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Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis - Nature Genetics

  • ️Zhang, Xue
  • ️Sun Jan 04 2009

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  • 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.

References

  1. Paus, R. & Cotsarelis, G. The biology of hair follicles. N. Engl. J. Med. 341, 491–497 (1999).

    Article  CAS  PubMed  Google Scholar 

  2. Stenn, K.S. & Paus, R. Controls of hair follicle cycling. Physiol. Rev. 81, 449–494 (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Cotsarelis, G. Epithelial stem cells: a folliculocentric view. J. Invest. Dermatol. 126, 1459–1468 (2006).

    Article  CAS  PubMed  Google Scholar 

  4. Alonso, L. & Fuchs, E. Stem cells in the skin: waste not, Wnt not. Genes Dev. 17, 1189–1200 (2003).

    Article  CAS  PubMed  Google Scholar 

  5. Huelsken, J., Vogel, R., Erdmann, B., Cotsarelis, G. & Birchmeier, W. beta-Catenin controls hair follicle morphogenesis and stem cell differentiation in the skin. Cell 105, 533–545 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Andl, T., Reddy, S.T., Gaddapara, T. & Millar, S.E. WNT signals are required for the initiation of hair follicle development. Dev. Cell 2, 643–653 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Van Mater, D., Kolligs, F.T., Dlugosz, A.A. & Fearon, E.R. Transient activation of beta-catenin signaling in cutaneous keratinocytes is sufficient to trigger the active growth phase of the hair cycle in mice. Genes Dev. 17, 1219–1224 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Ito, M. et al. Wnt-dependent de novo hair follicle regeneration in adult mouse skin after wounding. Nature 447, 316–320 (2007).

    Article  CAS  PubMed  Google Scholar 

  9. Potter, G.B. et al. The hairless gene mutated in congenital hair loss disorders encodes a novel nuclear receptor corepressor. Genes Dev. 15, 2687–2701 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Beaudoin, G.M. III, Sisk, J.M., Coulombe, P.A. & Thompson, C.C. Hairless triggers reactivation of hair growth by promoting Wnt signaling. Proc. Natl. Acad. Sci. USA 102, 14653–14658 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Thompson, C.C., Sisk, J.M. & Beaudoin, G.M. III. Hairless and Wnt signaling: allies in epithelial stem cell differentiation. Cell Cycle 5, 1913–1917 (2006).

    Article  CAS  PubMed  Google Scholar 

  12. Ahmad, W. et al. Alopecia universalis associated with a mutation in the human hairless gene. Science 279, 720–724 (1998).

    Article  CAS  PubMed  Google Scholar 

  13. 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).

    Article  CAS  PubMed  Google Scholar 

  14. Sprecher, E., Bergman, R., Szargel, R., Friedman-Birnbaum, R. & Cohen, N. Identification of a genetic defect in the hairless gene in atrichia with papular lesions: evidence for phenotypic heterogeneity among inherited atrichias. Am. J. Hum. Genet. 64, 1323–1329 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Unna, M. Über hypotrichosis congenita hereditaria. Dermatol. Wochenschr. 81, 1167–1178 (1925).

    Google Scholar 

  16. van Steensel, M. et al. The gene for hypotrichosis of Marie Unna maps between D8S258 and D8S298: exclusion of the hr gene by cDNA and genomic sequencing. Am. J. Hum. Genet. 65, 413–419 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Sreekumar, G.P., Roberts, J.L., Wong, C.Q., Stenn, K.S. & Parimoo, S. Marie Unna hereditary hypotrichosis gene maps to human chromosome 8p21 near hairless. J. Invest. Dermatol. 114, 595–597 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Lefevre, P. et al. Linkage of Marie-Unna hypotrichosis locus to chromosome 8p21 and exclusion of 10 genes including the hairless gene by mutation analysis. Eur. J. Hum. Genet. 8, 273–279 (2000).

    Article  CAS  PubMed  Google Scholar 

  19. Cichon, S. et al. A distinct gene close to the hairless locus on chromosome 8p underlies hereditary Marie Unna type hypotrichosis in a German family. Br. J. Dermatol. 143, 811–814 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. He, P.P. et al. Refinement of a locus for Marie Unna hereditary hypotrichosis to a 1.1-cM interval at 8p21.3. Br. J. Dermatol. 150, 837–842 (2004).

    Article  CAS  PubMed  Google Scholar 

  21. Scheper, G.C., van der Knaap, M.S. & Proud, C.G. Translation matters: protein synthesis defects in inherited disease. Nat. Rev. Genet. 8, 711–723 (2007).

