CYSTINURIA IN NEWFOUNDLAND DOGS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。胱氨酸尿症是一种遗传性肾脏疾病，其特征是氨基酸重吸收缺陷和胱氨酸尿石的形成。不同形式的疾病，被称为I型和非I型，可以在临床和生物化学上区分，并且在胱氨酸尿患者中分别与SLC3A1 （rBAT）和SLC7A9基因突变有关。胱氨酸尿主要是作为一种常染色体隐性遗传性状在人类和I型形式的疾病是最常见的。胱氨酸尿症在许多品种的狗中都有发现，在纽芬兰品种中有一种严重的形式，类似于I型胱氨酸尿症。育种研究（由该基金支持）先前证明了纽芬兰犬的胱氨酸尿常染色体隐性遗传，表明SLC3A1是该疾病的候选基因。我们克隆了正常和患病纽芬兰犬的SLC3A1 cDNA和基因，并对其进行了测序，在胱氨酸犬的基因外显子2上发现了无义突变。这一发现证实了纽芬兰病是人类I型胱氨酸尿症的真正同源物。犬模型中基因突变的知识为使用大型动物模型研究胱氨酸尿症和其他肾小管疾病的分子治疗方法提供了机会。鬃狼是南美洲一种受威胁的犬科动物，其胱氨酸尿的发病率极高，目前正在研究鬃狼的胱氨酸尿。我们分析了美国许多圈养动物的尿液样本，以确定遗传模式并确定胱氨酸尿的类型。这些研究正在进行中，部分资金由莫里斯动物基金会提供。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cystinuria is an inherited renal disease characterized by defective amino acid reabsorption and by the formation of cystine uroliths. Different forms of the disease, designated type I and non-type I, can be distinguished clinically and biochemically, and have been associated in cystinuric humans with mutations in the SLC3A1 (rBAT) and SLC7A9 genes, respectively. Cystinuria is primarily inherited as an autosomal recessive trait in humans and the type I form of the disease is most common. Cystinuria has been recognized in many breeds of dogs and a severe form, resembling type I cystinuria, has been characterized in the Newfoundland breed. Breeding studies (supported by this grant) previously demonstrated autosomal recessive inheritance of cystinuria in the Newfoundland dog, suggesting SLC3A1 as a candidate gene for the disease. We cloned and sequenced the canine SLC3A1 cDNA and gene from normal and affected Newfoundland dogs and identified a nonsense mutation in exon 2 of the gene in the cystinuric dogs. This discovery confirms the Newfoundland disease as a true homologue of human type I cystinuria. The knowledge of the gene mutation in the canine model provides the opportunity to use a large animal model to investigate molecular approaches for the treatment of cystinuria and other renal tubular diseases. Studies are also ongoing to investigate cystinuria in the Maned Wolf, a threatened South American canid species with an extremely high incidence of cystinuria. We have analyzed urine samples from many captive animals in the United States in order to determine the mode of inheritance and characterize the type of cystinuria. These studies are ongoing and funded in part by the Morris Animal Foundation.