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.
Publication Date: 2014-10-08 PubMed ID: 25295861PubMed Central: PMC4190318DOI: 10.1371/journal.pone.0110125Google Scholar: Lookup
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- Journal Article
- Research Support
- Non-U.S. Gov't
Summary
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This research investigated a deadly, genetically inherited disease known as congenital hepatic fibrosis within the Swiss Franches-Montagnes horse breed. Researchers found a strong link between this disease and a specific gene, polycystic kidney and hepatic disease 1 (PKHD1), which is also associated with polycystic disease in humans and other animals.
Overall Research Aim
- The primary objective of the study was to explore the genetic basis of congenital hepatic fibrosis, a lethal disease found in the Swiss Franches-Montagnes horse breed. The researchers examined potential genetic associations and sought to pinpoint the causal gene/s associated with the condition.
Methods and Approach
- A genome-wide association study was conducted using 5 cases (horses with the disease) and 12 controls (healthy individuals). The researchers detected an association on chromosome 20.
- The researchers engaged in homozygosity mapping, which highlighted a critical interval of 952 kb containing 10 annotated genes and loci, where they discovered the PKHD1 gene.
- The researchers sequenced the genomes of an affected foal and 46 control horses to establish a comprehensive list of variants within that 952 kb interval.
Findings
- They identified two missense variants in the PKHD1 gene which showed strong – though not perfect – association with congenital hepatic fibrosis, leading to speculation about reduced penetrance and potential interactions with potentially modifying genes.
- They discovered that most pathogenic PKHD1 variants lead to polycystic defects in kidney and liver, but a small subset only demonstrate liver symptoms; a pattern that closely mirrors the behaviour of the disease in their horses.
Significance or Implication of the Study
- These findings suggest that horses with congenital hepatic fibrosis could serve as valuable models for studying the liver-restricted subtype of human ARPKD.
- Understanding the genetic causes of the disease in horses could lead to advancements in understanding, diagnosing, and treating similar diseases in other species, including humans.
Cite This Article
APA
Drögemüller M, Jagannathan V, Welle MM, Graubner C, Straub R, Gerber V, Burger D, Signer-Hasler H, Poncet PA, Klopfenstein S, von Niederhäusern R, Tetens J, Thaller G, Rieder S, Drögemüller C, Leeb T.
(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.
https://doi.org/10.1371/journal.pone.0110125 Publication
Researcher Affiliations
- 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.
- 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.
- Institute of Animal Pathology, University of Bern, Bern, Switzerland.
- Swiss Institute of Equine Medicine, University of Bern and Agroscope, Bern, Switzerland.
- Swiss Institute of Equine Medicine, University of Bern and Agroscope, Bern, Switzerland.
- Swiss Institute of Equine Medicine, University of Bern and Agroscope, Bern, Switzerland.
- Swiss Institute of Equine Medicine, University of Bern and Agroscope, Bern, Switzerland.
- 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.
- HIPPOP, Lignerolle, Switzerland.
- Swiss Franches-Montagnes Breeding Association, Avenches, Switzerland.
- 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.
- Institute of Animal Breeding and Husbandry, Christian-Albrechts-University, Kiel, Germany.
- Institute of Animal Breeding and Husbandry, Christian-Albrechts-University, Kiel, Germany.
- 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.
- 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.
- 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.
MeSH Terms
- Alleles
- Animals
- Breeding
- Chromosome Mapping
- Female
- Genetic Association Studies
- Genetic Diseases, Inborn / genetics
- Genome-Wide Association Study
- Horses
- Humans
- Liver / metabolism
- Liver Cirrhosis / genetics
- Male
- Receptors, Cell Surface / genetics
- Sequence Analysis, DNA
Conflict of Interest Statement
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.
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