G protein–coupled receptor P2Y5 and its ligand LPA are involved in maintenance of human hair growth

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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Figure 1: Clinical appearance and underlying genetic defect of autosomal recessive hypotrichosis simplex.
Figure 2: Structure and biochemical analysis of P2Y5 wild type and mutant proteins.
Figure 3: Pharmacological analysis of P2Y5 and expression analysis of LPA receptors in different tissues.
Figure 4: Schematic depicting signaling of lysophosphatidic acid via the P2Y5 receptor.

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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.

Corresponding author

Correspondence to Regina C Betz.

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Competing interests

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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Supplementary Methods, Supplementary Figures 1–5, Supplementary Tables 1–5 (PDF 362 kb)

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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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