Biallelic Variants in Lanosterol Synthase (LSS) Cause Palmoplantar Keratoderma- Congenital Alopecia Syndrome Type 2

摘要

Palmoplantar keratoderma-congenital alopecia syndrome type 2 is an autosomal recessive disorder with an unknown genetic basis. In this study, we identified biallelic variants in the LSS gene in two unrelated palmo-plantar keratoderma-congenital alopecia syndrome type 2 cases (c.3G > A, p.Met1? and c.1025T > G, p.Ile342Ser in patient 1; c.1522G > T, p.Gly508Trp and c.428+42T > A in patient 2) presenting with additional clinical features, including early-onset cataracts, pseudoainhum, and agenesis of the corpus callosum. LSS encodes lanosterol synthase (LSS), which functions in the cholesterol biosynthesis pathway by converting (S)-2,3-oxidosqualene to lanosterol. The c.3G > A variant resulted in an alternative translation initiation at residue Met81, producing an N-terminal truncated protein (LSS-delta N80), as shown by immunoblotting. The c.428+42T > A variant introduced a potential splicing site, leading to a premature stop codon. Ex vivo studies revealed downregulation of LSS in both patients. Remarkably decreased lanosterol levels were found in vitro in three LSS variants, LSS-delta N80, p.Ile342Ser, and p.Gly508Trp, suggesting a loss of enzymatic activity. Transmission electron microscopy and immunofluorescence showed abnormal cornified envelope formation in the stratum corneum of the patients. Taken together, our findings indicate LSS as a causative gene for palmoplantar keratoderma-congenital alopecia syndrome type 2, which emphasizes the importance of the cholesterol synthesis pathway in human skin cornification.

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