Mutations in the cholesterol transporter gene ABCA5 are associated with excessive hair overgrowth.
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.
Department of Genetics and Development, Columbia University, New York, New York, United States of America.
Gina M
GM
DeStefano
Department of Dermatology, Columbia University, New York, New York, United States of America.
Mazen
M
Kurban
Department of Pediatrics, Columbia University Medical Center, New York, New York, United States of America.
Kwame
K
Anyane-Yeboa
Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York, United States of America.
Claudia
C
Dall'Armi
Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Medical Center, New York, New York, United States of America.
Gilbert
G
Di Paolo
St. Luke's-Roosevelt Hospital Center, New York, New York, United States of America.
Heather
H
Feenstra
St. Luke's-Roosevelt Hospital Center, New York, New York, United States of America.
Nanette
N
Silverberg
Department of Pediatrics, Columbia University Medical Center, New York, New York, United States of America.
Luis
L
Rohena
Centro Dermatológico Pascua, Mexico City, Mexico.
Larissa D
LD
López-Cepeda
Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America.
Vaidehi
V
Jobanputra
Department of Dermatology, Columbia University, New York, New York, United States of America.
Katherine A
KA
Fantauzzo
Department of Dermatology, Columbia University, New York, New York, United States of America.
Maija
M
Kiuru
Department of Genetics and Development, Columbia University, New York, New York, United States of America.
Marija
M
Tadin-Strapps
New York Presbyterian Hospital, New York, New York, United States of America.
Antonio
A
Sobrino
Department of Genetics and Development, Columbia University, New York, New York, United States of America.
Anna
A
Vitebsky
Department of Genetics and Development, Columbia University, New York, New York, United States of America; Department of Pediatrics, Columbia University Medical Center, New York, New York, United States of America.
Dorothy
D
Warburton
Department of Pathology and Cell Biology, Columbia University, New York, New York, United States of America.
Brynn
B
Levy
Basic Science, Universidad de Monterrey, Nueva Leon, Mexico.
Julio C
JC
Salas-Alanis
Department of Genetics and Development, Columbia University, New York, New York, United States of America; Department of Dermatology, Columbia University, New York, New York, United States of America.
Angela M
AM
Christiano
D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D002675:Child, Preschool; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D002872:Chromosome Deletion; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000473:pathology; D006197:Hair / Q000254:growth & development* / Q000473:pathology; D006801:Humans; D006983:Hypertrichosis / Q000151:congenital* / Q000235:genetics / Q000473:pathology; D007223:Infant; D015603:Keratinocytes / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D012326:RNA Splicing / Q000235:genetics; D017384:Sequence Deletion
C471294:ABCA5 protein, human; D018528:ATP-Binding Cassette Transporters; D002784:Cholesterol