We performed mutational analysis in three patients suggestive of familial juvenile hyperuricemic nephropathy (FJHN), examininga ll coding exons of the uromodulin (UMOD) gene by exon PCR and direct sequencing of the exon PCR products. In family M, a single nucleotide substitution(c.860G>A) was found in exon 4, resulting in the amino acid change from cysteine to tyrosine at codon 287 (C287Y). In family Y, c.890G>C mutation was detected in exon 5, causing the amino acid change C297S. None of these mutations was found in family I. UMOD contains four epidermal growth factor (EGF)-like domains that are predicted to mediate protein-protein interaction and maintain the tertiary structure of the UMOD protein. Two previously undescribed mutations, C287Y and C297S, are located within the fourth EGF-like domain. We suggest that replacement of the cysteine residue, which stabilizes the native domain fold by a disulfide bond, affects the function of UMOD, resulting in the development of FJHN.
