Abstract
Marie Unna hereditary hypotrichosis (MUHH) is an autosomal dominant form of genetic hair loss. In a large Chinese family carrying MUHH, we identified a pathogenic initiation codon mutation in U2HR, an inhibitory upstream ORF in the 5′ UTR of the gene encoding the human hairless homolog (HR). U2HR is predicted to encode a 34–amino acid peptide that is highly conserved among mammals. In 18 more families from different ancestral groups, we identified a range of defects in U2HR, including loss of initiation, delayed termination codon and nonsense and missense mutations. Functional analysis showed that these classes of mutations all resulted in increased translation of the main HR physiological ORF. Our results establish the link between MUHH and U2HR, show that fine-tuning of HR protein levels is important in control of hair growth, and identify a potential mechanism for preventing hair loss or promoting hair removal.
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Change history
28 April 2009
NOTE: The affiliation of the 24th author, Alessandro Terrinoni, was listed incorrectly. It should read IDI-IRCCS Biochemistry Laboratory c/o Univ. Tor Vergata, 00133 Rome, Italy. The error has been corrected in the HTML and PDF versions of this article.
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Acknowledgements
We thank the family members for their participation in the study, and J. Zeller, S. Burge and M. Young for referring patients. This work was supported mainly by the National Natural Science Foundation of China (funds 30730097 and 30721063 to X.Z.). X.Z. is a Chang Jiang Scholar of Genetic Medicine supported by the Ministry of Education, China. C.-D.H. was supported by the National Natural Science Foundation of China (30771948). The McLean laboratory is supported by grants from the Dystrophic Epidermolysis Bullosa Research Association, the Pachyonychia Congenita Project, the British Skin Foundation, the National Eczema Society and the Medical Research Council (G0700314). S.Y. is supported by the Ministry of Education, China (SRFDP 20050366004). The German group is supported by grants from the Deutsche Forschungsgemeinschaft (Research Unit FOR 423 to M.M.N. and R.K. and Emmy Noether Programme to R.C.B.). M.M.N. holds an Alfried Krupp von Bohlen and Halbach-Chair in Genetic Medicine. R.S. and J.G. are supported by Epiderm, the Scientific Research Fund of the Australasian College of Dermatologists and the Scientific Research Fund of the Skin and Cancer Foundation of Victoria.
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X.Z. designed and oversaw the entire project. X.Z. and C.-D.H. initiated the study. X.Z. and W.H.I.M. coordinated the mutation screening work and prepared the manuscript. Y.W., Y. Liu, Y.Z. and M.v.G. carried out the linkage analysis and mutation screening. Y.X., R.H., K.W. and Y.W. conducted the mRNA and protein expression experiments. X.Z. and Y.W. conducted the bioinformatics analysis. M.S., D.S., Q.L., Y. Luo and L.J. supported the genetic analyses. H.-D.C. and W.H.-Y.L. supported the study design. Y. Liu, S.Y., X.-J.Z., R.K., S.C., R.C.B., M.M.N., M.A.M.v.S., P.M.S., D.H., M.H., G.S.D., C.K., A.M., C.S.M., A.T., A.H., C.B., Y.d.P., A.S.P., A.D.I., R.S. and J.G. were responsible for clinical evaluation and sample collection, including earlier published linkage studies.
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X.Z., C.-D.H., Y.W., Y. Liu, Y.X., R.H., K.W. and M.S. have applied for a patent relating to the U2HR sequence.
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Wen, Y., Liu, Y., Xu, Y. et al. Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis. Nat Genet 41, 228–233 (2009). https://doi.org/10.1038/ng.276
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DOI: https://doi.org/10.1038/ng.276
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