    Article  CAS  PubMed  Google Scholar 

  22. Cazzola, M. & Skoda, R.C. Translational pathophysiology: a novel molecular mechanism of human disease. Blood 95, 3280–3288 (2000).

    CAS  PubMed  Google Scholar 

  23. Wiestner, A., Schlemper, R.J., van der Maas, A.P. & Skoda, R.C. An activating splice donor mutation in the thrombopoietin gene causes hereditary thrombocythaemia. Nat. Genet. 18, 49–52 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Liu, L. et al. Mutation of the CDKN2A 5′ UTR creates an aberrant initiation codon and predisposes to melanoma. Nat. Genet. 21, 128–132 (1999).

    Article  PubMed  Google Scholar 

  25. Panteleyev, A.A., Paus, R. & Christiano, A.M. Patterns of hairless (hr) gene expression in mouse hair follicle morphogenesis and cycling. Am. J. Pathol. 157, 1071–1079 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Yang, S. et al. Identification of a novel locus for Marie Unna hereditary hypotrichosis to a 17.5 cM interval at 1p21.1–1q21.3. J. Invest. Dermatol. 125, 711–714 (2005).

    Article  CAS  PubMed  Google Scholar 

  27. Iacono, M., Mignone, F. & Pesole, G. uAUG and uORFs in human and rodent 5′untranslated mRNAs. Gene 349, 97–105 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Churbanov, A., Rogozin, I.B., Babenko, V.N., Ali, H. & Koonin, E.V. Evolutionary conservation suggests a regulatory function of AUG triplets in 5′-UTRs of eukaryotic genes. Nucleic Acids Res. 33, 5512–5520 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sachs, M.S. & Geballe, A.P. Downstream control of upstream open reading frames. Genes Dev. 20, 915–921 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Niiyama, S., Freyschmidt-Paul, P., Happle, R. & Hoffmann, R. Hypotrichosis of congenital of Marie Unna. Eur. J. Dermatol. 11, 379–380 (2001).

    CAS  PubMed  Google Scholar 

Download references

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

  1. Yaran Wen, Yang Liu, Yiming Xu and Yiwei Zhao: These authors contributed equally to this work.

Authors and 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. Division of Molecular Medicine, Epithelial Genetics Group, 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, Düsseldorf, D-40225, Germany

    Roland Kruse

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

    Sven Cichon, Regina C Betz & Markus M Nöthen

  8. Department of Genomics, Life & Brain Center, University of Bonn, Bonn, D-53127, Germany

    Sven Cichon & Markus M Nöthen

  9. Maastricht University Center for Molecular Dermatology, University Hospital Maastricht, Maastricht, 6202AZ, The Netherlands

    Maurice A M van Steensel, Michel van Geel & Peter M Steijlen

  10. CHUV, Hôpital de Beaumont, Lausanne, CH-1011, 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, Rome, 00133, Italy

    Alessandro Terrinoni

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

    Alain Hovnanian

  16. Department of Dermatology, Necker Hospital, Paris, 75105, France

    Christine Bodemer & Yves de Prost

  17. Departments of Dermatology and Pediatrics, Northwestern University, Chicago, 60611, Illinois, 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, 3065, Victoria, Australia

    Rod Sinclair & Jack Green

Authors

  1. Yaran Wen

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  2. Yang Liu

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  3. Yiming Xu

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  4. Yiwei Zhao

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  5. Rui Hua

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  6. Kaibo Wang

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  7. Miao Sun

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  8. Yuanhong Li

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  9. Sen Yang

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  10. Xue-Jun Zhang

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  11. Roland Kruse

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  12. Sven Cichon

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  13. Regina C Betz

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  14. Markus M Nöthen

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  15. Maurice A M van Steensel

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  16. Michel van Geel

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  17. Peter M Steijlen

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  18. Daniel Hohl

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  19. Marcel Huber

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  20. Giles S Dunnill

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  21. Cameron Kennedy

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  22. Andrew Messenger

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  23. Colin S Munro

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  24. Alessandro Terrinoni

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  25. Alain Hovnanian

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  26. Christine Bodemer

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  27. Yves de Prost

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  28. Amy S Paller

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  29. Alan D Irvine

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  30. Rod Sinclair

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  31. Jack Green

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  32. Dandan Shang

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  33. Qing Liu

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  34. Yang Luo

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  35. Li Jiang

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  36. Hong-Duo Chen

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  37. Wilson H-Y Lo

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  38. W H Irwin McLean

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  39. Chun-Di He

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  40. Xue Zhang

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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.

Corresponding authors

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

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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.

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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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  • Received: 08 August 2008

  • Accepted: 14 October 2008

  • Published: 04 January 2009

  • Issue Date: February 2009

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