Genotype and Phenotype of Familial Nephropathy with Gout

痛风家族性肾病的基因型和表型

• 批准号: 6926996
• 负责人: Mary L. Marazita
• 金额: $ 24.91万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-15 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6926996
• 关键词: autosomal dominant trait; chronic renal failure; clinical research; disease /disorder classification; early diagnosis; family genetics; gene mutation; genetic mapping; gout; human subject; interstitial nephritis; linkage mapping; pathologic process; patient oriented research; renal tubular transport; urate

DESCRIPTION (provided by applicant): Familial Nephropathy with Gout (FGN) is a rare kidney disorder characterized by reduced fractional excretion of uric acid, precocious and tophaceous gout, and development of chronic renal failure leading to end-stage renal disease. FGN is transmitted as an autosomal dominant trait, clinical fmdings are variable, response to treatment not predictable and the disease pathophysiology is poorly understood. The goals of this proposal are to identify the gene(s) responsible for FGN and to characterize the clinical manifestations of this condition. We have identified two large families with FGN providing unique opportunities to characterize clinical manifestations and progression of FGN and to identify the gene responsible. Our preliminary studies sublocalize an FGN gene to a 2.0 cM region of chromosome l6p in one family. Linkage data from a second, smaller family is consistent with a broader candidate interval. Additional studies will determine if the same gene is responsible for FGN in both families. The genetic interval we have mapped FGN to is not well characterized. Genetic and physical maps of the region are incomplete and there are no obvious candidate genes for FGN. We propose an integrated clinical and laboratory approach to identify the gene(s) responsible for FGN. We will longitudinally follow affected family members to better characterize clinical manifestations of FGN (Specific Aim#1). To identify the FGN gene (Specific Aim #2) we propose a hierarchical strategy to 1). Clarify and integrate genetic and physical maps of the candidate interval(s), 2). Continue linkage studies to narrow the candidate interval(s), and 3). Systematically evaluate genes within the interval to identify the gene mutation(s) responsible for FGN in these families. Identification of the specific gene mutation will provide an important discovery that will (a) elucidate important aspects of uric acid tubular transport, (b) provide an understanding of interstitial kidney disease and chronic renal failure, and (c) help to better define relationships between hyperuricemia, uric acid excretion, and the development of renal failure. Completion of these studies will permit pre-symptomatic diagnosis for individuals with FGN and enhance our ability to evaluate current treatment strategies as well as to develop new, more effective intervention strategies.

描述（由申请人提供）：家族性痛风肾病（FGN）是一种罕见的肾脏疾病，其特征是尿酸排泄分数减少、早熟痛风石性痛风以及导致终末期肾病的慢性肾功能衰竭。 FGN 作为常染色体显性性状传播，临床发现变化多端，对治疗的反应不可预测，并且对该疾病的病理生理学了解甚少。该提案的目标是确定导致 FGN 的基因并描述这种情况的临床表现。 我们已经确定了两个 FGN 大家族，这为表征 FGN 的临床表现和进展以及确定相关基因提供了独特的机会。我们的初步研究将 FGN 基因亚定位于一个家族中染色体 16p 的 2.0 cM 区域。来自第二个较小家族的连锁数据与更广泛的候选区间一致。其他研究将确定是否同一基因导致两个家族中的 FGN。我们将 FGN 映射到的遗传区间尚未得到很好的表征。该区域的遗传和物理图谱不完整，并且没有明显的 FGN 候选基因。 我们提出了一种综合的临床和实验室方法来识别导致 FGN 的基因。我们将纵向追踪受影响的家庭成员，以更好地表征 FGN 的临床表现（具体目标#1）。为了识别 FGN 基因（具体目标 #2），我们提出了一种分层策略 1)。澄清并整合候选区间的遗传和物理图谱，2)。继续进行连锁研究以缩小候选区间，并且 3)。系统评估该区间内的基因，以确定这些家族中导致 FGN 的基因突变。 特定基因突变的鉴定将提供一个重要的发现，它将（a）阐明尿酸肾小管转运的重要方面，（b）提供对间质性肾病和慢性肾衰竭的理解，以及（c）帮助更好地确定高尿酸血症、尿酸排泄和肾衰竭发展之间的关系。这些研究的完成将允许对 FGN 个体进行症状前诊断，并增强我们评估当前治疗策略以及开发新的、更有效的干预策略的能力。