Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy
Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy
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DOI：
10.1136/jmg.39.12.882
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发表时间：
2002-12-01
影响因子：
4
通讯作者：
Bleyer, AJ
中科院分区：
文献类型：
--
作者：
Hart, TC;Gorry, MC;Bleyer, AJ
简介：髓质囊性肾病2（MCKD 2）和家族性幼年高尿酸血症肾病（FJHN）均为常染色体显性遗传性肾病，其特征为幼年高尿酸血症、痛风和进行性肾衰竭。这两种疾病的临床特征在存在和严重程度上有所不同。通常，只有在发生重大病理变化后，才有可能做出明确诊断。遗传连锁研究将这两种疾病的基因定位在染色体16 p11-p13的重叠区域。这些临床和遗传学研究结果表明，这些条件可能是allelic.Aim：确定基因和相关的突变（S）负责FJHN和MCKD 2。方法：两个大的，多代分离FJHN的家庭进行了遗传连锁和单倍型分析，亚定位染色体16 p FJHN基因位点。为了允许候选区间的细化和候选基因的定位，开发了候选区域的综合物理和遗传图谱。进行候选基因的DNA测序以检测受FJHN影响的受试者的突变（三个不相关的家庭）和MCKD 2结果：在3个FJHN家系和1个MCKD 2家系中发现了4个新的UMOD基因突变，这些突变与疾病表型分离。这些数据提供了第一个直接证据，MCKD 2和FJHN产生于UMOD基因的突变，是等位基因疾病。UMOD是GPI锚定的糖蛋白，是正常尿液中最丰富的蛋白质。我们推测UMOD的突变破坏了UMOD的三级结构，并导致MCKD 2和FJHN中发现的间质性肾病、多尿和高尿酸血症的临床变化。
Introduction: Medullary cystic kidney disease 2 (MCKD2) and familial juvenile hyperuricaemic nephropathy (FJHN) are both autosomal dominant renal diseases characterised by juvenile onset of hyperuricaemia, gout, and progressive renal failure. Clinical features of both conditions vary in presence and severity. Often definitive diagnosis is possible only after significant pathology has occurred. Genetic linkage studies have localised genes for both conditions to overlapping regions of chromosome 16p11-p13. These clinical and genetic findings suggest that these conditions may be allelic.Aim: To identify the gene and associated mutation(s) responsible for FJHN and MCKD2.Methods: Two large, multigenerational families segregating FJHN were studied by genetic linkage and haplotype analyses to sublocalise the chromosome 16p FJHN gene locus. To permit refinement of the candidate interval and localisation of candidate genes, an integrated physical and genetic map of the candidate region was developed. DNA sequencing of candidate genes was performed to detect mutations in subjects affected with FJHN (three unrelated families) and MCKD2 (one family).Results: We identified four novel uromodulin (UMOD) gene mutations that segregate with the disease phenotype in three families with FJHN and in one family with MCKD2.Conclusion: These data provide the first direct evidence that MCKD2 and FJHN arise from mutation of the UMOD gene and are allelic disorders. UMOD is a GPI anchored glycoprotein and the most abundant protein in normal urine. We postulate that mutation of UMOD disrupts the tertiary structure of UMOD and is responsible for the clinical changes of interstitial renal disease, polyuria, and hyperuricaemia found in MCKD2 and FJHN.