title: Congenital hepatic fibrosis in the Franches-Montagnes horse is associated with the polycystic kidney and hepatic disease 1 (PKHD1) gene.
abstract: 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.
authors.affiliation: Institute of Genetics, University of Bern, Bern, Switzerland; Swiss Competence Center of Animal Breeding and Genetics, University of Bern, Bern University of Applied Sciences HAFL and Agroscope, Bern, Switzerland.
authors.forename: Michaela
authors.initials: M
authors.lastname: Drögemüller
authors.affiliation: Institute of Genetics, University of Bern, Bern, Switzerland; Swiss Competence Center of Animal Breeding and Genetics, University of Bern, Bern University of Applied Sciences HAFL and Agroscope, Bern, Switzerland.
authors.forename: Vidhya
authors.initials: V
authors.lastname: Jagannathan
authors.affiliation: Institute of Animal Pathology, University of Bern, Bern, Switzerland.
authors.forename: Monika M
authors.initials: MM
authors.lastname: Welle
authors.affiliation: Swiss Institute of Equine Medicine, University of Bern and Agroscope, Bern, Switzerland.
authors.forename: Claudia
authors.initials: C
authors.lastname: Graubner
authors.affiliation: Swiss Institute of Equine Medicine, University of Bern and Agroscope, Bern, Switzerland.
authors.forename: Reto
authors.initials: R
authors.lastname: Straub
authors.affiliation: Swiss Institute of Equine Medicine, University of Bern and Agroscope, Bern, Switzerland.
authors.forename: Vinzenz
authors.initials: V
authors.lastname: Gerber
authors.affiliation: Swiss Institute of Equine Medicine, University of Bern and Agroscope, Bern, Switzerland.
authors.forename: Dominik
authors.initials: D
authors.lastname: Burger
authors.affiliation: Swiss Competence Center of Animal Breeding and Genetics, University of Bern, Bern University of Applied Sciences HAFL and Agroscope, Bern, Switzerland; Bern University of Applied Sciences HAFL, Zollikofen, Switzerland.
authors.forename: Heidi
authors.initials: H
authors.lastname: Signer-Hasler
authors.affiliation: HIPPOP, Lignerolle, Switzerland.
authors.forename: Pierre-André
authors.initials: PA
authors.lastname: Poncet
authors.affiliation: Swiss Franches-Montagnes Breeding Association, Avenches, Switzerland.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Klopfenstein
authors.affiliation: Swiss Competence Center of Animal Breeding and Genetics, University of Bern, Bern University of Applied Sciences HAFL and Agroscope, Bern, Switzerland; Agroscope, Swiss National Stud Farm, Avenches, Switzerland.
authors.forename: Ruedi
authors.initials: R
authors.lastname: von Niederhäusern
authors.affiliation: Institute of Animal Breeding and Husbandry, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Tetens
authors.affiliation: Institute of Animal Breeding and Husbandry, Christian-Albrechts-University, Kiel, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Thaller
authors.affiliation: Swiss Competence Center of Animal Breeding and Genetics, University of Bern, Bern University of Applied Sciences HAFL and Agroscope, Bern, Switzerland; Agroscope, Swiss National Stud Farm, Avenches, Switzerland.
authors.forename: Stefan
authors.initials: S
authors.lastname: Rieder
authors.affiliation: Institute of Genetics, University of Bern, Bern, Switzerland; Swiss Competence Center of Animal Breeding and Genetics, University of Bern, Bern University of Applied Sciences HAFL and Agroscope, Bern, Switzerland.
authors.forename: Cord
authors.initials: C
authors.lastname: Drögemüller
authors.affiliation: Institute of Genetics, University of Bern, Bern, Switzerland; Swiss Competence Center of Animal Breeding and Genetics, University of Bern, Bern University of Applied Sciences HAFL and Agroscope, Bern, Switzerland.
authors.forename: Tosso
authors.initials: T
authors.lastname: Leeb
mesh_terms: D000483:Alleles; D000818:Animals; D001947:Breeding; D002874:Chromosome Mapping; D005260:Female; D056726:Genetic Association Studies; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D055106:Genome-Wide Association Study; D006736:Horses; D006801:Humans; D008099:Liver / Q000378:metabolism; D008103:Liver Cirrhosis / Q000235:genetics*; D008297:Male; D011956:Receptors, Cell Surface / Q000235:genetics*; D017422:Sequence Analysis, DNA
chemical_list: D011956:Receptors, Cell Surface