Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice

Abstract

Skin lesions, cataracts, and congenital anomalies have been frequently associated with inherited deficiencies in enzymes that synthesize cholesterol. Lanosterol synthase (LSS) converts (S)-2,3-epoxysqualene to lanosterol in the cholesterol biosynthesis pathway. Biallelic mutations in LSS have been reported in families with congenital cataracts and, very recently, have been reported in cases of hypotrichosis. However, it remains to be clarified whether these phenotypes are caused by LSS enzymatic deficiencies in each tissue, and disruption of LSS enzymatic activity in vivo has not yet been validated. We identified two patients with novel biallelic LSS mutations who exhibited congenital hypotrichosis and midline anomalies but did not have cataracts. We showed that the blockade of the LSS enzyme reaction occurred in the patients by measuring the (S)-2,3-epoxysqualene/lanosterol ratio in the forehead sebum, which would be a good biomarker for the diagnosis of LSS deficiency. Epidermis-specific Lss knockout mice showed neonatal lethality due to dehydration, indicating that LSS could be involved in skin barrier integrity. Tamoxifen-induced knockout of Lss in the epidermis caused hypotrichosis in adult mice. Lens-specific Lss knockout mice had cataracts. These results confirmed that LSS deficiency causes hypotrichosis and cataracts due to loss-of-function mutations in LSS in each tissue. These mouse models will lead to the elucidation of the pathophysiological mechanisms associated with disrupted LSS and to the development of therapeutic treatments for LSS deficiency.

Two cases of severe congenital hypotrichosis caused by compound heterozygous mutations in the LSS gene

“…The growth of Patient 1 with the missense mutation p.R177Q was apparently normal, whereas patients with the identical mutation showed growth retardation according to a recent report 13 . In our case, the other LSS allele carried a missense mutation p.V487E.…”

“…On the other hand, patients with growth retardation had a frameshift mutation p.R234Pfs*2 on the other allele, which was likely a null mutation (Table 1). 13 We postulate that the p.V487E is a hypomorphic mutation maintaining its function to some extent, which, therefore, resulted in showing only hair symptoms.…”

“…a). Of these, the variant c.530G>A (p.R177Q) has recently been reported to be responsible for hypotrichosis with growth retardation 13 . Another variant c.1460T>A (p.V487E) was not found in the gnomAD (https://gnomad.broadinstitute.org) or the Human Genetic Variation Database (http://www.hgvd.genome.med.kyoto-u.ac.jp).…”

“…The mutations identified in this study are colored in red. Mutations associated with hypotrichosis simplex 7,8 or hypotrichosis with growth retardation 13 are indicated by a red box. Those responsible for alopecia with intellectual disability 12 and cataracts 10,11 are indicated by blue and green boxes, respectively.…”

“…More recently, it has been reported that the LSS is a causative gene for alopecia with intellectual disability (OMIM 618840) 12 . Furthermore, bi‐allelic mutations in the LSS gene have been reported to underlie hypotrichosis with growth retardation 13 . Therefore, mutations in the LSS gene can cause a total of five distinct disorders.…”