Loss-of-function mutations in HOXC13 cause pure hair and nail ectodermal dysplasia.
Pure hair and nail ectodermal dysplasia (PHNED) is a congenital condition characterized by hypotrichosis and nail dystrophy. Autosomal-recessive PHNED has previously been mapped to chromosomal region 12q12-q14.1, which contains the type II hair keratin and HOXC clusters. Hoxc13-null mice are known to develop hair and nail defects very similar to those seen in human PHNED. We performed whole-exome sequencing in a consanguineous Chinese family affected by PHNED and identified a homozygous nonsense mutation (c.390C>A [p.Tyr130(∗)]) in HOXC13 in all affected individuals. In an additional affected female from a consanguineous Afghan family, we found a 27.6 kb homozygous microdeletion involving the first exon of HOXC13. We examined HOXC13 expression in scalp specimen obtained from the index individual of the Chinese family and detected dramatically reduced mRNA levels in skin tissue and nearly absent protein staining in hair follicles, suggesting a mechanism of nonsense-mediated mRNA decay. We also observed markedly decreased expression of four HOXC13 target genes in the specimen. Taken together, our results demonstrate that loss-of-function mutations in HOXC13 cause autosomal-recessive PHNED and further highlight the importance of HOXC13 in hair and nail development.
Department of Dermatology, Peking University First Hospital, Beijing, China.
Zhimiao
Z
Lin
Quan
Q
Chen
Lei
L
Shi
Mingyang
M
Lee
Kathrin A
KA
Giehl
Zhanli
Z
Tang
Huijun
H
Wang
Jie
J
Zhang
Jinghua
J
Yin
Lingshen
L
Wu
Ruo
R
Xiao
Xuanzhu
X
Liu
Lanlan
L
Dai
Xuejun
X
Zhu
Ruoyu
R
Li
Regina C
RC
Betz
Xue
X
Zhang
Yong
Y
Yang
D000818:Animals; D044466:Asian People / Q000235:genetics; D002681:China; D003241:Consanguinity; D004476:Ectodermal Dysplasia / Q000235:genetics* / Q000473:pathology; D059472:Exome; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005808:Genes, Recessive; D018398:Homeodomain Proteins / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D007039:Hypotrichosis / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009260:Nail Diseases / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012867:Skin / Q000473:pathology
C410305:HOXC13 protein, human; D018398:Homeodomain Proteins