The Long-Evans Agouti (LEA/Tohm) rat has recently been established as a new rat model of type 2 diabetes. The onset of diabetes mellitus was observed only in male LEA/Tohm rats; however, urinary glucose appeared before the onset of diabetes. To clarify the genetic basis of urinary glucose, we performed genetic linkage analysis using (BN × LEA) F2 intercross progeny. A recessively acting locus responsible for urinary glucose excretion (ugl) was mapped to a 7.9 Mb region of chromosome 10, which contains the cystinosin (Ctns) gene. The Ctns gene encodes the cystine transporter, which transports cystine out of the lysosome and is responsible for nephropathic cystinosis in humans. Sequence analysis identified a 13-bp deletion in the Ctns gene, leading to a truncated and loss-of-function protein, which cause cystine accumulation in various tissues. We also developed a novel congenic rat strain harboring the Ctnsugl mutation on the F344 genetic background. Phenotypic analysis of F344-Ctnsugl rats indicated that the incidence of urinary glucose was 100% in both males and females at around 40 weeks of age, and marked cystine accumulation was observed in the tissues, as well as remarkable renal lesions and cystine crystals in the lysosomes of the renal cortex. Furthermore, treatment with cysteamine depleted the cystine contents in F344-Ctnsugl rat embryonic fibroblasts. These results indicated that the F344-Ctnsugl rat provides a novel rat model of cystinosis, which allows not only a better understanding of the pathogenesis and pathophysiology of cystinosis but will also contribute to the development of new therapies.

中文翻译：

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Ctns基因的缺失会导致LEA / Tohm大鼠肾小管功能障碍和胱氨酸蓄积。

Long-Evans Agouti（LEA / Tohm）大鼠最近已被建立为2型糖尿病的新大鼠模型。仅在雄性LEA / Tohm大鼠中观察到糖尿病的发作。然而，尿糖在糖尿病发作之前就出现了。为了阐明尿葡萄糖的遗传基础，我们使用（BN×LEA）F2杂交后代进行了遗传连锁分析。一个隐性起作用的位点负责尿葡萄糖排泄（ugl）被定位到10号染色体的7.9 Mb区域，该区域包含胱氨酸（Ctns）基因。Ctns基因编码胱氨酸转运蛋白，其将胱氨酸转运出溶酶体，并导致人类肾病性胱氨酸病。序列分析确定了Ctns基因中13 bp的缺失，导致蛋白被截断和功能丧失，从而导致胱氨酸在各种组织中积累。我们还开发了一种新型的同系大鼠品系，其在F344遗传背景上具有Ctnsugl突变。对F344-Ctnsugl大鼠的表型分析表明，在40周龄左右，雄性和雌性中尿葡萄糖的发生率均为100％，并且在组织中观察到明显的胱氨酸蓄积，并且在大鼠中观察到明显的肾脏病变和胱氨酸晶体。肾皮质溶酶体。此外，用半胱胺处理可减少F344-Ctnsugl大鼠胚胎成纤维细胞中的胱氨酸含量。这些结果表明F344-Ctnsugl大鼠提供了一种新型的胱氨酸病大鼠模型，它不仅可以更好地了解胱氨酸病的发病机理和病理生理，而且还将有助于新疗法的发展。