X-LINKED NEPHROLITHIASIS--MOLECULAR AND CLINICAL STUDIES

X连锁肾结石——分子和临床研究

• 批准号: 2770430
• 负责人: STEVEN J SCHEINMAN
• 金额: $ 28.36万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-17 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2770430
• 关键词: calcium binding protein; family genetics; genetic disorder; genetic mapping; genetic markers; human genetic material tag; human subject; hypercalciuria; molecular cloning; molecular pathology; nephrolithiasis; sex linked trait

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.

描述（改编自申请人摘要）：申请人已 最近描述了一种以肾结石为特征的疾病， 近端肾小管功能障碍，肾钙质沉着，最终肾 失败，只影响男性和遗传在一个X连锁隐性 格局尽管对这些患者进行了广泛的生理评估， 该疾病未发现原发性致病异常， X连锁隐性肾结石（XRN）。高钙尿和低钙尿 分子量（LMW）蛋白尿是这种疾病的常见特征， 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，是结构和功能异常的载体 和XRN患者。据报道，类似的家庭 英国、日本、加拿大和意大利。这种疾病可能 代表了特发性钙离子缺乏症人群的一部分， 肾结石或慢性肾病。申请人已本地化 将XRN基因转移到基因组上跨越大约三Mb的区域 X染色体的短臂（Xpll.23），靠近类似的基因， 英国家庭中的一种疾病（“登特病”）， Xp11.22上的基因座。本提案旨在定义生物化学 XRN的基础，通过使用定位克隆来克隆基因 approach.我们的目标是进一步完善基因定位 准确地说，然后使用YAC构建该地区的物理地图， P1克隆，并鉴定候选基因， 突变。申请人计划研究的表达和功能， XRN的基因，如果在此期间克隆了XRN的基因， 丹特氏病也是。申请人的研究小组最近 增加了两个人，两人都是 有着广泛的分子学经验， 提议的工作。作为次要的努力，将进行临床研究， 平行地，研究肾钙蛋白产生的异常， XRN，并通过筛查几个大的XRN病例来确定其他XRN病例， 低分子量钙结石形成者群体 蛋白尿是XRN和Dent病的敏感标志物。 在这种额外的情况下，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有助于 我们对肾结石和慢性肾衰竭的理解。