Letter abstract
Nature Genetics 41, 228 - 233 (2009)
Published online: 4 January 2009 | Corrected online: 28 April 2009 | doi:10.1038/ng.276
There is a Corrigendum (June 2009) associated with this Letter.
Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis
Yaran Wen1,21, Yang Liu2,21, Yiming Xu1,21, Yiwei Zhao3,21, Rui Hua1, Kaibo Wang4, Miao Sun1, Yuanhong Li4, Sen Yang5, Xue-Jun Zhang5, Roland Kruse6, Sven Cichon7,8, Regina C Betz7, Markus M Nöthen7,8, Maurice A M van Steensel9, Michel van Geel9, Peter M Steijlen9, Daniel Hohl10, Marcel Huber10, Giles S Dunnill11, Cameron Kennedy11, Andrew Messenger12, Colin S Munro13, Alessandro Terrinoni14, Alain Hovnanian15, Christine Bodemer16, Yves de Prost16, Amy S Paller17, Alan D Irvine18,19, Rod Sinclair20, Jack Green20, Dandan Shang1, Qing Liu1, Yang Luo2, Li Jiang2, Hong-Duo Chen4, Wilson H-Y Lo1, W H Irwin McLean3, Chun-Di He4 & Xue Zhang1,2
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.
- 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.
- The Research Center for Medical Genomics, China Medical University, Shenyang 110001, China.
- Epithelial Genetics Group, Division of Molecular Medicine, Colleges of Life Sciences and Medicine, Dentistry & Nursing, University of Dundee, Dundee DD1 5EH, Scotland, UK.
- Department of Dermatology, No. 1 Hospital of China Medical University, Shenyang 110001, China.
- Institute of Dermatology, Anhui Medical University, Hefei 230032, China.
- Department of Dermatology, University of Düsseldorf, D-40225 Düsseldorf, Germany.
- Institute of Human Genetics, University of Bonn, D-53111 Bonn, Germany.
- Department of Genomics, Life & Brain Center, University of Bonn, D-53127 Bonn, Germany.
- Maastricht University Center for Molecular Dermatology, University Hospital Maastricht, 6202AZ Maastricht, The Netherlands.
- CHUV, Hôpital de Beaumont, CH-1011 Lausanne, Switzerland.
- Department of Dermatology, Bristol Royal Infirmary, Bristol BS2 8HW, UK.
- Department of Dermatology, Royal Hallamshire Hospital, Sheffield S10 2JF, UK.
- Department of Dermatology, Southern General Hospital, Glasgow G51 4TF, UK.
- IDI-IRCCS Biochemistry Laboratory, c/o Univ. of Tor Vergata, 00133 Rome, Italy.
- INSERM U563, Centre de Physiopathologie de Toulouse Purpan, Toulouse F-313000, France.
- Department of Dermatology, Necker Hospital, 75105 Paris, France.
- Departments of Dermatology and Pediatrics, Northwestern University, Chicago, Illinois 60611, USA.
- Department of Paediatric Dermatology, Our Lady's Children's Hospital, Dublin 12, Ireland.
- Department of Clinical Medicine, Trinity College Dublin, Dublin 2, Ireland.
- Department of Dermatology, St. Vincent's Hospital, Melbourne, Victoria 3065, Australia.
- These authors contributed equally to this work.
Correspondence to: Xue Zhang1,2 e-mail: xuezhang@pumc.edu.cn
Correspondence to: W H Irwin McLean3 e-mail: w.h.i.mclean@dundee.ac.uk
Correspondence to: Chun-Di He4 e-mail: chundihe@hotmail.com
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