Autosomal dominant hyperuricemia, gout, renal cysts, and progressive renal insufficiency are hallmarks of a disease complex comprising familial juvenile hyperuricemic nephropathy and medullary cystic kidney diseases type 1 and type 2. In some families the disease is associated with mutations of the gene coding for uromodulin, but the link between the genetic heterogeneity and mechanism(s) leading to the common phenotype symptoms is not clear. In 19 families, we investigated relevant biochemical parameters, performed linkage analysis to known disease loci, sequenced uromodulin gene, expressed and characterized mutant uromodulin proteins, and performed immunohistochemical and electronoptical investigation in kidney tissues. We proved genetic heterogeneity of the disease. Uromodulin mutations were identified in six families. Expressed, mutant proteins showed distinct glycosylation patterns, impaired intracellular trafficking, and decreased ability to be exposed on the plasma membrane, which corresponded with the observations in the patient's kidney tissue. We found a reduction in urinary uromodulin excretion as a common feature shared by almost all of the families. This was associated with case-specific differences in the uromodulin immunohistochemical staining patterns in kidney. Our results suggest that various genetic defects interfere with uromodulin biology, which could lead to the development of the common disease phenotype. 'Uromodulin-associated kidney diseases' may be thus a more appropriate term for this syndrome.
- MeSH
- bazální membrána patologie ultrastruktura MeSH
- biopsie MeSH
- dítě MeSH
- dna (nemoc) MeSH
- dospělí MeSH
- financování organizované MeSH
- genetická heterogenita MeSH
- genetická vazba MeSH
- hyperurikemie genetika metabolismus MeSH
- hypofýza cytologie MeSH
- imunohistochemie MeSH
- kultivované buňky MeSH
- ledvinové kanálky patologie ultrastruktura MeSH
- ledviny chirurgie metabolismus patologie ultrastruktura MeSH
- lidé MeSH
- lidské chromozomy, pár 16 MeSH
- missense mutace MeSH
- mladiství MeSH
- mukoproteiny genetika metabolismus moč MeSH
- mutační analýza DNA MeSH
- polycystické ledviny autozomálně dominantní genetika MeSH
- polymorfismus délky restrikčních fragmentů MeSH
- rodokmen MeSH
- sekvence nukleotidů MeSH
- syndrom MeSH
- transfekce MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- srovnávací studie MeSH
BACKGROUND: Autosomal-dominant juvenile hyperuricemia, gouty arthritis, medullary cysts, and progressive renal insufficiency are features associated with familial juvenile hyperuricemic nephropathy (FJHN), medullary cystic kidney disease type 1 (MCKD1) and type 2 (MCKD2). MCKD1 has been mapped to chromosome 1q21. FJHN and MCKD2 have been mapped to chromosome 16p11.2. FJHN and MCKD2 are allelic, result from uromodulin (UMOD) mutations and the term uromodulin-associated kidney disease (UAKD) has been proposed for them. Linkage studies also reveal families that do not show linkage to any of the identified loci. To identify additional UAKD loci, we analyzed one of these families, with features suggestive of FJHN. METHODS: Clinical, biochemical, and immunohistochemical investigations were used for phenotype characterization. Genotyping, linkage and haplotype analyses were employed to identify the candidate disease region. Bioinformatics and sequencing were used for candidate gene selection and analyses. RESULTS: We identified a new candidate UAKD locus on chromosome 1q41, bounded by markers D1S3470 and D1S1644. We analyzed and found no linkage to this region in eight additional families, who did not map to the previously established loci. We noted that affected individuals showed, in addition to the characteristic urate hypoexcretion, significant reductions in urinary excretion of calcium and UMOD. Immunohistochemical analysis showed that low UMOD excretion resulted from its reduced expression, which is a different mechanism to intracellular UMOD accumulation observed in cases with UMOD mutations. CONCLUSION: We have mapped a new candidate UAKD locus and shown that UAKD may be a consequence of various defects affecting uromodulin biology.
- MeSH
- chronická renální insuficience genetika metabolismus MeSH
- dítě MeSH
- dospělí MeSH
- financování organizované MeSH
- genetická vazba MeSH
- genotyp MeSH
- hyperurikemie genetika metabolismus MeSH
- ledviny metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- lidské chromozomy, pár 1 MeSH
- mapování chromozomů MeSH
- mladiství MeSH
- mukoproteiny genetika metabolismus MeSH
- rodokmen MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- Check Tag
- dítě MeSH
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
