Abstract
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-α-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.
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References
Ahmad, W. et al. Alopecia universalis associated with a mutation in the human hairless gene. Science 279, 720–724 (1998).
Cichon, S. et al. Cloning, genomic organization, alternative transcripts and mutational analysis of the gene responsible for autosomal recessive universal congenital alopecia. Hum. Mol. Genet. 7, 1671–1679 (1998).
Miller, J. et al. Atrichia caused by mutations in the vitamin D receptor gene is a phenocopy of generalized atrichia caused by mutations in the hairless gene. J. Invest. Dermatol. 117, 612–617 (2001).
Levy-Nissenbaum, E. et al. Hypotrichosis simplex of the scalp is associated with nonsense mutations in CDSN encoding corneodesmosin. Nat. Genet. 34, 151–153 (2003).
Kljuic, A. et al. Desmoglein 4 in hair follicle differentiation and epidermal adhesion: evidence from inherited hypotrichosis and acquired pemphigus vulgaris. Cell 113, 249–260 (2003).
Kazantseva, A. et al. Human hair growth deficiency is linked to a genetic defect in the phospholipase gene LIPH. Science 314, 982–985 (2006).
Betz, R.C., Kruse, R., Cichon, S. & Nöthen, M.M. in Progress in Monogenic Hair Disorders (ed. Sprecher, E.) Hypotrichosis simplex 43–51 (Nova Science Publishers, Inc., New York, 2006).
Al Aboud, D., Al Aboud, K., Al Hawsawi, K. & Al Aboud, A. Hereditary hypotrichosis simplex of the scalp: a report of 2 additional families. Sudan J. Dermatol. 3, 128–131 (2005).
Al Aboud, K., Al Hawsawi, K., Al Aboud, D. & Al Githami, A. Hereditary hypotrichosis simplex: report of a family. Clin. Exp. Dermatol. 27, 654–656 (2002).
Wali, A. et al. Localization of a novel autosomal recessive hypotrichosis locus (LAH3) to chromosome 13q14.11-q21.32. Clin. Genet. 72, 23–29 (2007).
Herzog, H., Darby, K., Hort, Y.J. & Shine, J. Intron 17 of the human retinoblastoma susceptibility gene encodes an actively transcribed G protein-coupled receptor gene. Genome Res. 6, 858–861 (1996).
Webb, T.E., Kaplan, M.G. & Barnard, E.A. Identification of 6H1 as a P2Y purinoceptor: P2Y5. Biochem. Biophys. Res. Commun. 219, 105–110 (1996).
Li, Q., Schachter, J.B., Harden, T.K. & Nicholas, R.A. The 6H1 orphan receptor, claimed to be the p2y5 receptor, does not mediate nucleotide-promoted second messenger responses. Biochem. Biophys. Res. Commun. 236, 455–460 (1997).
von Kügelgen, I. Pharmacological profiles of cloned mammalian P2Y-receptor subtypes. Pharmacol. Ther. 110, 415–432 (2006).
Kotarsky, K. et al. Lysophosphatidic acid binds to and activates GPR92, a G protein-coupled receptor highly expressed in gastrointestinal lymphocytes. J. Pharmacol. Exp. Ther. 318, 619–628 (2006).
Hollopeter, G. et al. Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409, 202–207 (2001).
Johnston, C.A. & Siderovski, D.P. Receptor-mediated activation of heterotrimeric G-proteins: current structural insights. Mol. Pharmacol. 72, 219–230 (2007).
Pin, J.P. et al. International Union of Basic and Clinical Pharmacology. LXVII. Recommendations for the recognition and nomenclature of G protein-coupled receptor heteromultimers. Pharmacol. Rev. 59, 5–13 (2007).
Wang, D.A. et al. A single amino acid determines lysophospholipid specificity of the S1P1 (EDG1) and LPA1 (EDG2) phospholipid growth factor receptors. J. Biol. Chem. 276, 49213–49220 (2001).
Chun, J. et al. International Union of Pharmacology. XXXIV. Lysophospholipid receptor nomenclature. Pharmacol. Rev. 54, 265–269 (2002).
