Congenital hepatic fibrosis in the Franches-Montagnes horse is associated with the polycystic kidney and hepatic disease 1 (PKHD1) gene.
Authors: Drögemüller Michaela, Jagannathan Vidhya, Welle Monika M, Graubner Claudia, Straub Reto, Gerber Vinzenz, Burger Dominik, Signer-Hasler Heidi, Poncet Pierre-André, Klopfenstein Stéphane, von Niederhäusern Ruedi, Tetens Jens, Thaller Georg, Rieder Stefan, Drögemüller Cord, Leeb Tosso
Journal: PloS one
Summary
Congenital hepatic fibrosis (CHF) in Franches-Montagnes horses is a lethal autosomal recessive condition whose genetic basis remained unknown until researchers performed a genome-wide association study combined with homozygosity mapping to identify a critical 952 kb interval on chromosome 20. Two missense variants within the polycystic kidney and hepatic disease 1 (PKHD1) gene showed strong but incomplete association with disease, suggesting that reduced penetrance or epistatic interactions with modifier genes may influence disease expression. The findings are particularly significant because whilst PKHD1 mutations typically cause polycystic changes in both kidney and liver tissue across humans, mice and rats, these affected horses display liver pathology in isolation—a presentation mirrored in only a minority of human autosomal recessive polycystic kidney disease (ARPKD) patients. For equine practitioners, this research establishes a genetic test opportunity for Franches-Montagnes breeders and validates horses with CHF as a valuable large animal model for the rarer liver-restricted form of human ARPKD, potentially enabling translational research that could benefit both species. Carrier screening within the breed could substantially reduce the incidence of this fatal condition whilst advancing understanding of how PKHD1 dysfunction produces tissue-specific pathology.
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Practical Takeaways
- •Breeders of Franches-Montagnes horses should be aware this is a lethal monogenic recessive condition; genetic testing can identify carriers to prevent affected foals
- •Affected foals present with congenital hepatic fibrosis; there is no treatment, making prevention through selective breeding the only management option
- •This breed may serve as a large animal research model for understanding human liver-restricted ARPKD, potentially advancing human medical knowledge
Key Findings
- •Congenital hepatic fibrosis in Franches-Montagnes horses is associated with PKHD1 gene mutations on chromosome 20
- •Two missense variants in PKHD1 were strongly associated with the disease, though not with perfect penetrance
- •This condition represents a liver-restricted phenotype similar to a subset of human autosomal recessive polycystic kidney and hepatic disease (ARPKD) cases
- •Reduced penetrance and potential epistatic interactions with modifier genes may explain incomplete genotype-phenotype correlation