KIF12 variants and disturbed hepatocyte polarity in children with a phenotypic spectrum of cholestatic liver disease

Objectives and study Recently, KIF12 has been identified as a cholestasis-associated candidate gene. As KIF12 is a member of a microtubule-associated motor protein family involved in organizing the cytoskeleton and intracellular transport, KIF12-associated cholestasis is assumed to be a result of disturbed cell polarity.

We describe six cases with likely pathogenic KIF12 variants from four unrelated families, their different phenotypes and our investigations to study hepatocyte polarity.

Methods Children with familial cholestasis and a likely pathogenic variant in the KIF12 gene were identified by NGS screening. Parents and siblings were tested for the variants to analyze segregation. Immunofluorescence imaging of apical markers MRP2 und BSEP, basolateral marker OATP1B1, tight junction protein ZO-1 and KIF12 itself was performed on patient’s liver tissue sections.

Results We detected two different homozygous KIF12 variants in five patients (4 patients: nonsense variant; 1 patient: splice site deletion). Segregation analyses confirmed autosomal recessive inheritance. The patient’s clinical manifestation ranged from neonatal cholestasis with complete clinical remission, or absent clinical symptoms with the diagnosis made incidentally, to a progressive course ending in liver transplantation. Immunofluorescence imaging of liver sections of KIF12 patients revealed an ectopic cytoplasmic MRP2 staining. BSEP, and partly ZO-1 staining appeared in long clustered structures. KIF12 and OATP1B1 staining was widely unremarkable.

Conclusion Our results strongly support pathogenic KIF12 variants as cause for familial cholestatic liver disease and suggest that these variants result in functional cell polarity disturbance. Due its wide clinical presentation with even asymptomatic cases, KIF12-associated cholestatic liver diseases are potentially underdiagnosed.

Poster Visit Session ll Clinical Hepatology, Surgery, LTX

28/01/2022, 15.55 pm – 16.40 pm

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Artikel online veröffentlicht:
26. Januar 2022