KRT18 – Familial Cirrhosis

Keratin 18 (KRT18) is a type I intermediate filament protein expressed in simple epithelia, including hepatocytes. A germline missense variant, c.383A>T (p.His128Leu), was identified in a patient with cryptogenic cirrhosis and demonstrated autosomal dominant transmission (PMID:9011570). In vitro, the p.His128Leu protein showed altered migration on two-dimensional gels and defective filament assembly by electron microscopy. Concordantly, transgenic mice expressing mutant K18 develop chronic hepatitis with hepatocyte fragility and elevated transaminases (PMID:9011570; PMID:8522591). Given a single proband and limited segregation data, the clinical validity is rated as Limited. Moderate experimental evidence from biochemical and animal models supports a pathogenic mechanism of defective filament assembly. Key take-home: KRT18 missense variants, such as c.383A>T (p.His128Leu), represent candidate genetic risk factors for familial cirrhosis.

References

• The Journal of clinical investigation • 1997 • Mutation of human keratin 18 in association with cryptogenic cirrhosis. PMID:9011570
• The Journal of cell biology • 1995 • Chronic hepatitis, hepatocyte fragility, and increased soluble phosphoglycokeratins in transgenic mice expressing a keratin 18 conserved arginine mutant. PMID:8522591

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