Glomerulocystic Kidney Disease With Hyperuricemia And Isosthenuria

A number sign (#) is used with this entry because of evidence that familial glomerulocystic kidney disease (GCKD) with hyperuricemia and isosthenuria is caused by heterozygous mutation in the UMOD gene (191845) on chromosome 16p12.

UMOD mutations can also cause medullary cystic kidney disease type-2 (MCKD2; 603860) and juvenile hyperuricemic nephropathy (FJHN; 162000).

For a phenotypic description and a discussion of genetic heterogeneity of medullary cystic kidney disease, see MCKD1 (174000).

Description

Glomerulocystic kidney disease is characterized by cystic dilatation of the Bowman space and the initial proximal convoluted tubule. Both sporadic and familial occurrences have been observed. Sharp et al. (1997) noted that GCKD had primarily been recognized in infants with a family history of classic, autosomal dominant polycystic kidney disease (PKD). However, dominantly transmitted GCKD associated with either hypoplastic or normal-sized kidneys has also been reported in older children and adults. Hypoplastic GCKD has been identified in some families with mutations in the TCF2 gene (189907) as part of the clinical phenotype of renal cysts and diabetes syndrome (137920).

Clinical Features

Sharp et al. (1997) reported a 3-generation African American family in which 7 affected individuals out of 20 available for study were identified by renal sonogram or renal histopathology. GCKD in this family was transmitted as an autosomal dominant trait as evidenced by its apparent transmission from a father to his sons. Linkage analysis excluded the PKD1 (601313) and PKD2 (613095) loci on chromosomes 16 and 4, respectively. Sharp et al. (1997) also excluded linkage markers in the human genome homologous to a mouse cystic kidney locus, jcpk, on 10q21 and 22q11 (Flaherty et al., 1995).

Lens et al. (2005) reported a 3-generation Spanish family in which 5 members had GCKD. The 2 affected females in the third generation had early onset of hyperuricemia at 12 and 15 years of age and renal insufficiency at 15 and 18 years of age, respectively. Proteinuria was absent. Renal biopsy when they were 15 and 18 years old showed marked dilatation of Bowman space in most glomeruli, with reduced or rudimentary glomerular tufts attached to the capsule without tubular dilatations or dysplastic elements. Their father and his sister developed end-stage renal disease at 55 and 62 years of age, respectively.

Molecular Genetics

Rampoldi et al. (2003) described a missense mutation (C315R; 191845.0010) in the UMOD gene in a family with GCKD. Patients had cyst dilatation and collapse of glomeruli with hyperuricemia and isosthenuria (urine concentration impairment); the latter two features are seen in MCKD2 and FJHN. Affected family members did not harbor HNF1B mutation, nor did they demonstrate glucose intolerance. Experiments in transfected cells showed that the uromodulin mutation caused a delay in protein export to the plasma membrane due to a longer retention time in the endoplasmic reticulum. Immunohistochemistry of kidney biopsies revealed dense intracellular accumulation of uromodulin in tubular epithelia of the thick ascending limb of Henle loop. Electron microscopy demonstrated accumulation of dense fibrillar material within the endoplasmic reticulum. Patient urine samples consistently showed a severe reduction of excreted uromodulin. The maturation impairment was consistent with the clinical findings and suggested a pathogenetic mechanism leading to the disease.

In affected members of a Spanish family (F3) with GCKD with hyperuricemia and isosthenuria, Lens et al. (2005) identified heterozygosity for a missense mutation (C300G; 191845.0009) in the UMOD gene.