Abstract
Inherited hypertrichoses are rare syndromes characterized by excessive hair growth that does not result from androgen stimulation, and are often associated with additional congenital abnormalities. In this study, we investigated the genetic defect in a case of autosomal recessive congenital generalized hypertrichosis terminalis (CGHT) (OMIM135400) using whole-exome sequencing. We identified a single base pair substitution in the 5′ donor splice site of intron 32 in the ABC lipid transporter gene ABCA5 that leads to aberrant splicing of the transcript and a decrease in protein levels throughout patient hair follicles. The homozygous recessive disruption of ABCA5 leads to reduced lysosome function, which results in an accumulation of autophagosomes, autophagosomal cargos as well as increased endolysosomal cholesterol in CGHT keratinocytes. In an unrelated sporadic case of CGHT, we identified a 1.3 Mb cryptic deletion of chr17q24.2-q24.3 encompassing ABCA5 and found that ABCA5 levels are dramatically reduced throughout patient hair follicles. Collectively, our findings support ABCA5 as a gene underlying the CGHT phenotype and suggest a novel, previously unrecognized role for this gene in regulating hair growth.
Highlights
Inherited hypertrichosis, first described in the sixteenth century, is characterized by hair growth that is excessive for the body site and age of an individual and is independent of androgen stimulation [1], [2]
We investigated the genetic basis of a case of congenital generalized hypertrichosis terminalis (CGHT) using whole-exome sequencing and identified a homozygous recessive loss-of-function mutation in a donor splice site of ABCA5 that cosegregates with the phenotype
The c.4320+1G.C mutation leads to loss of ABCA5 expression and localization within patient keratinocytes, fibroblasts and hair follicles compared to controls
Summary
First described in the sixteenth century, is characterized by hair growth that is excessive for the body site and age of an individual and is independent of androgen stimulation [1], [2]. These syndromes are categorized as ectodermal dysplasias and are often associated with additional congenital defects, including cardiomyopathy, gingival hyperplasia, and craniofacial malformations [3]. We found that a position effect occurs on a distant gene, FGF13, whose expression was markedly and selectively reduced in patient hair follicles, suggesting a novel role for this growth factor in hair follicle growth and cycling [10]
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.