• A Corrigendum to this article was published on 01 June 2009

This article has been updated

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.

Author information

Author notes

    • Yaran Wen
    • , Yang Liu
    • , Yiming Xu
    •  & Yiwei Zhao

    These authors contributed equally to this work.

Affiliations

  1. McKusick-Zhang Center for Genetic Medicine and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100005, China.

    • Yaran Wen
    • , Yiming Xu
    • , Rui Hua
    • , Miao Sun
    • , Dandan Shang
    • , Qing Liu
    • , Wilson H-Y Lo
    •  & Xue Zhang
  2. The Research Center for Medical Genomics, China Medical University, Shenyang 110001, China.

    • Yang Liu
    • , Yang Luo
    • , Li Jiang
    •  & Xue Zhang
  3. Epithelial Genetics Group, Division of Molecular Medicine, Colleges of Life Sciences and Medicine, Dentistry & Nursing, University of Dundee, Dundee DD1 5EH, Scotland, UK.

    • Yiwei Zhao
    •  & W H Irwin McLean
  4. Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang 110001, China.

    • Kaibo Wang
    • , Yuanhong Li
    • , Hong-Duo Chen
    •  & Chun-Di He
  5. Institute of Dermatology, Anhui Medical University, Hefei 230032, China.

    • Sen Yang
    •  & Xue-Jun Zhang
  6. Department of Dermatology, University of Düsseldorf, D-40225 Düsseldorf, Germany.

    • Roland Kruse
  7. Institute of Human Genetics, University of Bonn, D-53111 Bonn, Germany.

    • Sven Cichon
    • , Regina C Betz
    •  & Markus M Nöthen
  8. Department of Genomics, Life & Brain Center, University of Bonn, D-53127 Bonn, Germany.

    • Sven Cichon
    •  & Markus M Nöthen
  9. Maastricht University Center for Molecular Dermatology, University Hospital Maastricht, 6202AZ Maastricht, The Netherlands.

    • Maurice A M van Steensel
    • , Michel van Geel
    •  & Peter M Steijlen
  10. CHUV, Hôpital de Beaumont, CH-1011 Lausanne, Switzerland.

    • Daniel Hohl
    •  & Marcel Huber
  11. Department of Dermatology, Bristol Royal Infirmary, Bristol BS2 8HW, UK.

    • Giles S Dunnill
    •  & Cameron Kennedy
  12. Department of Dermatology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK.

    • Andrew Messenger
  13. Department of Dermatology, Southern General Hospital, Glasgow G51 4TF, UK.

    • Colin S Munro
  14. IDI-IRCCS Biochemistry Laboratory, c/o Univ. of Tor Vergata, 00133 Rome, Italy.

    • Alessandro Terrinoni
  15. INSERM U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse F-313000, France.

    • Alain Hovnanian
  16. Department of Dermatology, Necker Hospital, 75105 Paris, France.

    • Christine Bodemer
    •  & Yves de Prost
  17. Departments of Dermatology and Pediatrics, Northwestern University, Chicago, Illinois 60611, USA.

    • Amy S Paller
  18. Department of Paediatric Dermatology, Our Lady's Children's Hospital, Dublin 12, Ireland.

    • Alan D Irvine
  19. Department of Clinical Medicine, Trinity College Dublin, Dublin 2, Ireland.

    • Alan D Irvine
  20. Department of Dermatology, St. Vincent's Hospital, Melbourne, Victoria 3065, Australia.

    • Rod Sinclair
    •  & Jack Green

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Contributions

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.

Competing interests

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.

Corresponding authors

Correspondence to W H Irwin McLean or Chun-Di He or Xue Zhang.

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DOI

https://doi.org/10.1038/ng.276

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