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

Yaran Wen, Yang Liu, Yiming Xu, Yiwei Zhao, Rui Hua, Kaibo Wang, Miao Sun, Yuanhong Li, Sen Yang, Xue-Jun Zhang, Roland Kruse, Sven Cichon, Regina C. Betz, Markus M. Noethen, Maurice A. M. van Steensel, Michel van Geel, Peter M. Steijlen, Daniel Hohl, Marcel Huber, Giles S. DunnillCameron Kennedy, Andrew Messenger, Colin S. Munro, Alessandro Terrinoni, Alain Hovnanian, Christine Bodemer, Yves de Prost, Amy S. Paller, Alan D. Irvine, Rod Sinclair, Jack Green, Dandan Shang, Qing Liu, Yang Luo, Li Jiang, Hong-Duo Chen, Wilson H-Y Lo, W. H. Irwin McLean, Chun-Di He, Xue Zhang

Research output: Contribution to journalLetter

112 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)228-233
Number of pages6
JournalNature Genetics
Volume41
Issue number2
DOIs
Publication statusPublished - Feb 2009

Keywords

  • STEM-CELL DIFFERENTIATION
  • FOLLICLE MORPHOGENESIS
  • CHROMOSOME 8P21
  • HR GENE
  • WNT
  • UNNA,MARIE
  • LOCUS
  • SKIN
  • IDENTIFICATION
  • INITIATION

Cite this

Wen, Yaran ; Liu, Yang ; Xu, Yiming ; Zhao, Yiwei ; Hua, Rui ; Wang, Kaibo ; Sun, Miao ; Li, Yuanhong ; Yang, Sen ; Zhang, Xue-Jun ; Kruse, Roland ; Cichon, Sven ; Betz, Regina C. ; Noethen, Markus M. ; van Steensel, Maurice A. M. ; van Geel, Michel ; Steijlen, Peter M. ; Hohl, Daniel ; Huber, Marcel ; Dunnill, Giles S. ; Kennedy, Cameron ; Messenger, Andrew ; Munro, Colin S. ; Terrinoni, Alessandro ; Hovnanian, Alain ; Bodemer, Christine ; de Prost, Yves ; Paller, Amy S. ; Irvine, Alan D. ; Sinclair, Rod ; Green, Jack ; Shang, Dandan ; Liu, Qing ; Luo, Yang ; Jiang, Li ; Chen, Hong-Duo ; Lo, Wilson H-Y ; McLean, W. H. Irwin ; He, Chun-Di ; Zhang, Xue. / Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis. In: Nature Genetics. 2009 ; Vol. 41, No. 2. pp. 228-233.
@article{9e5403fe40bb405094e03320e4aa9866,
title = "Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis",
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.",
keywords = "STEM-CELL DIFFERENTIATION, FOLLICLE MORPHOGENESIS, CHROMOSOME 8P21, HR GENE, WNT, UNNA,MARIE, LOCUS, SKIN, IDENTIFICATION, INITIATION",
author = "Yaran Wen and Yang Liu and Yiming Xu and Yiwei Zhao and Rui Hua and Kaibo Wang and Miao Sun and Yuanhong Li and Sen Yang and Xue-Jun Zhang and Roland Kruse and Sven Cichon and Betz, {Regina C.} and Noethen, {Markus M.} and {van Steensel}, {Maurice A. M.} and {van Geel}, Michel and Steijlen, {Peter M.} and Daniel Hohl and Marcel Huber and Dunnill, {Giles S.} and Cameron Kennedy and Andrew Messenger and Munro, {Colin S.} and Alessandro Terrinoni and Alain Hovnanian and Christine Bodemer and {de Prost}, Yves and Paller, {Amy S.} and Irvine, {Alan D.} and Rod Sinclair and Jack Green and Dandan Shang and Qing Liu and Yang Luo and Li Jiang and Hong-Duo Chen and Lo, {Wilson H-Y} and McLean, {W. H. Irwin} and Chun-Di He and Xue Zhang",
year = "2009",
month = "2",
doi = "10.1038/ng.276",
language = "English",
volume = "41",
pages = "228--233",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "2",

