Loss-of-function mutations of an inhibitory upstream ORF in the human hairless transcript cause Marie Unna hereditary hypotrichosis.
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.
Wen
Yaran
Y
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.
Liu
Yang
Y
Xu
Yiming
Y
Zhao
Yiwei
Y
Hua
Rui
R
Wang
Kaibo
K
Sun
Miao
M
Li
Yuanhong
Y
Yang
Sen
S
Zhang
Xue-Jun
XJ
Kruse
Roland
R
Cichon
Sven
S
Betz
Regina C
RC
Nöthen
Markus M
MM
van Steensel
Maurice A M
MA
van Geel
Michel
M
Steijlen
Peter M
PM
Hohl
Daniel
D
Huber
Marcel
M
Dunnill
Giles S
GS
Kennedy
Cameron
C
Messenger
Andrew
A
Munro
Colin S
CS
Terrinoni
Alessandro
A
Hovnanian
Alain
A
Bodemer
Christine
C
de Prost
Yves
Y
Paller
Amy S
AS
Irvine
Alan D
AD
Sinclair
Rod
R
Green
Jack
J
Shang
Dandan
D
Liu
Qing
Q
Luo
Yang
Y
Jiang
Li
L
Chen
Hong-Duo
HD
Lo
Wilson H-Y
WH
McLean
W H Irwin
WH
He
Chun-Di
CD
Zhang
Xue
X
D000293:Adolescent; D000595:Amino Acid Sequence; D001483:Base Sequence; D002648:Child; D002681:China; D015536:Down-Regulation / Q000235:genetics; D005190:Family; D005260:Female; D006801:Humans; D007039:Hypotrichosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000502:physiology; D016366:Open Reading Frames / Q000235:genetics*; D010375:Pedigree; D014176:Protein Biosynthesis / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid / Q000502:physiology; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics*
C490267:HR protein, human; D014157:Transcription Factors