Institute of Genetics, Vetsuisse Faculty, University of Bern, 3012 Bern, Switzerland.
Royal GD, Postbus 9, 7400 AA Deventer, The Netherlands.
Genes (Basel). 2020 Sep 29;11(10):1147. doi: 10.3390/genes11101147.
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 gene (c.584G>A; p.Cys195Tyr). Variants in 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 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).
先前有报道称绵羊发生严重草酸盐肾病，且主要与饮食中草酸盐过量有关。然而，一种罕见的荷兰本土品种（Zwartbles）似乎容易发生原发性高草酸尿症的遗传性少年型，且迄今尚未描述其致病的遗传变异。本研究旨在描述在几头纯种 Zwartbles 绵羊中观察到的遗传性代谢疾病的表型和遗传病因。受影响的动物表现出广泛的临床症状，包括状况下降、食欲不振、不适，偶尔还会出现呼吸症状，以及明显的意外突然死亡。组织病理学显示病例的肾脏中广泛存在草酸晶体沉积。对两只受影响绵羊的全基因组测序发现了一个在羊基因中的错义变异（c.584G>A；p.Cys195Tyr）。在犬和人中， 基因中的变异已知会导致 I 型原发性高草酸尿症。在此，我们提供的证据表明，观察到的临床病理表型可以描述为一种绵羊 I 型原发性高草酸尿症。这种疾病是由一种特定于品种的隐性遗传致病性 变异引起的。遗传检测可用于在 Zwartbles 绵羊中选择这种致命疾病，以及对具有类似临床表型的动物进行更精确的诊断。我们的研究结果已被纳入在线孟德尔遗传在动物（OMIA）数据库（OMIA 001672-9940）。
