LSS – Cataract 44

Lanosterol synthase (LSS) is a key enzyme in the cholesterol biosynthesis pathway converting (S)-2,3-epoxysqualene to lanosterol. Biallelic pathogenic variants in LSS have been implicated in a spectrum of neuroectodermal syndromes, prominently including congenital cataracts (Cataract 44).

Initial genetic evidence came from a multicenter study identifying ten affected individuals from six unrelated families with biallelic LSS variants presenting congenital cataracts, hypotrichosis, and intellectual disability ([PMID:30723320]). Subsequent reports described two independent families with palmoplantar keratoderma–congenital alopecia syndrome type 2, where affected individuals also exhibited early-onset cataracts ([PMID:35413293]), and a Chinese girl with congenital alopecia-cataract syndrome carrying c.1025T>G (p.Ile342Ser) and a novel splice-altering synonymous variant c.1011G>A (p.Pro337=) ([PMID:39436000]). In total, 13 probands across nine unrelated families have been documented with biallelic LSS variants and congenital cataracts.

The variant spectrum includes loss-of-function alleles such as c.443del (p.Lys148fs), missense changes like c.1025T>G (p.Ile342Ser), splicing perturbations (c.1011G>A (p.Pro337=)), and start-codon disruption (c.3G>A (p.Met1Ile)). These variants segregate in an autosomal recessive manner in multiplex sibships and demonstrate full concordance with the cataract phenotype ([PMID:30723320]; [PMID:35413293]).

Functional studies support a loss-of-function mechanism: lens-specific LssG589S knock-in and knockout mouse models exhibit embryonic lens opacity and disrupted fiber differentiation ([PMID:34926465]), and minigene assays confirm that c.1011G>A generates a cryptic splice donor leading to a frameshift ([PMID:39436000]).

Mechanistically, deficient LSS activity impairs cholesterol synthesis in the lens, leading to aberrant protein aggregation and fiber cell differentiation defects. Together, robust genetic segregation data and concordant animal and cellular models fulfill criteria for a definitive gene-disease relationship.

Key Take-home: Biallelic LSS variants should be included in diagnostic gene panels for congenital cataracts, and functional assays measuring cholesterol intermediates may serve as useful biomarkers.

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
• The Journal of investigative dermatology • 2022 • Biallelic Variants in Lanosterol Synthase (LSS) Cause Palmoplantar Keratoderma-Congenital Alopecia Syndrome Type 2. PMID:35413293
• Frontiers in cell and developmental biology • 2021 • Defect of LSS Disrupts Lens Development in Cataractogenesis. PMID:34926465
• The Journal of dermatology • 2025 • Biallelic pathogenic variants in the LSS gene cause congenital alopecia-cataract syndrome. PMID:39436000

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