LSS – Alopecia-Intellectual Disability Syndrome 4

Lanosterol synthase (LSS) catalyzes the cyclization of (S)-2,3-oxidosqualene to lanosterol in the cholesterol biosynthesis pathway. Autosomal recessive biallelic variants in LSS have been implicated in a neuroectodermal disorder characterized by congenital alopecia, intellectual disability, and frequently early-onset epilepsy, designated Alopecia-Intellectual Disability Syndrome 4 (MONDO_0030009).

In a multicenter international collaborative study, ten affected individuals from six unrelated families were found to harbor biallelic LSS pathogenic variants, confirming autosomal recessive inheritance and broadening the phenotypic spectrum of LSS-related disorders (PMID:30723320). Probands presented with hypotrichosis or congenital alopecia alongside intellectual disability and developmental delay; several exhibited early seizures and dermatologic anomalies.

The variant spectrum includes missense, truncating, and splice-site alterations. Notably, the missense change c.35G>A (p.Gly12Asp) and splice acceptor variant c.1989-1G>A were each identified in multiple families, while two truncating alleles (e.g., c.422G>A (p.Trp141Ter)) further support a loss-of-function mechanism (PMID:30723320).

Segregation analyses demonstrated that all identified variants co-segregated with disease phenotypes within the six kindreds, consistent with compound heterozygous or homozygous genotypes.

Functional assays provide concordant experimental evidence: epidermis-specific Lss knockout mice recapitulate congenital hypotrichosis and barrier defects, whereas lens-specific knockouts develop cataracts, mirroring human skin and ocular manifestations (PMID:32101538). In vitro analyses of patient-derived and engineered LSS variants (e.g., c.401T>G (p.Val134Gly)) reveal reduced protein expression and stability, confirming impaired enzyme function (PMID:38800572).

Together, genetic and functional data support a loss-of-function mechanism underlying Alopecia-Intellectual Disability Syndrome 4. The robust association between biallelic LSS variants and the core clinical features fulfills ClinGen Strong criteria. Key Take-home: Testing for LSS variants is clinically useful for definitive diagnosis and genetic counseling in patients with congenital alopecia and intellectual disability.

References

• Genetics in medicine • 2019 • Biallelic pathogenic variants in the lanosterol synthase gene LSS involved in the cholesterol biosynthesis cause alopecia with intellectual disability, a rare recessive neuroectodermal syndrome. PMID:30723320
• PLoS genetics • 2020 • Metabolic and pathologic profiles of human LSS deficiency recapitulated in mice. PMID:32101538
• Frontiers in neuroscience • 2024 • Clinical and genetic analyses of APMR4 syndrome caused by novel biallelic LSS variants. PMID:38800572

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