Meyer zu Heringdorf, D. & Jakobs, K.H. Lysophospholipid receptors: signalling, pharmacology and regulation by lysophospholipid metabolism. Biochim. Biophys. Acta 1768, 923–940 (2007).
Lee, C.W., Rivera, R., Gardell, S., Dubin, A.E. & Chun, J. GPR92 as a new G12/13- and Gq-coupled lysophosphatidic acid receptor that increases cAMP, LPA5. J. Biol. Chem. 281, 23589–23597 (2006).
Noguchi, K., Ishii, S. & Shimizu, T. Identification of p2y9/GPR23 as a novel G protein-coupled receptor for lysophosphatidic acid, structurally distant from the Edg family. J. Biol. Chem. 278, 25600–25606 (2003).
Tabata, K. et al. The orphan GPCR GPR87 was deorphanized and shown to be a lysophosphatidic acid receptor. Biochem. Biophys. Res. Commun. 363, 861–866 (2007).
Takahashi, T., Kamimura, A., Hamazono-Matsuoka, T. & Honda, S. Phosphatidic acid has a potential to promote hair growth in vitro and in vivo, and activates mitogen-activated protein kinase/extracellular signal-regulated kinase kinase in hair epithelial cells. J. Invest. Dermatol. 121, 448–456 (2003).
O'Connell, J.R. & Weeks, D.E. PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am. J. Hum. Genet. 63, 259–266 (1998).
Lathrop, G.M., Lalouel, J.M., Julier, C. & Ott, J. Strategies for multilocus linkage analysis in humans. Proc. Natl. Acad. Sci. USA 81, 3443–3446 (1984).
Abecasis, G.R., Cherny, S.S., Cookson, W.O. & Cardon, L.R. Merlin–rapid analysis of dense genetic maps using sparse gene flow trees. Nat. Genet. 30, 97–101 (2002).
Sobel, E. & Lange, K. Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics. Am. J. Hum. Genet. 58, 1323–1337 (1996).
Molderings, G.J. et al. S1P-receptors in PC12 and transfected HEK293 cells: molecular targets of hypotensive imidazoline I(1) receptor ligands. Neurochem. Int. 51, 476–485 (2007).
Acknowledgements
We thank all individuals for their participation in the study. We thank W. Friedl and S. Uhlhaas for their help with the PTT, C. Schmael for her help in preparing the manuscript, and M. Michels, G. Eversloh, N. Schäfer, A. Pietrosiuk and E. Mertens for their technical help. We thank S. A. Farooq and K. S. Al-Dhafri (Department of Biology, Sultan Qaboos University, Sultanate of Oman) for providing DNA samples of 69 Arabian control individuals. E. Sprecher (Laboratory of Molecular Dermatology, Department of Dermatology, Rambam Medical Center, Haifa, Israel) provided DNA samples of 50 control individuals of Arabian origin. M.M.N. is the recipient of a grant from the Alfried Krupp von Bohlen und Halbach-Stiftung. R.C.B. is a recipient of an Emmy Noether grant from the German Research Foundation (DFG).
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R.C.B. and M.M.N. initiated the study. S.M.P and I.V.K. contributed to the study design. S.M.P, I.V.K., M.M.N. and R.C.B. coordinated the work and prepared the manuscript, with feedback from the other authors. K.A.A. diagnosed the affected individuals and collected the blood samples; R.C.B., F.R., Y.-A.L. and P.N. performed and interpreted the linkage analysis; S.M.P conducted most of the genetic and protein experiments; K.V., A.R and A.M.H. supported the protein analyses; G.J.M. and I.V.K. performed the pharmacological analyses; T.F. performed the RNA blot analysis; R.C.B. oversaw the entire project.
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S.M.P., K.A.A., M.M.N. and R.C.B. declare competing financial interests, because of their patent application (European patent 07 01 8771.9).
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Pasternack, S., von Kügelgen, I., Aboud, K. et al. G protein–coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth. Nat Genet 40, 329–334 (2008). https://doi.org/10.1038/ng.84
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DOI: https://doi.org/10.1038/ng.84
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