CYSTINURIA IN NEWFOUNDLAND DOGS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。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有缺陷，并形成胱氨酸尿结石。不同形式的疾病，指定为I型和非I型，可以在临床和生化上加以区分，并分别与SLC3A1(RBAT)和SLC7A9基因突变的胱氨酸尿症患者有关。胱氨酸尿症在人类中主要作为一种常染色体隐性遗传，I型是最常见的疾病。在许多品种的狗中都发现了胱氨酸尿症，纽芬兰犬的特征是一种严重的形式，类似于I型胱氨酸尿症。育种研究(由这笔赠款支持)之前证明了纽芬兰犬的胱氨酸尿症是常染色体隐性遗传的，这表明SLC3A1是这种疾病的候选基因。我们从正常和患病的纽芬兰犬中克隆并测序了犬SLC3A1基因和基因，并在半胱氨酸尿症犬中发现了该基因外显子2的无义突变。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利用大型动物模型研究治疗胱氨酸尿症和其他肾小管疾病的分子方法提供了机会。研究还在进行中，以调查螳螂的半胱氨酸尿症，这是一种受威胁的南美犬种，半胱氨酸尿症的发生率极高。我们分析了美国许多圈养动物的尿样，以确定遗传模式和确定胱氨酸尿症的类型。这些研究正在进行中，部分资金来自莫里斯动物基金会。

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.