X-LINKED NEPHROLITHIASIS--MOLECULAR AND CLINICAL STUDIES

描述(改编自申请人摘要)：申请人有 最近描述了一种以肾结石为特征的疾病，肾 近端肾小管功能障碍、肾脏钙质沉着，最终导致肾脏 仅影响男性并以X连锁隐性遗传的失败 图案。尽管对这些患者进行了广泛的生理评估， 本病未发现原发致病异常， X连锁隐性肾结石(XRN)。高钙低尿 分子量(LMW)蛋白尿是本病的共同特征， 而后者在几乎所有携带者女性中也是异常的。 肾钙素，一种抑制钙结石的尿蛋白 结晶，在载体中是结构和功能都不正常的 和XRN患者。据报道，类似的家庭来自 英国、日本、加拿大和意大利。有可能这种疾病可能 代表患有特发性钙的人群中的一定比例 肾结石或慢性肾脏疾病。申请人已本地化 XRN的基因位于一个大约3Mb的区域 X染色体的短臂(Xpll.23)，与该基因相近 英国家庭的疾病(“登特氏病”)映射到不同的 Xp11.22上的基因座。本提案的目的是定义生化 用定位克隆法克隆XRN基因的基础 接近。我们的目标是进一步完善基因定位 准确地说，然后使用YAC和YAC构建该地区的物理地图 P1克隆，并确定候选基因并筛选它们 突变。申请人计划研究的表达和功能的 XRN基因，如果在此期间克隆，则XRN基因 登特氏病也是如此。申请人的研究小组最近 通过增加两个人而得到加强，他们都是 有丰富的分子经验，直接与 建议的工作。作为次要工作，临床研究将继续进行。 同时，为了研究肾钙素在体内产生的异常 XRN，并通过筛查几个大的 低分子量钙结石形成菌群的研究 蛋白尿是XRN和登特氏病的敏感标志。 在这些额外的案例中，将寻找XRN基因的突变。这些 临床研究将在锡拉丘兹进行，并与 芝加哥大学、西北大学和 宾夕法尼亚大学。申请人建议： 阐明这种疾病的病理生理学应该有助于 我们对肾结石和慢性肾功能衰竭的理解。

DESCRIPTION (Adapted from the Applicant's Abstract): The applicant has recently described a disease characterized by nephrolithiasis, renal proximal tubular dysfunction, nephrocalcinosis, and ultimately renal failure, affecting only males and inherited in an X-linked recessive pattern. Despite extensive physiologic evaluation of these patients, no primary pathogenic abnormality could be identified for this disease, X-linked recessive nephrolithiasis (XRN). Hypercalciuria and low molecular-weight (LMW) proteinuria are common features of this disease, and the latter is also abnormal in nearly all carrier females. Nephrocalcin, a urinary protein that inhibits calcium stone crystallization, is structurally and functionally abnormal in carriers and patients with XRN. Similar families have been reported from Britain, Japan, Canada, and Italy. It is possible that this disease may represent some proportion of the population with idiopathic calcium nephrolithiasis or chronic renal disease. The applicant has localized the gene for XRN to a region spanning approximately three Mb on the short arm of the X-chromosome (Xpll.23), close to the gene for a similar disease in British families ("Dent's disease") which maps to a different locus on Xp11.22. The present proposal aims to define the biochemical basis of XRN through cloning the gene using a positional cloning approach. The goals are to refine the genetic localization more precisely, then to construct a physical map of the region using YACs and P1 clones, and to identify candidate genes and screen them for mutations. The applicant plans to study expression and function of the gene for XRN and, if it is cloned during this period, the gene for Dent's disease as well. The applicant's research group has recently been strengthened with the addition of two individuals, both of whom have had extensive molecular experience directly relevant to the proposed work. As a secondary effort, clinical studies will be pursued in parallel, to study the abnormalities in the nephrocalcin produced in XRN, and to identify additional cases of XRN by screening several large populations of calcium stone-formers for low molecular-weight proteinuria, a sensitive marker for both XRN and Dent's disease. Mutations in the XRN gene will be sought in such additional cases. These clinical studies will be performed in Syracuse and in collaboration with colleagues at the University of Chicago, Northwestern University and the University of Pennsylvania. It is suggested by the applicant that elucidation of the pathophysiology of this disease should contribute to our understanding of both nephrolithiasis and chronic renal failure.