Homozygosity for uromodulin disorders:: FJHN and MCKD-type 2
Homozygosity for uromodulin disorders:: FJHN and MCKD-type 2
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DOI：
10.1111/j.1523-1755.2004.00774.x
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发表时间：
2004-08-01
影响因子：
19.6
通讯作者：
Lens, XM
中科院分区：
文献类型：
--
作者：
Rezende-Lima, W;Parreira, KS;Lens, XM
背景常染色体显性遗传型髓质囊性肾病2型（MCKD 2）和家族性青少年高尿酸血症肾病（FJHN）是具有常染色体显性遗传和共同特征的遗传性肾脏疾病，包括多尿、进行性肾衰竭和异常尿酸盐处理，导致高尿酸血症和痛风。UMOD基因的突变破坏了尿调素的三级结构，导致MCKD 2和FJHN。对一个患有MCKD的西班牙大家族进行了单倍型分析，以确定与MCKD 2基因座的遗传连锁。通过UMOD基因的直接测序进行突变检测。采用十二烷基硫酸钠-聚丙烯酰胺凝胶电泳（SDS-PAGE）和蛋白质印迹法检测尿中Tamm-Horsfall蛋白水平。证明了与MCKD 2基因座的连锁（LOD评分：4.13），在外显子4中发现了已知的致病性尿调蛋白突变，对应于Cys 255 Tyr，破坏了蛋白质的轻链结合结构域。在这个近亲家族中，有三名患者为C255 Y突变纯合子，和多个杂合子的情况下，允许与一个或两个突变等位基因相关的MCKD表型进行比较。纯合子个体存活至成年，但与杂合子个体相比，出现高尿酸血症的时间更早，进展至终末期肾病的速度更快。Western分析显示，与正常对照组患者相比，一名杂合子患者的尿THP水平较低，两名患者的肾功能均正常。这项研究表明，具有两个UMOD突变的个体是可行的，但他们平均比杂合子有更严重的疾病。这个家族揭示了这种疾病的可能发病机制。
Background. Autosomal-dominant medullary cystic kidney disease type 2 (MCKD2) and familial juvenile hyperuricemic nephropathy (FJHN) are heritable renal diseases with autosomal-dominant transmission and shared features, including polyuria, progressive renal failure, and abnormal urate handling, which leads to hyperuricemia and gout. Mutations of the UMOD gene, disrupting the tertiary structure of uromodulin, cause MCKD2 and FJHN.Methods. Haplotype analysis of a large Spanish family with MCKD was carried out to determinate genetic linkage to MCKD2 locus. Mutation detection was performed by direct sequencing of the UMOD gene. The level of Tamm-Horsfall protein in the urine was measured by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot analysis.Results. Linkage to MCKD2 locus was demonstrated (LOD score: 4.13), and a known pathogenic uromodulin mutation was found in exon 4, corresponding to Cys255Tyr, disrupting the light chain binding domain of the protein. In this consanguineous family there were three patients homozygous for the C255Y mutation, and multiple heterozygous cases, allowing the MCKD phenotypes associated with one or two mutant alleles to be compared. The homozygous individuals survived to adulthood, although presenting an earlier onset of hyperuricemia and faster progression to end-stage renal disease than heterozygous individuals. Western analysis revealed lower levels of urine THP in one heterozygous patient compared with a normal control patient, both with normal renal function.Conclusion. The study shows that individuals with two UMOD mutations are viable, but they do have more severe disease on average than heterozygotes. This family sheds light on the possible disease mechanism in this disorder.