Deleterious AGXT Missense Variant Associated with Type 1 Primary Hyperoxaluria (PH1) in Zwartbles Sheep

Abstract

Severe oxalate nephropathy has been previously reported in sheep and is mostly associated with excessive oxalate in the diet. However, a rare native Dutch breed (Zwartbles) seems to be predisposed to an inherited juvenile form of primary hyperoxaluria and no causative genetic variant has been described so far. This study aims to characterize the phenotype and genetic etiology of the inherited metabolic disease observed in several purebred Zwartbles sheep. Affected animals present with a wide range of clinical signs including condition loss, inappetence, malaise, and, occasionally, respiratory signs, as well as an apparent sudden unexpected death. Histopathology revealed widespread oxalate crystal deposition in kidneys of the cases. Whole-genome sequencing of two affected sheep identified a missense variant in the ovine AGXT gene (c.584G>A; p.Cys195Tyr). Variants in AGXT are known to cause type I primary hyperoxaluria in dogs and humans. Herein, we present evidence that the observed clinicopathological phenotype can be described as a form of ovine type I primary hyperoxaluria. This disorder is explained by a breed-specific recessively inherited pathogenic AGXT variant. Genetic testing enables selection against this fatal disorder in Zwartbles sheep as well as more precise diagnosis in animals with similar clinical phenotype. Our results have been incorporated in the Online Mendelian Inheritance in Animals (OMIA) database (OMIA 001672-9940).

Monitoring and Surveillance of Small Ruminant Health in The Netherlands

“…Hyperoxaluria is a recessively inherited juvenile form of primary hyperoxaluria in Zwartbles sheep that was first reported during the Veterinary Laboratories Agency Weybridge meeting of the European Veterinary Surveillance Network in 2011, published as severe oxalate nephropathy in the same year [51], and found in The Netherlands afterwards until a breed-specific recessively inherited pathogenic alanine-glyoxylate aminotransferase variant was demonstrated as its cause [8,46].…”

Locating a novel autosomal recessive genetic variant in the cattle glucokinase gene using only WGS data from three cases and six carriers

“…Using one dog example ( Sayyab et al, 2016 ), a filtering pipeline was established with seven steps, including genotype criteria and SIFT analysis, Sanger sequencing verification and sequencing of an additional 24 cases/controls. Runs of homozygosity methods have been widely used with SNP-chip data ( Pollott, 2018 ) and Letko et al (2020) report an example of using this method in Zwartbles sheep to locate a novel autosomal recessive condition associated with type 1 primary hyperoxaluria. Their study relied upon additional data from both the Sheep genomes project and 79 publicly available genomes of various breeds to provide “control” data for the GCR method.…”

A Nonsense Variant in CCDC65 Gene Causes Respiratory Failure Associated with Increased Lamb Mortality in French Lacaune Dairy Sheep

“…Since the last few decades, this method is efficient to map genetic defects and their associated variants as shown by the growing number of discovered causal variants referenced in the OMIA: Online Mendelian Inheritance in Animal database (https: //www.omia.org/; accessed 2 September 2021). As example, with this approach, several pathogenic variants were identified causing junctional epidermolysis bullosa in cattle [12,13] and sheep [14][15][16] and the affected animals died shortly after birth due to skin disorders (injuries on limb extremities, mucous membranes). However, when mutations affect viability of developing embryos during gestation, phenotype or biological samples are not available.…”