Mutations in the SLC2A9 gene cause hyperuricosuria and hyperuricemia in the dog.
Mutations in the SLC2A9 gene cause hyperuricosuria and hyperuricemia in the dog.
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DOI：
10.1371/journal.pgen.1000246
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发表时间：
2008-11
期刊：
影响因子：
4.5
通讯作者：
Ling, G. V.
中科院分区：
文献类型：
--
作者：
Bannasch, Danika;Safra, Noa;Young, Amy;Karmi, Nili;Schaible, R. S.;Ling, G. V.
尿囊素是所有哺乳动物体内嘌呤分解代谢的最终产物，除了人类、类人猿和一种狗--斑点狗。人类和斑点狗在嘌呤降解过程中会产生尿酸，这会导致血液和尿液中尿酸水平升高，并可能导致这两个物种的重大疾病。斑点狗的缺陷是由于尿酸在肝脏和肾脏近端小管中的运输效率低下所致。高尿酸尿症和高尿酸血症(HUU)是一种简单的常染色体隐性遗传性状，所有的斑点狗都是纯合的。因此，为了定位该基因座，采用了异种回交。连锁作图将沪性状定位于CFA03，排除了明显的尿酸转运蛋白1基因SLC22A12。位置克隆将该基因座放置在2.5Mb的最小间隔内，LOD得分为17.45。在所有斑点狗中，333kb的临界区间只包含4个基因是纯合的。SLC2A9基因的序列和表达分析表明，有三个可能的突变，一个错义突变(G616T；C188F)和两个启动子突变，这些突变一起似乎降低了其中一个亚型的表达水平。错义突变与斑点狗的高尿酸尿症有关，而启动子SNPs出现在其他未受影响的犬种中。当来自其他几个品种的高尿酸尿症犬被发现具有与斑点狗相同的突变组合时，这些变化的致病性质得到了验证。斑点狗的高尿酸尿症和高尿酸血症模型强调了SLC2A9在哺乳动物尿酸运输中的重要性。动物在尿液中排泄废物。当大多数哺乳动物代谢称为嘌呤的化合物时，它们会在尿液中产生尿囊素作为废物。人类、类人猿和斑点狗会产生一种不同的分解产物--尿酸。这会导致尿液和血液中尿酸含量过高。在人类中，这可能会导致肾结石和痛风等疾病，并可能导致高血压。在斑点狗中，高尿酸水平会导致膀胱结石，通常必须通过手术清除。人类和类人猿体内尿酸水平升高的原因与达尔马提亚犬不同。在这里，我们报告了达尔马提亚人疾病的遗传原因。来自不同品种的狗都有这种变化，这表明这种变化早于狗品种的分离。导致斑点狗尿酸排泄的基因对控制人类血液中的尿酸含量很重要，因此对人类疾病也很重要。目前尚不清楚为什么人类和类人猿进化到排泄尿酸，但似乎一些狗已经发展出一种不同的机制，导致相同的结果：尿液和血液尿酸水平升高。
Allantoin is the end product of purine catabolism in all mammals except humans, great apes, and one breed of dog, the Dalmatian. Humans and Dalmatian dogs produce uric acid during purine degradation, which leads to elevated levels of uric acid in blood and urine and can result in significant diseases in both species. The defect in Dalmatians results from inefficient transport of uric acid in both the liver and renal proximal tubules. Hyperuricosuria and hyperuricemia (huu) is a simple autosomal recessive trait for which all Dalmatian dogs are homozygous. Therefore, in order to map the locus, an interbreed backcross was used. Linkage mapping localized the huu trait to CFA03, which excluded the obvious urate transporter 1 gene, SLC22A12. Positional cloning placed the locus in a minimal interval of 2.5 Mb with a LOD score of 17.45. A critical interval of 333 kb containing only four genes was homozygous in all Dalmatians. Sequence and expression analyses of the SLC2A9 gene indicated three possible mutations, a missense mutation (G616T;C188F) and two promoter mutations that together appear to reduce the expression levels of one of the isoforms. The missense mutation is associated with hyperuricosuria in the Dalmatian, while the promoter SNPs occur in other unaffected breeds of dog. Verification of the causative nature of these changes was obtained when hyperuricosuric dogs from several other breeds were found to possess the same combination of mutations as found in the Dalmatian. The Dalmatian dog model of hyperuricosuria and hyperuricemia underscores the importance of SLC2A9 for uric acid transport in mammals. Animals excrete waste products in their urine. When most mammals metabolize compounds, called purines, they produce allantoin as one waste product in their urine. Humans, great apes, and Dalmatian dogs produce a different breakdown product, uric acid. This leads to high levels of uric acid in the urine and blood. In humans, this can result in diseases such as kidney stones and gout and may cause hypertension. In Dalmatians, high uric acid levels result in bladder stones that often have to be removed surgically. The cause of high uric acid levels in humans and great apes is not the same as in the Dalmatian dog. Here we report the genetic cause of the Dalmatian condition. This change is shared by dogs from unrelated breeds, indicating that it predates the separation of dog breeds. The gene that causes excretion of uric acid in Dalmatians is important for controlling the amount of uric acid in human blood and is therefore important for human diseases. It is not clear why humans and great apes have evolved to excrete uric acid, but it appears that some dogs have developed a different mechanism that leads to the same result: elevations in urine and blood uric acid levels.
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影响因子：
13.6
作者：
Feig, Daniel I.;Mazzali, Marilda;Johnson, Richard J.
通讯作者：
Johnson, Richard J.
DOI：
10.1016/0305-0491(85)90381-5
发表时间：
1985-01-01
影响因子：
2.2
作者：
FRIEDMAN, TB;POLANCO, GE;MAYLE, JE
通讯作者：
MAYLE, JE
影响因子：
64.8
作者：
Enomoto, A;Kimura, H;Endou, H
通讯作者：
Endou, H
影响因子：
7
作者：
Ng, PC;Henikoff, S
通讯作者：
Henikoff, S
影响因子：
16.2
作者：
Brandstätter A;Kiechl S;Kollerits B;Hunt SC;Heid IM;Coassin S;Willeit J;Adams TD;Illig T;Hopkins PN;Kronenberg F
通讯作者：
Kronenberg F