Molecular Analysis of Heredity Hypotrichosis in Consanguineous Families in the District of Karak, Pakistan

Abstract

Background: Hereditary hypotrichosis is a rare genetic disorder characterized by sparse or absent scalp and body hair. It can manifest as an isolated condition or in association with other ectodermal abnormalities and follows either an autosomal dominant or recessive inheritance pattern. Variants in several genes, including HR, DSG4, LIPH, DSC3, KRT25, and LPAR6 (P2RY5), have been implicated in recessive forms of the disease. Among these, LPAR6, which encodes a G-protein–coupled receptor involved in lysophosphatidic acid (LPA) signaling, plays a crucial role in hair follicle morphogenesis and hair shaft differentiation. Objective: To investigate the clinical, genetic, and molecular basis of autosomal recessive non-syndromic hereditary hypotrichosis in two consanguineous families from the Karak district of Pakistan and to identify the underlying pathogenic variant. Methods: Two unrelated consanguineous families with multiple members affected by hypotrichosis were recruited for this study. Detailed clinical examinations and pedigree analyses were performed to document the phenotype and inheritance pattern. Genomic DNA was extracted from affected and unaffected individuals, and linkage mapping was conducted using highly polymorphic microsatellite markers. Sanger sequencing of the LPAR6 gene was performed to identify pathogenic variants. Conservation analysis, in silico pathogenicity prediction, and three-dimensional protein modeling were used to assess the functional impact of the identified mutation. Results: All affected individuals exhibited early-onset, sparse, woolly scalp hair that remained thin and lightly pigmented throughout life, with no additional ectodermal anomalies. Linkage analysis localized the disease locus to chromosome 13q14.2, where LPAR6 resides. Sanger sequencing revealed a homozygous missense variant, c.436G>A (p.Gly146Arg), which co-segregated with the disease phenotype in both families. Conservation analysis showed that glycine at position 146 is highly conserved across species, indicating functional importance. In silico tools predicted the variant as “probably damaging,” and protein modeling suggested that substitution with arginine disrupts the transmembrane helix, impairing receptor conformation and signaling. Conclusion: This study confirms the pathogenic role of the c.436G>A (p.Gly146Arg) variant in LPAR6 as the cause of autosomal recessive hereditary hypotrichosis in two Pakistani families. The findings expand the known mutational landscape of LPAR6, highlight the essential role of the LPA–LPAR6 signaling pathway in hair follicle development, and underscore the importance of genetic diagnosis and counseling in populations with high consanguinity. These results provide a basis for future research into targeted therapeutic approaches for hereditary hair growth disorders