}

Wen, Y, Liu, Y, Xu, Y, Zhao, Y, Hua, R, Wang, K, Sun, M, Li, Y, Yang, S, Zhang, X-J, Kruse, R, Cichon, S, Betz, RC, Noethen, MM, van Steensel, MAM, van Geel, M, Steijlen, PM, Hohl, D, Huber, M, Dunnill, GS, Kennedy, C, Messenger, A, Munro, CS, Terrinoni, A, Hovnanian, A, Bodemer, C, de Prost, Y, Paller, AS, Irvine, AD, Sinclair, R, Green, J, Shang, D, Liu, Q, Luo, Y, Jiang, L, Chen, H-D, Lo, WH-Y, McLean, WHI, He, C-D & Zhang, X 2009, 'Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis', Nature Genetics, vol. 41, no. 2, pp. 228-233. https://doi.org/10.1038/ng.276

Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis. / Wen, Yaran; Liu, Yang; Xu, Yiming; Zhao, Yiwei; Hua, Rui; Wang, Kaibo; Sun, Miao; Li, Yuanhong; Yang, Sen; Zhang, Xue-Jun; Kruse, Roland; Cichon, Sven; Betz, Regina C.; Noethen, Markus M.; van Steensel, Maurice A. M.; van Geel, Michel; Steijlen, Peter M.; Hohl, Daniel; Huber, Marcel; Dunnill, Giles S.; Kennedy, Cameron; Messenger, Andrew; Munro, Colin S.; Terrinoni, Alessandro; Hovnanian, Alain; Bodemer, Christine; de Prost, Yves; Paller, Amy S.; Irvine, Alan D.; Sinclair, Rod; Green, Jack; Shang, Dandan; Liu, Qing; Luo, Yang; Jiang, Li; Chen, Hong-Duo; Lo, Wilson H-Y; McLean, W. H. Irwin (Lead / Corresponding author); He, Chun-Di (Lead / Corresponding author); Zhang, Xue (Lead / Corresponding author).

In: Nature Genetics, Vol. 41, No. 2, 02.2009, p. 228-233.

Research output: Contribution to journalLetter

TY - JOUR

T1 - Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis

AU - Wen, Yaran

AU - Liu, Yang

AU - Xu, Yiming

AU - Zhao, Yiwei

AU - Hua, Rui

AU - Wang, Kaibo

AU - Sun, Miao

AU - Li, Yuanhong

AU - Yang, Sen

AU - Zhang, Xue-Jun

AU - Kruse, Roland

AU - Cichon, Sven

AU - Betz, Regina C.

AU - Noethen, Markus M.

AU - van Steensel, Maurice A. M.

AU - van Geel, Michel

AU - Steijlen, Peter M.

AU - Hohl, Daniel

AU - Huber, Marcel

AU - Dunnill, Giles S.

AU - Kennedy, Cameron

AU - Messenger, Andrew

AU - Munro, Colin S.

AU - Terrinoni, Alessandro

AU - Hovnanian, Alain

AU - Bodemer, Christine

AU - de Prost, Yves

AU - Paller, Amy S.

AU - Irvine, Alan D.

AU - Sinclair, Rod

AU - Green, Jack

AU - Shang, Dandan

AU - Liu, Qing

AU - Luo, Yang

AU - Jiang, Li

AU - Chen, Hong-Duo

AU - Lo, Wilson H-Y

AU - McLean, W. H. Irwin

AU - He, Chun-Di

AU - Zhang, Xue

PY - 2009/2

Y1 - 2009/2

N2 - 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.

AB - 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.

KW - STEM-CELL DIFFERENTIATION

KW - FOLLICLE MORPHOGENESIS

KW - CHROMOSOME 8P21

KW - HR GENE

KW - WNT

KW - UNNA,MARIE

KW - LOCUS

KW - SKIN

KW - IDENTIFICATION

KW - INITIATION

UR - http://www.scopus.com/inward/record.url?scp=59149083659&partnerID=8YFLogxK

U2 - 10.1038/ng.276

DO - 10.1038/ng.276

M3 - Letter

C2 - 19122663

VL - 41

SP - 228

EP - 233

JO - Nature Genetics

JF - Nature Genetics

SN - 1061-4036

IS - 2

ER -