Deleterious <i>AGXT</i> Missense Variant Associated with Type 1 Primary Hyperoxaluria (PH1) in Zwartbles Sheep
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 descri...
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MDPI AG
2020-09-01
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| Online Access: | https://www.mdpi.com/2073-4425/11/10/1147 |
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| author | Anna Letko Reinie Dijkman Ben Strugnell Irene M. Häfliger Julia M. Paris Katrina Henderson Tim Geraghty Hannah Orr Sandra Scholes Cord Drögemüller |
| author_facet | Anna Letko Reinie Dijkman Ben Strugnell Irene M. Häfliger Julia M. Paris Katrina Henderson Tim Geraghty Hannah Orr Sandra Scholes Cord Drögemüller |
| author_sort | Anna Letko |
| collection | DOAJ |
| description | 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 <i>AGXT</i> gene (c.584G>A; p.Cys195Tyr). Variants in <i>AGXT</i> 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 <i>AGXT</i> 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). |
| first_indexed | 2024-03-10T15:58:53Z |
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| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-10T15:58:53Z |
| publishDate | 2020-09-01 |
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| series | Genes |
| spelling | doaj.art-7c41a797b13e431e83a9a008413720a12023-11-20T15:29:05ZengMDPI AGGenes2073-44252020-09-011110114710.3390/genes11101147Deleterious <i>AGXT</i> Missense Variant Associated with Type 1 Primary Hyperoxaluria (PH1) in Zwartbles SheepAnna Letko0Reinie Dijkman1Ben Strugnell2Irene M. Häfliger3Julia M. Paris4Katrina Henderson5Tim Geraghty6Hannah Orr7Sandra Scholes8Cord Drögemüller9Institute of Genetics, Vetsuisse Faculty, University of Bern, 3012 Bern, SwitzerlandRoyal GD, Postbus 9, 7400 AA Deventer, The NetherlandsFarm Post Mortems Ltd., Hamsterley, Bishop Auckland, County Durham DL13 3QF, UKInstitute of Genetics, Vetsuisse Faculty, University of Bern, 3012 Bern, SwitzerlandInstitute of Genetics, Vetsuisse Faculty, University of Bern, 3012 Bern, SwitzerlandSRUC Consulting Veterinary Services, Pentlands Science Park, Bush Estate Loan, Penicuik, Midlothian EH26 0PZ, UKSRUC Consulting Veterinary Services, Pentlands Science Park, Bush Estate Loan, Penicuik, Midlothian EH26 0PZ, UKSRUC Consulting Veterinary Services, Pentlands Science Park, Bush Estate Loan, Penicuik, Midlothian EH26 0PZ, UKSRUC Consulting Veterinary Services, Pentlands Science Park, Bush Estate Loan, Penicuik, Midlothian EH26 0PZ, UKInstitute of Genetics, Vetsuisse Faculty, University of Bern, 3012 Bern, SwitzerlandSevere 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 <i>AGXT</i> gene (c.584G>A; p.Cys195Tyr). Variants in <i>AGXT</i> 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 <i>AGXT</i> 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).https://www.mdpi.com/2073-4425/11/10/1147<i>Ovis aries</i>oxalate nephropathywhole-genome sequencingmetabolic diseaseprecision medicinegenetic test |
| spellingShingle | Anna Letko Reinie Dijkman Ben Strugnell Irene M. Häfliger Julia M. Paris Katrina Henderson Tim Geraghty Hannah Orr Sandra Scholes Cord Drögemüller Deleterious <i>AGXT</i> Missense Variant Associated with Type 1 Primary Hyperoxaluria (PH1) in Zwartbles Sheep Genes <i>Ovis aries</i> oxalate nephropathy whole-genome sequencing metabolic disease precision medicine genetic test |
| title | Deleterious <i>AGXT</i> Missense Variant Associated with Type 1 Primary Hyperoxaluria (PH1) in Zwartbles Sheep |
| title_full | Deleterious <i>AGXT</i> Missense Variant Associated with Type 1 Primary Hyperoxaluria (PH1) in Zwartbles Sheep |
| title_fullStr | Deleterious <i>AGXT</i> Missense Variant Associated with Type 1 Primary Hyperoxaluria (PH1) in Zwartbles Sheep |
| title_full_unstemmed | Deleterious <i>AGXT</i> Missense Variant Associated with Type 1 Primary Hyperoxaluria (PH1) in Zwartbles Sheep |
| title_short | Deleterious <i>AGXT</i> Missense Variant Associated with Type 1 Primary Hyperoxaluria (PH1) in Zwartbles Sheep |
| title_sort | deleterious i agxt i missense variant associated with type 1 primary hyperoxaluria ph1 in zwartbles sheep |
| topic | <i>Ovis aries</i> oxalate nephropathy whole-genome sequencing metabolic disease precision medicine genetic test |
| url | https://www.mdpi.com/2073-4425/11/10/1147 |
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