Medullary Cystic Kidney Disease 2

A number sign (#) is used with this entry because medullary cystic kidney disease-2 (MCKD2) is caused by heterozygous mutation in the UMOD gene (191845) on chromosome 16p12. Mutation in the same gene causes familial juvenile hyperuricemic nephropathy-1 (HNFJ1; 162000).

Description

Medullary cystic kidney disease (MCKD) is an autosomal dominant form of tubulointerstitial nephropathy characterized by formation of renal cysts at the corticomedullary junction. It is characterized by adult onset of impaired renal function and salt wasting resulting in end-stage renal failure by the sixth decade (Wolf et al., 2004).

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

Clinical Features

Lens et al. (2005) reported a 4-generation Spanish family (F1) in which 11 members had a phenotype consistent with MCKD. Medullary cysts were seen on ultrasound in 2 patients at 42 and 51 years of age. Renal biopsy results available from 1 patient showed chronic interstitial nephritis with marked thickening of tubular membranes. End-stage renal disease developed at 64, 67, and 70 years of age.

Mapping

By genomewide linkage mapping in a 4-generation Italian pedigree, Scolari et al. (1999) identified a locus for autosomal dominant medullary cystic disease, MCKD2, on chromosome 16p12. The family fulfilled the typical diagnostic criteria of autosomal dominant MCKD, complicated by hyperuricemia and gouty arthritis. Marker D16S3036 showed a maximum 2-point lod score of 3.68, and the defined critical region spanned 10.5 cM, between D16S500 and SCNN1B1-2. Scolari et al. (1999) noted that the UMOD gene, which maps to the MCKD2 critical region, is expressed mainly in the kidney, where it is localized to the epithelial cells of the thick ascending limb (TAL) of the Henle loop. Uromodulin has been functionally associated with the water nonpermeability of the TAL, a function that is altered in autosomal dominant MCKD. Thus, UMOD was considered a candidate gene for MCKD2.

Molecular Genetics

Hart et al. (2002) showed that MCKD2 and familial juvenile hyperuricemic nephropathy can be caused by mutation in the UMOD gene (see, e.g., 191845.0001 and 191845.0004), which maps to chromosome 16p13.11-p12.3, and are thus allelic disorders. Noting that hyperuricemia is not always present in HNFJ1 and medullary cysts are not always present in MCKD2, and that the 2 conditions result from mutations of the same gene, the authors suggested that it would be appropriate to designate these 2 conditions 'uromodulin-associated kidney disease.'

Rampoldi et al. (2003) described missense mutations in the UMOD gene in 3 families with MCKD2/HNJF1 and demonstrated allelism (191845.0010) in 1 family with a glomerulocystic kidney disease variant (609886), showing association of cyst dilatation and collapse of glomeruli with some clinical features similar to MCKD2/HNJF1 such as hyperuricemia and impairment of urine-concentrating ability. Experiments in transfected cells showed that all uromodulin mutations caused a delay in protein export to the plasma membrane due to a longer retention time in the endoplasmic reticulum. Immunohistochemistry on GCKD and MCKD2/HNJF1 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 showed a severe reduction of excreted uromodulin. The maturation impairment was consistent with the clinical findings and suggested a pathogenetic mechanism leading to these kidney diseases.

In 2 apparently unrelated Spanish families, one (F1) segregating medullary cystic kidney disease-2 and the other (F2) segregating familial juvenile hyperuricemia nephropathy-1, Lens et al. (2005) identified heterozygosity for a missense mutation in the UMOD gene (Q316P; 191845.0014). The mutation segregated with the phenotype in the families and was not found in 100 control chromosomes.