Academic Endocrine Unit, Oxford Centre for Diabetes Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Headington, Oxford, OX3 7LJ, UK.
Hum Genet. 2011 Jan;129(1):51-8. doi: 10.1007/s00439-010-0897-1. Epub 2010 Oct 26.
Familial juvenile hyperuricaemic (gouty) nephropathy (FJHN), is an autosomal dominant disease associated with a reduced fractional excretion of urate, and progressive renal failure. FJHN is genetically heterogeneous and due to mutations of three genes: uromodulin (UMOD), renin (REN) and hepatocyte nuclear factor-1beta (HNF-1β) on chromosomes 16p12, 1q32.1, and 17q12, respectively. However, UMOD, REN or HNF-1β mutations are found in only approximately 45% of FJHN probands, indicating the involvement of other genetic loci in approximately 55% of probands. To identify other FJHN loci, we performed a single nucleotide polymorphism (SNP)-based genome-wide linkage analysis, in six FJHN families in whom UMOD, HNF-1β and REN mutations had been excluded. Parametric linkage analysis using a 'rare dominant' model established linkage in five of the six FJHN families, with a LOD score >+3, at 0% recombination, between FJHN and SNPs at chromosome 2p22.1-p21. Analysis of individual recombinants in two unrelated affected individuals defined a approximately 5.5 Mbp interval, flanked telomerically by SNP RS372139 and centromerically by RS896986 that contained the locus, designated FJHN3. The interval contains 28 genes, and DNA sequence analysis of the most likely candidate, solute carrier family 8 member 1 (SLC8A1), did not identify any abnormalities in the FJHN3 probands. FJHN3 is likely located within a approximately 5.5 Mbp interval on chromosome 2p22.1-p21, and identifying the genetic abnormality will help to further elucidate mechanisms predisposing to gout and renal failure.
家族性青少年高尿酸血症（痛风性）肾病（FJHN）是一种常染色体显性遗传疾病，与尿酸排泄分数降低和进行性肾功能衰竭有关。FJHN 在遗传上具有异质性，是由三个基因的突变引起的：尿调蛋白（UMOD）、肾素（REN）和肝细胞核因子-1β（HNF-1β），分别位于 16p12、1q32.1 和 17q12 染色体上。然而，在大约 45%的 FJHN 先证者中发现 UMOD、REN 或 HNF-1β 突变，这表明在大约 55%的先证者中存在其他遗传位点的参与。为了鉴定其他 FJHN 位点，我们对 6 个排除 UMOD、HNF-1β 和 REN 突变的 FJHN 家系进行了基于单核苷酸多态性（SNP）的全基因组连锁分析。使用“罕见显性”模型的参数连锁分析在 6 个 FJHN 家系中的 5 个家系中建立了连锁，LOD 评分>+3，在 0%重组率下，FJHN 与染色体 2p22.1-p21 上的 SNP 之间存在连锁。在两个无关受影响个体的个体重组分析中，定义了一个大约 5.5 Mbp 的间隔，在 telomere 端由 SNP RS372139 侧翼，在 centromere 端由 RS896986 侧翼，该间隔包含该位点，命名为 FJHN3。该间隔包含 28 个基因，对 FJHN3 先证者中最可能的候选基因溶质载体家族 8 成员 1（SLC8A1）的 DNA 序列分析未发现任何异常。FJHN3 可能位于染色体 2p22.1-p21 上的一个大约 5.5 Mbp 的间隔内，确定遗传异常将有助于进一步阐明导致痛风和肾功能衰竭的机制。
