Mutations in the Cholesterol Transporter Gene ABCA5 Are Associated with Excessive Hair Overgrowth

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.

Congenital Generalized Hypertrichosis Terminalis with Gingival Hyperplasia and a Coarse Face: a Case Report

“…Apart from diaphragmatic hernia, genital disorders in females and pulmonary cysts, deletion producing MCA also include renal cysts which can cause obstruction/ hydronephrosis (15). Another rare form of CGHT with gingival hyperplasia was previously described showing AR mode of inheritance (11,12,16). DeStefano et al identifi ed two girls with CGHT.…”

“…Th e fi rst with gingival hyperplasia and normal face was from a consanguineous family for whom whole-exome sequencing revealed a novel, rare homozygous variant of ABCA5 gen, demonstrating AR mode of inheritance. Th e second girl represented an unrelated case with gingival hyperplasia and a coarse face, showed a [t(3;17)] translocation and cryptic 1.3 megabase (Mb) deletion involving ABCA5 gen, demonstrating AD mode of inheritance, indicating that ABCA5 defects might be the primary cause of many features of the CGHT phenotype (11). Furthermore, signifi cantly reduced levels of ABCA5 transcripts and transcribed proteins in the patient's hair follicles suggested an important role of ABCA5 in hair growth regulation (11).…”

“…Th e second girl represented an unrelated case with gingival hyperplasia and a coarse face, showed a [t(3;17)] translocation and cryptic 1.3 megabase (Mb) deletion involving ABCA5 gen, demonstrating AD mode of inheritance, indicating that ABCA5 defects might be the primary cause of many features of the CGHT phenotype (11). Furthermore, signifi cantly reduced levels of ABCA5 transcripts and transcribed proteins in the patient's hair follicles suggested an important role of ABCA5 in hair growth regulation (11). Th erefore, ABCA5 has attracted the most attention as a causative gene for either AR-or AD-CGHT (11).…”

“…Serbian Journal of Dermatology and Venereology 2016; 8 (1): [5][6][7][8][9][10][11][12] congenital hypertrichosis lanuginose, which is thought to occur as an autosomal dominant trait with variable expressivity; if it is possible to make distinction between lanugo and vellus hair, those with vellus hair may be classifi ed as a form of universal hypertrichosis known as autosomal dominant Ambras syndrome, or congenital hypertrichosis universalis which is a subtype of a unique congenital hypertrichosis universalis, that is associated with a balanced pericentric inversion on chromosome 8 (p11.2; q22); X-linked generalized hypertrichosis and congenital generalized hypertrichosis terminalis (CGHT) with or without gingival hyperplasia (1,6,7).…”

“…Its pathogenesis may be caused by one of the following mechanisms: conversion of vellus to terminal hairs and/or prolonged anagenetic stage, and/or increase in the number of hair follicles. Since the Middle Ages, less than 60 individuals with congenital hypertrichosis terminalis have been described, and, according to the most recent estimates, less than 40 cases were documented adequately and defi nitively in the literature (9,8,(10)(11)(12)(13)(14). Recent articles identifi ed CGHT as a genomic disorder (8).…”