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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.

SUBMITTER: Drogemuller M

PROVIDER: S-EPMC4190318 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Congenital hepatic fibrosis in the Franches-Montagnes horse is associated with the polycystic kidney and hepatic disease 1 (PKHD1) gene.

Drögemüller Michaela M Jagannathan Vidhya V Welle Monika M MM Graubner Claudia C Straub Reto R Gerber Vinzenz V Burger Dominik D Signer-Hasler Heidi H Poncet Pierre-André PA Klopfenstein Stéphane S von Niederhäusern Ruedi R Tetens Jens J Thaller Georg G Rieder Stefan S Drögemüller Cord C Leeb Tosso T

PloS one 20141008 10

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 exc ...[more]

PMID: 25295861

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Project description:Background and objectivesWe have previously published the characteristics of kidney and liver disease in a cohort of 73 individuals with molecularly confirmed autosomal recessive polycystic kidney disease-congenital hepatic fibrosis, based upon cross-sectional data. Here, we present prospective data on the same cohort.Design, setting, participants, and measurementsComprehensive biochemical and imaging data on progression of kidney and liver disease in 60 of the 73 patients were prospectively collected at the NIH Clinical Center on multiple visits between 2003 and 2019.Results and conclusionsOf the 73 patients, 23 received a renal allograft at an average age of 17.5 years and 10 underwent liver transplantation at an average age of 20.3 years. Patients who presented perinatally and those who had corticomedullary disease required kidney transplantation significantly earlier. The mean eGFR slope in patients with corticomedullary disease was -1.6 ml/min/1.73 m2/y, in comparison to -0.6 ml/min/1.73 m2/y in those with medullary disease. Kidney size remained the same over time and normalized to the upper limit of normal by 20-25 years of age. The extent of renal disease on ultrasound remained largely unchanged; no patient progressed from the "medullary" to the "corticomedullary" group. There was no correlation between eGFR slope and kidney size. The synthetic function of the liver remained largely intact even in patients with advanced portal hypertension. Based on spleen length/height ratio, two thirds of patients had portal hypertension which remained stable in 39% and worsened in 61%. Patients with portal hypertension had lower platelet counts and relatively higher levels of AST, GGT, direct bilirubin and ammonia. The progression rates of kidney and liver disease were independent of each other. Patients with bi-allelic non-truncating PKHD1 variants had similar progression of kidney and liver disease in comparison to those who were compound heterozygous for a non-truncating and a truncating variant.

Project description:Linear description (LD) of conformation traits was introduced in horse breeding to minimise subjectivity in scoring. However, recent studies have shown that LD traits show essentially the same problems as traditionally scored traits, such as data converging around the mean value with very small standard deviations. To improve the assessment of conformation traits of horses, we investigated the application of the recently described horse shape space model based upon 403 digitised photographs of 243 Franches-Montagnes (FM) stallions and extracted joint angles based on specific landmark triplets. Repeatability, reproducibility and consistency of the resulting shape data and joint angles were assessed with Procrustes ANOVA (Rep) and intra-class correlation coefficients (ICC). Furthermore, we developed a subjective score to classify the posture of the horses on each photograph. We derived relative warp scores (PCs) based upon the digitised photos conducting a principal component analysis (PCA). The PCs of the shapes and joint angles were compared to the posture scores and to the linear description data using linear mixed effect models including significant posture scores as random factors. The digitisation process was highly repeatable and reproducible for the shape (Rep = 0.72-0.99, ICC = 0.99). The consistency of the shape was limited by the age and posture (p < 0.05). The angle measurements were highly repeatable within one digitiser. Between digitisers, we found a higher variability of ICC values (ICC = 0.054-0.92), indicating digitising error in specific landmarks (e.g. shoulder point). The posture scores were highly repeatable (Fleiss' kappa = 0.713-0.857). We identified significant associations (p(X2) < 0.05) with traits describing the withers height, shoulder length and incline, overall leg conformation, walk and trot step length. The horse shape data and angles provide additional information to explore the morphology of horses and therefore can be applied to improve the knowledge of the genetic architecture of LD traits.

Project description:BACKGROUND & AIMS:Autosomal recessive polycystic kidney disease (ARPKD), the most common ciliopathy of childhood, is characterized by congenital hepatic fibrosis and progressive cystic degeneration of kidneys. We aimed to describe congenital hepatic fibrosis in patients with ARPKD, confirmed by detection of mutations in PKHD1. METHODS:Patients with ARPKD and congenital hepatic fibrosis were evaluated at the National Institutes of Health from 2003 to 2009. We analyzed clinical, molecular, and imaging data from 73 patients (age, 1-56 years; average, 12.7 ± 13.1 years) with kidney and liver involvement (based on clinical, imaging, or biopsy analyses) and mutations in PKHD1. RESULTS:Initial symptoms were liver related in 26% of patients, and others presented with kidney disease. One patient underwent liver and kidney transplantation, and 10 others received kidney transplants. Four presented with cholangitis and one with variceal bleeding. Sixty-nine percent of patients had enlarged left lobes on magnetic resonance imaging, 92% had increased liver echogenicity on ultrasonography, and 65% had splenomegaly. Splenomegaly started early in life; 60% of children younger than 5 years had enlarged spleens. Spleen volume had an inverse correlation with platelet count and prothrombin time but not with serum albumin level. Platelet count was the best predictor of spleen volume (area under the curve of 0.88905), and spleen length corrected for patient's height correlated inversely with platelet count (R(2) = 0.42, P < .0001). Spleen volume did not correlate with renal function or type of PKHD1 mutation. Twenty-two of 31 patients who underwent endoscopy were found to have varices. Five had variceal bleeding, and 2 had portosystemic shunts. Forty-percent had Caroli syndrome, and 30% had an isolated dilated common bile duct. CONCLUSIONS:Platelet count is the best predictor of the severity of portal hypertension, which has early onset but is underdiagnosed in patients with ARPKD. Seventy percent of patients with ARPKD have biliary abnormalities. Kidney and liver disease are independent, and variability in severity is not explainable by type of PKHD1 mutation; ClinicalTrials.gov number, NCT00068224.

Dataset Information

Congenital hepatic fibrosis in the Franches-Montagnes horse is associated with the polycystic kidney and hepatic disease 1 (PKHD1) gene.

Publications

Congenital hepatic fibrosis in the Franches-Montagnes horse is associated with the polycystic kidney and hepatic disease 1 (PKHD1) gene.

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