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: 6531816
• 负责人: Thomas C Hart
• 金额: $ 33.32万
• 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/6531816
• 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(申请人提供)：家族性痛风肾病(FGN)是一种罕见的肾脏疾病，其特征是尿酸排泄减少，性早熟和痛风，以及慢性肾功能衰竭导致终末期肾脏疾病。FGN是作为常染色体显性遗传遗传的，临床表现多种多样，对治疗的反应不可预测，对疾病的病理生理学了解甚少。这项建议的目标是确定导致FGN的基因(S)，并描述这种疾病的临床表现。 我们已经确定了两个FGN大家族，这为确定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基因亚区定位于一个家系染色体16p的2.0 cM区域。来自第二个较小家系的连锁数据与较大的候选区间一致。进一步的研究将确定这两个家族中是否有相同的基因导致FGN。我们将FGN定位到的遗传区间没有得到很好的描述。该区域的遗传和物理图谱不完整，没有明显的FGN候选基因。 我们提出了一种临床和实验室相结合的方法来确定与FGN有关的基因(S)。我们将纵向跟踪受影响的家庭成员，以更好地描述FGN的临床表现(具体目标1)。为了识别FGN基因(特定目标2)，我们提出了一种分层策略来1)。明确和整合候选区间的遗传图谱和物理图谱(S)，2)。继续进行连锁研究以缩小候选区间(S)，以及3)。对间隔内的基因进行系统评估，以确定导致这些家系FGN的基因突变(S)。 特定基因突变的鉴定将提供一项重要发现，将(A)阐明尿酸肾小管运输的重要方面，(B)提供对间质性肾脏疾病和慢性肾功能衰竭的了解，以及(C)有助于更好地确定高尿酸血症、尿酸排泄和肾功能衰竭发展之间的关系。这些研究的完成将使我们能够对FGN患者进行症状前诊断，并增强我们评估现有治疗策略以及开发新的、更有效的干预策略的能力。