Dahan Karin, Devuyst Olivier, Smaers Michèle, Vertommen Didier, Loute Guy, Poux Jean-Michel, Viron Béatrice, Jacquot Christian, Gagnadoux Marie-France, Chauveau Dominique, Büchler Mathias, Cochat Pierre, Cosyns Jean-Pierre, Mougenot Béatrice, Rider Mark H, Antignac Corinne, Verellen-Dumoulin Christine, Pirson Yves
Université Catholique de Louvain, Center for Human Genetics, Brussels, Belgium.
J Am Soc Nephrol. 2003 Nov;14(11):2883-93. doi: 10.1097/01.asn.0000092147.83480.b5.
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.
家族性青少年高尿酸血症肾病（FJHN [MIM 162000]）是一种常染色体显性疾病，其特征为尿酸盐的肾小管处理异常以及慢性间质性肾炎的晚期发展，最终导致进行性肾衰竭。FJHN的一个基因座先前已在16号染色体p12上靠近MCKD2基因座处被确定，MCKD2基因座与多种常染色体显性遗传性髓质囊性肾病（MCKD2）有关。UMOD基因编码Tamm-Horsfall/尿调节蛋白，定位于FJHN/MCKD2关键区域内。最近有报道称，在9个患有FJHN/MCKD2疾病的家族中发现了UMOD基因突变。在11个FJHN家族中鉴定出了UMOD基因突变（10个错义突变和1个框内缺失），其中10个是新发现的突变，集中在高度保守的第4外显子。对来自4个家族的9例患者的尿液样本和肾活检组织进行研究，以探讨UMOD突变对尿调节蛋白表达的影响。在一组肾小管轮廓中，尿调节蛋白的表达明显增加，提示该蛋白在肾小管细胞中蓄积。与该观察结果一致，野生型尿调节蛋白的尿排泄量显著降低。在无UMOD突变的FJHN患者中未观察到后一种现象。总之，本研究表明UMOD第4外显子的突变聚集是FJHN的主要遗传缺陷。UMOD突变可能严重影响尿调节蛋白的功能，导致其在肾小管细胞内异常蓄积并减少尿排泄。
