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.
authors.affiliation: 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.
authors.forename: Yaran
authors.initials: Y
authors.lastname: Wen
authors.forename: Yang
authors.initials: Y
authors.lastname: Liu
authors.forename: Yiming
authors.initials: Y
authors.lastname: Xu
authors.forename: Yiwei
authors.initials: Y
authors.lastname: Zhao
authors.forename: Rui
authors.initials: R
authors.lastname: Hua
authors.forename: Kaibo
authors.initials: K
authors.lastname: Wang
authors.forename: Miao
authors.initials: M
authors.lastname: Sun
authors.forename: Yuanhong
authors.initials: Y
authors.lastname: Li
authors.forename: Sen
authors.initials: S
authors.lastname: Yang
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Zhang
authors.forename: Roland
authors.initials: R
authors.lastname: Kruse
authors.forename: Sven
authors.initials: S
authors.lastname: Cichon
authors.forename: Regina C
authors.initials: RC
authors.lastname: Betz
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.forename: Maurice A M
authors.initials: MA
authors.lastname: van Steensel
authors.forename: Michel
authors.initials: M
authors.lastname: van Geel
authors.forename: Peter M
authors.initials: PM
authors.lastname: Steijlen
authors.forename: Daniel
authors.initials: D
authors.lastname: Hohl
authors.forename: Marcel
authors.initials: M
authors.lastname: Huber
authors.forename: Giles S
authors.initials: GS
authors.lastname: Dunnill
authors.forename: Cameron
authors.initials: C
authors.lastname: Kennedy
authors.forename: Andrew
authors.initials: A
authors.lastname: Messenger
authors.forename: Colin S
authors.initials: CS
authors.lastname: Munro
authors.forename: Alessandro
authors.initials: A
authors.lastname: Terrinoni
authors.forename: Alain
authors.initials: A
authors.lastname: Hovnanian
authors.forename: Christine
authors.initials: C
authors.lastname: Bodemer
authors.forename: Yves
authors.initials: Y
authors.lastname: de Prost
authors.forename: Amy S
authors.initials: AS
authors.lastname: Paller
authors.forename: Alan D
authors.initials: AD
authors.lastname: Irvine
authors.forename: Rod
authors.initials: R
authors.lastname: Sinclair
authors.forename: Jack
authors.initials: J
authors.lastname: Green
authors.forename: Dandan
authors.initials: D
authors.lastname: Shang
authors.forename: Qing
authors.initials: Q
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Luo
authors.forename: Li
authors.initials: L
authors.lastname: Jiang
authors.forename: Hong-Duo
authors.initials: HD
authors.lastname: Chen
authors.forename: Wilson H-Y
authors.initials: WH
authors.lastname: Lo
authors.forename: W H Irwin
authors.initials: WH
authors.lastname: McLean
authors.forename: Chun-Di
authors.initials: CD
authors.lastname: He
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
mesh_terms: 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*
chemical_list: C490267:HR protein, human; D014157:Transcription Factors