title: In silico analysis of missense mutations in LPAR6 reveals abnormal phospholipid signaling pathway leading to hypotrichosis.
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.
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan; Army Medical College, National University of Science and Technology NUST, Islamabad, Pakistan.
authors.forename: Syed Irfan
authors.initials: SI
authors.lastname: Raza
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Dost
authors.initials: D
authors.lastname: Muhammad
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Abid
authors.initials: A
authors.lastname: Jan
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Raja Hussain
authors.initials: RH
authors.lastname: Ali
authors.affiliation: National Center for Bioinformatics, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Mubashir
authors.initials: M
authors.lastname: Hassan
authors.affiliation: Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Wasim
authors.initials: W
authors.lastname: Ahmad
authors.affiliation: National Center for Bioinformatics, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan.
authors.forename: Sajid
authors.initials: S
authors.lastname: Rashid
mesh_terms: D001483:Base Sequence; D003198:Computer Simulation; D005808:Genes, Recessive / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007039:Hypotrichosis / Q000235:genetics*; D008246:Lysophospholipids / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D010743:Phospholipids / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics*; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics*
chemical_list: C545560:LPAR6 protein, human; D008246:Lysophospholipids; D010743:Phospholipids; D049368:Receptors, Lysophosphatidic Acid; C032881:lysophosphatidic acid