dense to complete absence of eyebrows and eyelashes. Autosomal recessive wooly hair/hypotrichosis phenotypes are mostly associated with pathogenic sequence variants in LIPH and LPAR6 genes.
To find out the molecular basis of the disease, five families with autosomal recessive wooly hair/hypotrichosis were recruited for genetic analysis. Direct Sanger sequencing of LIPH and LPAR6 genes was carried out using BigDye chain termination chemistry. P2RY5 protein homology models were developed to study the effect of mutation on protein structure in a family having novel mutation.
Sanger sequencing revealed a novel homozygous missense mutation (c.47A>T) in the LPAR6 gene in family A, while recurrent mutation (c.436G>A) was detected in the rest of the four families (B-E). Protein homology models for both native and mutant P2RY5 protein were developed to study the difference in subtle structural features because of Lys16Met (K16M) mutation. We observed that P2RY5 mutation results decrease in the number of ionic interactions detrimental to the protein stability. Protein modeling studies revealed that the novel mutation identified here decreased the number of ionic interactions by affecting physicochemical parameters of the protein, leading to an overall decrease in protein stability with no major secondary structural changes.
The molecular analysis further confirms the frequent involvement of LPAR6 in autosomal recessive wooly hair/hypotrichosis, while the bioinformatic study revealed that the missense mutation destabilizes the overall structure of P2RY5 protein.
常染色体隐性羊毛状发/毛发稀少症是一种遗传性毛发疾病，其特征是头皮上的毛发密度较低、较短且卷曲较紧，有时眉毛和睫毛的密度较低甚至完全缺失。常染色体隐性羊毛状发/毛发稀少症表型主要与 LIPH 和 LPAR6 基因的致病性序列变异相关。
为了找出该疾病的分子基础，我们招募了五个常染色体隐性羊毛状发/毛发稀少症的家系进行遗传分析。使用 BigDye 链终止化学法对 LIPH 和 LPAR6 基因进行直接 Sanger 测序。针对一个具有新突变的家系，我们构建了 P2RY5 蛋白同源模型，以研究突变对蛋白质结构的影响。
Sanger 测序显示，家系 A 的 LPAR6 基因中存在一个新的纯合错义突变（c.47A>T），而其余四个家系（B-E）均检测到了反复出现的突变（c.436G>A）。我们构建了天然和突变 P2RY5 蛋白的同源模型，以研究由于 Lys16Met（K16M）突变导致的细微结构特征差异。我们观察到，P2RY5 突变导致离子相互作用数量减少，从而对蛋白质稳定性产生不利影响。蛋白建模研究表明，这里鉴定的新突变通过影响蛋白质的理化参数，减少了离子相互作用的数量，导致蛋白质整体稳定性降低，而没有发生主要的二级结构变化。
分子分析进一步证实 LPAR6 频繁参与常染色体隐性羊毛状发/毛发稀少症，而生物信息学研究表明，该错义突变使 P2RY5 蛋白的整体结构不稳定。
