The clinical characteristics were similar to those of other patients suffering from uromodulin mutations and to those of patients suffering from medullary cystic kidney disease type 2 and familial juvenile hyperuricemic nephropathy.
In a large Belgian family with FJHN, a tight linkage between the disorder and the marker D16S3060, located within the MCKD2 locus on chromosome 16p12 (maximal two-point logarithmic odds score of 3.74 at a recombination fraction of theta = 0), was observed in this study.
A mutation in the uromodulin gene (16p11-13) has recently been linked to medullary cystic kidney disease type 2 and familial juvenile hyperuricemic nephropathy.
The uromodulin excretion pattern observed in the investigated family suggests that urinary uromodulin decreases in FJHN from low normal values at childhood to extremely low levels in early adulthood.
Uromodulin (UMOD) mutations were described in patients with medullary cystic kidney disease (MCKD2), familial juvenile hyperuricemic nephropathy (FJHN), and glomerulocystic kidney disease (GCKD).
Furthermore, the genetic basis of familial juvenile hyperuricemic nephropathy (FJHN), glomerulocystic kidney disease (GCKD) and autosomal dominant medullary cystic kidney disease 2 (MCKD2) has been recently attributed to mutations within the THP gene.
UMOD mutations cause familial juvenile hyperuricemic nephropathy (FJHN) and medullary cystic kidney disease (MCKD), although these phenotypes are nonspecific.
Our results suggested that the novel uromodulin mutations found in the Chinese families lead to misfolded protein, which was retained in the endoplasmic reticulum, finally contributed to the phenotype of FJHN.
Our observations support the hypothesis that ER accumulation of mutant uromodulin may cause ER stress, providing a potential mechanism for the progression of UMOD-related kidney disease.
Medullary cystic kidney disease type 2 (also known as uromodulin-associated kidney disease) likely represents a form of endoplasmic reticulum storage disease, with deposition of the abnormal uromodulin protein in the endoplasmic reticulum, leading to tubular cell atrophy and death.