In silico analysis of missense mutations in LPAR6 reveals abnormal phospholipid signaling pathway leading to hypotrichosis.

Syed Irfan Raza,Mubashir Hassan,Raja Hussain Ali,Dost Muhammad,Abid Jan,Sajid Rashid,Wasim Ahmad,Maurice A M Van Steensel

doi:10.1371/journal.pone.0104756

Abstract

Autosomal recessive hypotrichosis is a rare genetic irreversible hair loss disorder characterized by sparse scalp hair, sparse to absent eyebrows and eyelashes, and sparse axillary and body hair. The study, presented here, established genetic linkage in four families showing similar phenotypes to lysophosphatidic acid receptor 6 (LPAR6) gene on chromosome 13q14.11-q21.32. Subsequently, sequence analysis of the gene revealed two previously reported missense mutations including p.D63V in affected members of one and p.I188F in three other families. Molecular modeling and docking analysis was performed to investigate binding of a ligand oleoyl-L-alpha-lysophosphatidic acid (LPA) to modeled protein structures of normal and mutated (D63V, G146R, I188F, N248Y, S3T, L277P) LPAR6 receptors. The mutant receptors showed a complete shift in orientation of LPA at the binding site. In addition, hydropathy analysis revealed a significant change in the membrane spanning topology of LPAR6 helical segments. The present study further substantiated involvement of LPAR6-LPA signaling in the pathogenesis of hypotrichosis/woolly hair and provided additional insight into the molecular mechanism of hair development.

Highlights

Autosomal recessive hypotrichosis is a rare form of alopecia characterized by sparse hair on scalp, sparse to absent eyebrows and eyelashes, and sparse auxiliary and body hair
Genotyping and mutation analysis Based on clinical features exhibited by affected individuals, all the four families were tested for linkage to genes LIPH and lysophosphatidic acid receptor 6 (LPAR6) mapped on chromosome 3q and 13q14.11-q21.32, respectively
It has been recently shown that epithelial keratins colocalize with LPAR6 in the Henle’s (He) and Huxley’s (Hux) layers of follicle-specific inner root sheath (IRS) [4]

Summary

Introduction

Autosomal recessive hypotrichosis is a rare form of alopecia characterized by sparse hair on scalp, sparse to absent eyebrows and eyelashes, and sparse auxiliary and body hair. Over the past few years, mutations in at least eight genes causing variable phenotypes of autosomal recessive form of hypotrichosis have been reported. Presence of woolly hair has been reported in patients carrying mutations in keratin-74 gene with phenotype segregating in autosomal dominant fashion [4]. The LPAR6 is a nested gene residing within intron-17 of the RB1 and encodes a heptaspan transmembrane protein that belongs to an orphan G-protein-coupled receptor (GPCR). Both LIPH and LPAR6 express in the inner root sheath (IRS) of hair follicle [5,6,7] and are involved in the same pathway of hair growth regulation and differentiation [8]. Oleoyl-Lalpha-lysophosphatidic acid (LPA), a bioactive lipid and product of LIPH serves as a ligand for LPAR6 receptor [8]

Methods

Results

Conclusion