GENETIC MAPPING IN THE HYPERCALCIURIC STONE-FORMING RAT

高钙结石大鼠的基因图谱

• 批准号: 6664323
• 负责人: STEVEN J SCHEINMAN
• 金额: $ 1万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6664323
• 关键词: disease /disorder model; genetic mapping; genetic markers; hypercalciuria; inbreeding; laboratory rat; nephrolithiasis; quantitative trait loci

Idiopathic hypercalciuria (IH) is the most common metabolic abnormality associated with kidney stones in humans, and as many as 45 percent of patients with IH have a family history of nephrolithiasis. Defined subsets of patients with hypercalciuric nephrolithiasis include those with autosomal or X linked inheritance, but overall the phenotype of human IH is that of a complex, polygenic disease. A full-scale investigation of the genetics of human hypercalciuria would be made difficult by the large number of families required, dietary variables, and number of metabolic subsets described in patients with IH. However, an animal model exists in the genetic hypercalciuric stone-forming (GHS) rat, which is now in its 51st generation of inbreeding. The physiology of hypercalciuria in this model has been extensively characterized and resembles human IH in many important respects. The GHS rat colony was established by Dr. David Bushinsky by selectively breeding the most hypercalciuric littermates of each generation, and is likely to be enriched in alleles for genes that contribute to hypercalciuria. A robust armamentarium of tools for genetic and physical mapping in rats is now available, and expanding rapidly. The goal of this project is to map genes determining hypercalciuria in the GHS rat. The first aim of this project is to identify quantitative trait loci (QTL) linked to hypercalciuria through QTL mapping. This analysis will make use of selective genotyping of an F2 intercross between GHS and normocalciuric Wistar-Kyoto (WKY) rats, using simple sequence-length polymorphisms (SSLPs). The second aim is to refine the QTL localization further by constructing and analyzing congenic strains of rats. We have made substantial progress towards a whole-genome scan in an initial F2 of 156 rats, and have identified one QTL on chromosome 1 that meets conservative criteria for significance (LOD 4.5) and two loci that meet criteria "suggestive" of linkage. More precise localization should eventually make possible physical mapping and positional cloning of genes contributing strongly to hypercalciuria, which will allow for future work in which homologues of these genes can be studied to determine their role in human idiopathic hypercalciuria.

特发性高钙尿症（IH）是人类最常见的与肾结石相关的代谢异常，多达45%的IH患者有肾结石家族史。 高尿钙肾结石患者的定义子集包括那些具有常染色体或X连锁遗传的患者，但总体而言，人类IH的表型是一种复杂的多基因疾病。 由于需要大量家庭、饮食变量以及IH患者中描述的代谢子集数量，对人类高钙尿症的遗传学进行全面调查将变得困难。 然而，在遗传性高钙尿石形成（GHS）大鼠中存在一种动物模型，该模型现在处于近亲繁殖的第51代。该模型中高钙尿症的生理学已被广泛表征，并且在许多重要方面与人类IH相似。 GHS大鼠群由大卫布什斯基博士通过选择性繁殖每代最高钙尿症的同窝仔建立，并且可能富含导致高钙尿症的基因的等位基因。 一个强大的医疗器械的工具，遗传和物理映射的大鼠现在是可用的，并迅速扩大。这个项目的目标是定位基因决定高钙尿症的GHS大鼠。 本项目的第一个目的是通过QTL定位来确定与高钙尿症相关的数量性状位点。 该分析将使用简单序列长度多态性（SSLP）对GHS和正常钙尿Wistar-Kyoto（WKY）大鼠之间的F2杂交进行选择性基因分型。 第二个目标是通过构建和分析大鼠的同类品系来进一步完善QTL定位。 我们已经取得了实质性的进展，对全基因组扫描在最初的F2的156只大鼠，并确定了一个QTL的1号染色体上，符合保守的显着性标准（LOD 4.5）和两个位点，符合标准的“暗示”的连锁。 更精确的定位，最终可能的物理映射和定位克隆的基因有助于强烈的高钙尿症，这将使未来的工作，这些基因的同源物可以研究，以确定其在人类特发性高钙尿症的作用。