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).
Highlights
Primary hyperoxaluria is a rare autosomal recessive metabolic disease that leads to an accumulation of calcium oxalate in various tissues that result in renal failure [1]
Several purebred Zwartbles sheep of both sexes were submitted for laboratory investigation with a suspicion of breed-specific oxalate nephropathy in Scotland (n = 3), northern England (n = 1), and the Netherlands (n = 5) (Supplementary Table S1)
On the basis of the presented clinicopathological data, an inherited form of type I primary hyperoxaluria characterized by severe chronic crystalline nephropathy was diagnosed in seven Zwartbles sheep homozygous for the AGXT missense variant
Summary
Primary hyperoxaluria is a rare autosomal recessive metabolic disease that leads to an accumulation of calcium oxalate in various tissues that result in renal failure [1]. Three types of primary hyperoxaluria are known and caused by homozygous or compound heterozygous variants in three different genes [1]. Variants in the gene encoding alanine-glyoxylate aminotransferase (AGXT). Genes 2020, 11, 1147 are responsible for type I primary hyperoxaluria (PH1; OMIM 259900), type II (PH2; OMIM 260000) is caused by variants in the glyoxylate reductase/hydroxypyruvate reductase gene (GRHPR), and type III (PH3; OMIM 613616) is caused by variants in the mitochondrial dihydrodipicolinate synthase-like gene (HOGA1). PH1 has been described in dogs (OMIA 001672-9615) with a breed-specific homozygous missense variant in AGXT (XP_003639939.1:p.Gly102Ser) and identified as a cause in the Coton de Tulear breed [2]. Rare cases of neonatal oxalate nephropathy in purebred calves with no known exposure to exogenous oxalates were reported [4,5]
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