Bi-allelic Mutations in LSS, Encoding Lanosterol Synthase, Cause Autosomal-Recessive Hypotrichosis Simplex

Abstract

Hypotrichosis simplex (HS) is a rare form of hereditary alopecia characterized by childhood onset of diffuse and progressive scalp and body hair loss. Although research has identified a number of causal genes, genetic etiology in about 50% of HS cases remains unknown. The present report describes the identification via whole-exome sequencing of five different mutations in the gene LSS in three unrelated families with unexplained, potentially autosomal-recessive HS. Affected individuals showed sparse to absent lanugo-like scalp hair, sparse and brittle eyebrows, and sparse eyelashes and body hair. LSS encodes lanosterol synthase (LSS), which is a key enzyme in the cholesterol biosynthetic pathway. This pathway plays an important role in hair follicle biology. After localizing LSS protein expression in the hair shaft and bulb of the hair follicle, the impact of the mutations on keratinocytes was analyzed using immunoblotting and immunofluorescence. Interestingly, wild-type LSS was localized in the endoplasmic reticulum (ER), whereas mutant LSS proteins were localized in part outside of the ER. A plausible hypothesis is that this mislocalization has potential deleterious implications for hair follicle cells. Immunoblotting revealed no differences in the overall level of wild-type and mutant protein. Analyses of blood cholesterol levels revealed no decrease in cholesterol or cholesterol intermediates, thus supporting the previously proposed hypothesis of an alternative cholesterol pathway. The identification of LSS as causal gene for autosomal-recessive HS highlights the importance of the cholesterol pathway in hair follicle biology and may facilitate novel therapeutic approaches for hair loss disorders in general.

Cholesterol homeostasis: Links to hair follicle biology and hair disorders

“…A summary of cholesterol biosynthesis, including known mutations associated with hair disorders (as indicated by stars). Mutation to LSS has been associated with autosomal‐recessive hypotrichosis simplex presenting with sparse scalp hair . Mutations to EBP in Conradi–Hünermann syndrome are associated with Follicular atrophoderma and patchy scarring alopecia .…”

“…A number of studies have also identified mutations in genes linked with cholesterol homeostasis and hair phenotypes, as shown in Table . Indeed, a recent publication employing whole‐exome sequencing identified mutations in lanosterol synthase (LSS), linked to autosomal‐recessive hypotrichosis simplex . LSS is involved in the production of lanosterol during cholesterol biosynthesis (Figure A) .…”

“…The resulting dysfunction is suggested to lead to accumulation of cholesterol precursors, resulting in inflammation and disruption of Wnt/BMP signalling . As the authors did not specifically investigate intrafollicular sterol levels in these patients, a role for the accumulation of potential toxic cholesterol precursors remains to be conclusively shown.…”

Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice

“…In addition, very recently, hypotrichosis has been reported to be an associated phenotype with biallelic LSS mutations [7,8]. Out of 24 patients, all had either cataracts (5/24) or hypotrichosis (20/24), and one had both [5][6][7][8]. Thus, cataracts and hypotrichosis are core symptoms in patients with biallelic LSS mutations.…”

“…Biallelic mutations in LSS were first reported in families with congenital cataracts [5,6]. In addition, very recently, hypotrichosis has been reported to be an associated phenotype with biallelic LSS mutations [7,8]. Out of 24 patients, all had either cataracts (5/24) or hypotrichosis (20/24), and one had both [5][6][7][8].…”