A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin
A cluster of mutations in the UMOD gene causes familial juvenile hyperuricemic nephropathy with abnormal expression of uromodulin
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DOI：
10.1097/01.asn.0000092147.83480.b5
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发表时间：
2003-11-01
影响因子：
13.6
通讯作者：
Pirson, Y
中科院分区：
文献类型：
--
作者：
Dahan, K;Devuyst, O;Pirson, Y
家族性幼年型高尿酸血症肾病（FJHN [MIM 162000]）是一种常染色体显性遗传疾病，其特征为肾小管对尿酸盐的异常处理和慢性间质性肾炎的晚期发展，导致进行性肾衰竭。FJHN的基因座先前被确定在染色体16 p12上靠近MCKD 2基因座，其负责多种常染色体显性髓样囊性肾病（MCKD 2）。编码Tamm-Horsfall/尿调蛋白的基因UMOD在FJHN/MCKD 2关键区域内作图。最近在9个FJHN/MCKD 2病家族中报告了UMOD突变。已在11个FJHN家族中鉴定出UMOD突变（10个错义和1个框内缺失），其中10个是高度保守的外显子4中的新聚集。尿调素表达的UMOD突变的后果进行了研究，在尿液样本和肾活检从四个家庭的九名患者。有一个显着增加表达的尿调素在一组肾小管概况，表明在肾小管细胞中的蛋白质的积累。与该观察结果一致，野生型尿调节素的尿排泄显著减少。在无UMOD突变的FJHN患者中未观察到后一结果。总之，这项研究指出，突变聚集在外显子4的UMOD作为一个主要的遗传缺陷FJHN。UMOD的突变可能严重影响尿调蛋白的功能，导致肾小管细胞内异常蓄积和尿排泄减少。
Familial juvenile hyperuricemic nephropathy (FJHN [MIM 162000]) is an autosomal-dominant disorder characterized by abnormal tubular handling of urate and late development of chronic interstitial nephritis leading to progressive renal failure. A locus for FJHN was previously identified on chromosome 16p12 close to the MCKD2 locus, which is responsible for a variety of autosomal-dominant medullary cystic kidney disease (MCKD2). UMOD, the gene encoding the Tamm-Horsfall/uromodulin protein, maps within the FJHN/MCKD2 critical region. Mutations in UMOD were recently reported in nine families with FJHN/ MCKD2 disease. A mutation in UMOD has been identified in 11 FJHN families (10 missense and one in-frame deletion)-10 of which are novel-clustering in the highly conserved exon 4. The consequences of UMOD mutations on uromodulin expression were investigated in urine samples and renal biopsies from nine patients in four families. There was a markedly increased expression of uromodulin in a cluster of tubule profiles, suggesting an accumulation of the protein in tubular cells. Consistent with this observation, urinary excretion of wild-type uromodulin was significantly decreased. The latter findings were not observed in patients with FJHN without UMOD mutations. In conclusion, this study points to a mutation clustering in exon 4 of UMOD as a major genetic defect in FJHN. Mutations in UMOD may critically affect the function of uromodulin, resulting in abnormal accumulation within tubular cells and reduced urinary excretion.