G protein–coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth Sandra M Pasternack 1 , Ivar von Ku ¨gelgen 2 , Khalid Al Aboud 3 , Young-Ae Lee 4,5 , Franz Ru ¨schendorf 5 , Katrin Voss 6 , Axel M Hillmer 7 , Gerhard J Molderings 2 , Thomas Franz 8 , Alfredo Ramirez 9–11 , Peter Nu ¨rnberg 11,12 , Markus M No ¨then 1,7 & Regina C Betz 1 Hypotrichosis simplex is a group of nonsyndromic human alopecias. We mapped an autosomal recessive form of this disorder to chromosome 13q14.11–13q21.33, and identified homozygous truncating mutations in P2RY5, which encodes an orphan G protein–coupled receptor. Furthermore, we identified oleoyl-L-a-lysophosphatidic acid (LPA), a bioactive lipid, as a ligand for P2Y5 in reporter gene and radioligand binding experiments. Homology and studies of signaling transduction pathways suggest that P2Y5 is a member of a subgroup of LPA receptors, which also includes LPA4 and LPA5. Our study is the first to implicate a G protein–coupled receptor as essential for and specific to the maintenance of human hair growth. This finding may provide opportunities for new therapeutic approaches to the treatment of hair loss in humans. Hair loss is a common occurrence in humans and has a variety of causes. The causes include purely genetic factors, as in androgenetic alopecia, multifactorial factors (that is, genetic as well as external factors), as in alopecia areata, or mainly external factors, as in drug- induced alopecia. Hair loss causes considerable psychological distress in most of those affected. Currently available therapies are unsatisfac- tory, and there is a demand for new treatment strategies. A powerful approach to advance our understanding of the pathophysiology of human hair loss is to identify genes underlying mendelian isolated alopecias. Investigation of this type of hair loss offers the unique opportunity to identify factors that are not only necessary for, but also specific to, hair growth. Genes previously identified using this approach include HR (encoding hairless) 1,2 , VDR (encoding vitamin D receptor) 3 , CDSN (encoding corneodesmosin) 4 , DSG4 (encoding desmoglein 4) 5 and LIPH (encoding lipase, member H) 6 . Despite substantial progress in this research field, the complex pathophysio- logy of human hair growth is far from completely understood, and a major breakthrough in therapy has yet to be achieved. Hypotrichosis simplex (MIM 146520 and MIM 605389) is a group of hereditary isolated alopecias that affects men and women equally 7 . The hair loss is diffuse and progressive, and usually begins in early childhood. Autosomal recessive inheritance has been observed in a small number of families 5,8,9 . To identify the molecular cause of autosomal recessive hypotrichosis simplex in a consanguineous Saudi Arabian family (Fig. 1), we collected blood samples from 11 family members after obtaining informed consent. Four of the ten siblings present with progressive hair loss (Fig. 1a,b), thinning of scalp hair since early childhood (3– 6 years) and sparse body hair. The oldest and the youngest of the affected individuals are almost completely bald. Eyebrows, eyelashes and the pubic and axillary hair are normal in all but one individual (the oldest affected sibling showed a mild thinning of the eyebrows). The clinical characteristics and pedigree structure of the family have been described in detail elsewhere 9 . We carried out a genome-wide linkage analysis using 320 highly polymorphic microsatellite markers, after first excluding a number of candidate loci in this family (Supplementary Table 1a online). Through homozygosity mapping, we identified a gene locus for hypotrichosis simplex on chromosome 13q14.11–13q21.33, with a maximum lod score of 3.9 (y ¼ 0.0) between flanking recombinant markers D13S1233 and D13S634 (Fig. 1b, Supplementary Fig. 1a and Supplementary Table 1b online). We defined a critical interval of around 28 Mb through haplotype analysis based on the smallest homozygous haplotype segment shared by the affected siblings (Fig. 1b). This region overlaps with the hypotrichosis simplex– associated region reported recently in a Pakistani family 10 . Our region of interest contains 61 known genes. After excluding 37 of these by direct sequencing (Supplementary Table 2 online), we identified a nonsense mutation in P2RY5, which encodes the orphan G protein–coupled receptor P2Y5. According to standard designations, the symbol P2RY5 is used for the gene, and P2Y5 is used for the Received 16 August 2007; accepted 27 November 2007; published online 24 February 2008; doi:10.1038/ng.84 1 Institute of Human Genetics, University of Bonn, Bonn 53111, Germany. 2 Department of Pharmacology, University of Bonn, Bonn 53113, Germany. 3 Department of Dermatology, King Faisal Hospital, Makkah 5592, Saudi Arabia. 4 Department of Pediatric Pneumology and Immunology, Charite ´, Humboldt-University Berlin 13353, Berlin, Germany. 5 Max Delbru ¨ ck Center for Molecular Medicine, Berlin 13092, Germany. 6 Department of Human Genetics, University of Wu ¨ rzburg, Wu ¨ rzburg 97074, Germany. 7 Department of Genomics, Life and Brain Center, University of Bonn, Bonn 53127, Germany. 8 Department of Anatomy, University of Bonn, Bonn 53115, Germany. 9 Institute for Genetics, University of Cologne, Cologne 50674, Germany. 10 Institute of Human Genetics, University of Cologne, Cologne 50931, Germany. 11 Center for Molecular Medicine Cologne, University of Cologne, Cologne 50931, Germany. 12 Cologne Center for Genomics, University of Cologne, Cologne 50674, Germany. Correspondence should be addressed to R.C.B. (regina.betz@uni-bonn.de). NATURE GENETICS VOLUME 40 [ NUMBER 3 [ MARCH 2008 329 LETTERS © 2008 Nature Publishing Group http://www.nature.com/naturegenetics