Congenital Hepatic Fibrosis in the Franches-Montagnes Horse Is Associated with the Polycystic Kidney and Hepatic Disease 1 ( PKHD 1 ) Gene

Congenital hepatic fibrosis has been described as a lethal disease with monogenic autosomal recessive inheritance in the Swiss Franches-Montagnes horse breed. We performed a genome-wide association study with 5 cases and 12 controls and detected an association on chromosome 20. Subsequent homozygosity mapping defined a critical interval of 952 kb harboring 10 annotated genes and loci including the polycystic kidney and hepatic disease 1 (autosomal recessive) gene (PKHD1). PKHD1 represents an excellent functional candidate as variants in this gene were identified in human patients with autosomal recessive polycystic kidney and hepatic disease (ARPKD) as well as several mouse and rat mutants. Whereas most pathogenic PKHD1 variants lead to polycystic defects in kidney and liver, a small subset of the human ARPKD patients have only liver symptoms, similar to our horses with congenital hepatic fibrosis. The PKHD1 gene is one of the largest genes in the genome with multiple alternative transcripts that have not yet been fully characterized. We sequenced the genomes of an affected foal and 46 control horses to establish a comprehensive list of variants in the critical interval. We identified two missense variants in the PKHD1 gene which were strongly, but not perfectly associated with congenital hepatic fibrosis. We speculate that reduced penetrance and/or potential epistatic interactions with hypothetical modifier genes may explain the imperfect association of the detected PKHD1 variants. Our data thus indicate that horses with congenital hepatic fibrosis represent an interesting large animal model for the liver-restricted subtype of human ARPKD. Citation: Drögemüller M, Jagannathan V, Welle MM, Graubner C, Straub R, et al. (2014) Congenital Hepatic Fibrosis in the Franches-Montagnes Horse Is Associated with the Polycystic Kidney and Hepatic Disease 1 (PKHD1) Gene. PLoS ONE 9(10): e110125. doi:10.1371/journal.pone. 0110125 Editor: William Barendse, CSIRO, Australia Received June 11, 2014; Accepted September 15, 2014; Published October 8, 2014 Copyright: 2014 Drögemüller et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: The authors confirm that all data underlying the findings are fully available without restriction. The raw fastq files for the liver RNA-Seq experiment have been archived at EBI short read archive and can be accessed with the accession number PRJEB6068. The whole genome sequence of the affected horse has been deposited under accession number PRJEB5942. Funding: This study was financed in part by contributions from the Swiss Federal Office for Agriculture, the Swiss Federal Food Safety and Veterinary Office, and the Swiss Franches-Montagnes Breeding Association. No additional external funding was received for this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Following retirement as director of the Swiss National Stud in Avenches, Pierre-André Poncet is Chairman of the Swiss Board and Observatory of the Equine Industry (Conseil et Observatoire Suisse de la Filière du Cheval (COFICHEV)). This does not alter the authors’ adherence to PLOS ONE policies on sharing data and materials. * Email: tosso.leeb@vetsuisse.unibe. ch