Familial juvenile hyperuricemic nephropathy (FJHN) : clinical phenotype, gene cloning and UMOD gene mutation identification
(2004)
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- Patients with familial juvenile hyperuricemic nephropathy (FJHN) typically present with the triad of early hyperuricemia during childhood, gout and chronic interstitial nephritis leading to progressive renal failure during adulthood. The marked thickening of tubular basement membranes found in FJHN is similar to that found in the nephronophthisis-autosomal medullary cystic disease (NPH-MCKD) group of diseases. Nephronophthisis (NPH) is an autosomal recessive disease leading to ESRF in adolescence whereas autosomal dominant medullary cystic kidney disease (MCKD) leads to ESRF during adulthood. While a history of gout and/or hyperuricemia was mentioned in several kindreds with MCKD, we demonstrated the presence of small cysts at the corticomedullary junction in kidneys from Belgian patients with FJHN. Therefore, histologic and clinical similarities between FJHN and MCKD suggested the possibility of a connection between the two entities. Using a candidate gene approach, we mapped the gene for FJHN on 16p12 with a maximum two-point LOD-score value of 3.74 at recombination fraction ( èmax) of 0 for one marker D16S3060 located within the ~10.5 cM critical region previously described by Scolari as the MCKD2 locus responsible for a clinical variant of MCKD. Confirming our hypothesis of allelism, heterozygous mutations in UMOD encoding the Tamm-Horsfall protein (THP) have been then found to be responsible for both FJHN and MCKD2 (Hart, 2002). The second part of our work was to gain some insights into the nature and distribution of the UMOD mutations among a large cohort of 38 unrelated patients with a diagnosis of FJHN. We have identified a mutation in UMOD in 16 FJHN families (14 missense, one in-frame deletion and one splicing mutation)- 15 of which are novel-, clustering in the highly conserved exon 4. The phenotype was similar, with hyperuricemia and/or gout as an early manifestation, and later development of chronic interstitial nephritis. Detection of medullary cysts in 14/18 individuals belonging to 12 families with FJHN confirmed our previous hypothesis of allelism. In addition, our molecular analyses provided strong evidence for the implication of different genes responsible for the FJHN phenotype. In parallel, consequences of UMOD mutations on THP expression were investigated in urine samples and renal biopsies from 9 patients in 4 families. There was a markedly increased expression of THP in a cluster of tubule profiles, suggesting an accumulation of the protein in tubular cells. Consistent with this observation, urinary excretion of wild-type THP was significantly decreased. Furthermore, a study in heterologous expression system has documented that mutant THP (cysteine substitution) failed to mature and was trapped in the endoplasmic reticulum (ER) (Rampoldi, 2003).
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Dahan, K. (2004). Familial juvenile hyperuricemic nephropathy (FJHN) : clinical phenotype, gene cloning and UMOD gene mutation identification. https://hdl.handle.net/2078.5/110719