Mutations of the UMOD gene are responsible for medullary cystic kidney disease 2 and familial juvenile hyperuricaemic nephropathy

Abstract

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.

Uromodulin storage diseases: Clinical aspects and mechanisms

“…After the seminal observation by Hart et al, 6 a few confirmatory reports have been published. [7][8][9][10][11][12][13][14] UMOD mutations also were reported in a family with autosomal dominant GCKD.…”

“…[32][33][34][35][36][37][38] More recently, the clinical relevance of uromodulin has been emphasized by evidence that MCKD2 and FJHN arise from mutations of the UMOD gene. 6 …”

“…Overall, 8 families with MCKD2 and 24 families with FJHN have been described. [6][7][8][9][10][11][12][13] A common motif to all reports is that so many overlapping symptoms between MCKD2 and FJHN are present that separation between these 2 entities seems artful and probably clinically useless. For this reason, in the following sections devoted to the clinical description of UMOD-related diseases and genotype-phenotype correlations, MCKD2 and FJHN are discussed together.…”

“…In parallel to these developments, seminal work by Hart et al 6 led to the discovery of mutations in UMOD, the gene encoding uromodulin, in large pedigrees with MCKD type 2 (MCKD2; Mendelian Inheritance in Man 603860) and familial juvenile hyperuricemic nephropathy (FJHN; Mendelian Inheritance in Man 162000). This finding later was confirmed by other groups [7][8][9][10][11][12][13][14] and recently was extended to autosomal dominant GCKD.…”

Analysis of the human urine endogenous peptides by nanoparticle extraction and mass spectrometry identification

“…Uromodulin is a major glycoprotein produced by kidney cells [54] and it was recently found to be responsible for the clinical changes in interstitial renal disease, polyuria, and hyperuricaemia [55]. Dermcidin is an antibiotic peptide secreted by sweat glands first reported in 2001 [56].…”