Autosomal recessive hypotrichosis (LAH3) is a rare hair disorder characterized by sparse hair on scalp and the rest of the body of affected individuals. Recently mutations in a G protein-coupled receptor gene, P2RY5, located at LAH3 locus, have been reported in several families with autosomal recessive hypotrichosis simplex and woolly hair. For the present study, 22 Pakistani families with autosomal recessive hypotrichosis were enrolled. Genotyping using microsatellite markers linked to three autosomal recessive forms of hypotrichosis (LAH1, LAH2, LAH3) showed the linkage of 2 families to the LAH2 locus and 14 to the LAH3 locus. The remaining 6 families were not linked to any of the three loci. Families linked to LAH3 locus were further subjected to screening of the P2RY5 gene with direct DNA sequencing. Three previously reported variants, c.69insCATG (p.24insHfs52), c.188A > T (p.D63V) and c.565G > A (p.E189K) were observed in eight families. Four novel nonsynonymous sequence variants, c.8G > C (p.S3T), c.36insA (p.D13RfsX16), c.160insA (p.N54TfsX58) and c.436G > A (p.G146R) were found to segregate within six families.

FZD6 belongs to a family of proteins that serve as receptors in Wnt signalling pathways, and has been shown to act as a negative regulator of the canonical Wnt/β-catenin signalling cascade and a positive regulator of the noncanonical Wnt or planar cell polarity pathway. The present results therefore suggest that FZD6 plays a pivotal role in the growth and guidance of the nail plate in humans by acting as a molecular switch between different Wnt pathways. Previous studies have identified mutations in the RSPO4 and LMX1B components of the Wnt pathway in patients with the hypoplastic nail disorders anonychia and nail-patella syndrome, respectively. Only recently, FZD6 mutations were identified in isolated nail dysplasia. The present results emphasize the important role of the Wnt pathways in nail development and increase understanding of Wnt-mediated developmental events in general.

Mutations identified in the present study extend the body of evidence implicating LPAR6 and LIPH genes in pathogenesis of human hereditary hair loss.