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- Title
Alterations of uromodulin biology: a common denominator of the genetically heterogeneous FJHN/MCKD syndrome.
- Authors
Vylet'al, P.; Kublová, M.; Kalbáčová, M.; Hodaňová, K.; Barešová, V.; Stibůrková, B.; Sikora, J.; Hůlková, H.; Živný, J.; Majewski, J.; Simmonds, A.; Fryns, J.-P.; Venkat-Raman, G.; Elleder, M.; Kmoch, S.
- Abstract
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.Kidney International (2006) 70, 1155–1169. doi:10.1038/sj.ki.5001728; published online 2 August 2006
- Subjects
HYPERURICEMIA; GLYCOSYLATION; PHENOTYPES; KIDNEY tubules; CYSTIC kidney disease; DISEASES
- Publication
Kidney International, 2006, Vol 70, Issue 6, p1155
- ISSN
0085-2538
- Publication type
Article
- DOI
10.1038/sj.ki.5001728