CLINICAL AND LABORATORY INVESTIGATIONS BJD British Journal of Dermatology Mutations in the P2RY5 gene underlie autosomal recessive hypotrichosis in 13 Pakistani families M. Tariq, M. Ayub,* M. Jelani, S. Basit, G. Naz, N. Wasif, S.I. Raza, A.K. Naveed, S. ullah Khan, Z. Azeem, M. Yasinzai,* A. Wali, G. Ali, M.S. Chishti and W. Ahmad Department of Biochemistry, Faculty of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan *Institute of Biochemistry, University of Baluchistan, Quetta, Pakistan  Department of Biochemistry and Molecular Biology, National University of Sciences and Technology, Rawalpindi Cantt, Pakistan Correspondence Wasim Ahmad. E-mail: wahmad@qau.edu.pk Accepted for publication 9 November 2008 Key words autosomal recessive hypotrichosis, novel and recurrent mutations, P2RY5 gene Conflicts of interest None declared. M.T., M.A., M.J., S.B., G.N. and N.W. have contributed equally to this work. DOI 10.1111/j.1365-2133.2009.09046.x Summary Background Autosomal recessive hypotrichosis is a rare genetic irreversible hair loss characterized by sparse scalp hair, sparse to absent eyebrows and eyelashes, and sparse axillary and body hair. Affected male individuals have normal beard hair. Objectives To search for pathogenic mutations in the human P2RY5 gene in Pakistani families with autosomal recessive hereditary hypotrichosis. Methods In the present report, 16 unrelated consanguineous Pakistani families hav- ing multiple affected individuals with autosomal recessive hypotrichosis were investigated. Linkage in these families was searched by genotyping microsatellite markers linked to autosomal recessive hypotrichosis loci LAH1, LAH2 and LAH3. Thirteen of the families showed linkage to the LAH3 locus on chromosome 13q14.11–q21.32. These families were then subjected to direct sequencing of the P2RY5 gene, which encodes a G protein-coupled receptor. Results Sequence analysis of the P2RY5 gene revealed two novel missense mutations (c.742A>T; p.N248Y and c.830C>T; p.L277P) in three families. Five previously described mutations including three missense (c.188A>T; p.D63V, c.436G>A; p.G146R, c.562A>T; p.I188F), one insertion (c.69insCATG; p.24insHfsX52) and one complex deletion (c.172–175delAACT; 177delG; p.N58–L59delinsCfsX88) were detected in the other 10 families. Conclusions Mutations revealed in the present study extend the body of evidence implicating the P2RY5 gene in the pathogenesis of human hereditary hair loss. Over the past few years several studies have shown that defects in the hair growth cycle, hair structure, signalling mol- ecules and the pathways involved in developing hair follicles result in complete or partial hair loss. Several such forms of hair loss occur either alone or in association with abnormali- ties in other ectodermal structures. Autosomal recessive hypotrichosis is a rare form of hair loss characterized by sparse hair on scalp, sparse to absent eye- brows and eyelashes, and sparse axillary and body hair. Affected male adult individuals have normal beard hair. 1,2 Recently, three clinically similar forms of hereditary hypotri- chosis, LAH1, LAH2 and LAH3, segregating in an autosomal recessive fashion, have been mapped on human chromosomes 18q12.1, 3q27.3 and 13q14.11–q21.32, respectively. 1,3,4 These three forms of hypotrichosis have been reported to result from mutations in the desmoglein 4 (DSG4, MIM 607892), lipase H (LIPH, MIM 607365) and G protein- coupled receptor (GPCR) (P2RY5, MIM 609239) genes. Muta- tions in the DSG4 gene have been found to be responsible for LAH1 and monilethrix phenotypes. 5–8 The LAH2 locus was mapped by Aslam et al. 3 in a large Pakistani family. Kazantseva et al. 9 have reported a 985-bp deletion mutation containing exon 4 and the flanking intronic sequences of the LIPH gene, located at the LAH2 locus, in 50 families with hereditary hypo- trichosis belonging to two ethnic populations from the Volga– Ural region of Russia. Three other mutations, all deletions, were later identified in the same gene in four large Pakistani families with autosomal recessive hypotrichosis. 2,10,11 Most recently, mutations in the P2RY5 gene have been iden- tified in several Saudi Arabian and Pakistani families with autosomal recessive hypotrichosis simplex, 12 autosomal reces- sive woolly hair 13 and autosomal recessive hypotrichosis LAH3. 14 In the present study, we have sequenced the P2RY5 gene in 13 unrelated Pakistani families with hereditary hypotrichosis, which showed linkage to microsatellite markers linked to the Ó 2009 The Authors 1006 Journal Compilation Ó 2009 British Association of Dermatologists • British Journal of Dermatology 2009 160, pp1006–1010