Dataset Information

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).

SUBMITTER: Letko A

PROVIDER: S-EPMC7600965 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Deleterious <i>AGXT</i> Missense Variant Associated with Type 1 Primary Hyperoxaluria (PH1) in Zwartbles Sheep.

Letko Anna A Dijkman Reinie R Strugnell Ben B Häfliger Irene M IM Paris Julia M JM Henderson Katrina K Geraghty Tim T Orr Hannah H Scholes Sandra S Drögemüller Cord C

Genes 20200929 10

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 ran ...[more]

PMID: 33003365

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Project description:RationalePrimary hyperoxaluria (PH) is a rare autosomal recessive disorder more commonly diagnosed in children or adolescents. Owing to its rarity and heterogeneous phenotype, it is often underrecognized, resulting in delayed diagnosis, including diagnosis after end-stage kidney disease (ESKD) has occurred or recurrence after kidney-only transplantation.Case presentationA 40-year-old Caucasian Canadian woman with a history of recurrent nephrolithiasis since age 19 presented with ESKD and cutaneous symptoms. She had no known prior kidney disease and no family history of kidney disease or nephrolithiasis.DiagnosisA diagnosis of primary hyperoxaluria type 1 (PH1) due to homozygous splice donor mutation (AGXT c.680+1G>A) was made with kidney and cutaneous pathology demonstrating calcium oxalate deposition and ultrasound suggestive of nephrocalcinosis.InterventionsShe was initiated on frequent, high-efficiency, high-flux conventional hemodialysis and oral pyridoxine. Lumasiran was added 11 months later, after she developed bilateral swan-neck deformities.OutcomesAfter 14 months of high-intensity dialysis and 3 months of lumasiran, there have been no signs of renal recovery, and extra-renal involvement has increased with progressive swan-neck deformities, reduced cardiac systolic function, and pulmonary hypertension. The patient has been waitlisted for kidney-liver transplantation.Teaching pointsThis case report describes an adult presentation of PH1. The case highlights the importance of timely workup of metabolic causes of recurrent nephrolithiasis or nephrocalcinosis in adults which can be a presenting sign of PH and genetic testing for PH to facilitate early diagnosis and treatment especially in the era of novel therapeutics that may alter disease course and outcomes. The case also demonstrates the value of testing for PH in adults presenting with unexplained ESKD and a history of recurrent nephrolithiasis or nephrocalcinosis due to implications for organ transplantation strategy and presymptomatic family screening.

Dataset Information

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

Publications

Deleterious <i>AGXT</i> Missense Variant Associated with Type 1 Primary Hyperoxaluria (PH1) in Zwartbles Sheep.

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