| #603860 | ||||||||||
| MEDULLARY CYSTIC KIDNEY DISEASE 2; MCKD2 | ||||||||||
| Alternative titles; symbols | ||||||||||
| MEDULLARY CYSTIC KIDNEY DISEASE 2, AUTOSOMAL DOMINANT; ADMCKD2 | ||||||||||
| Phenotype Gene Relationships | ||||||||||
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| TEXT | ||||||||||
| A number sign (#) is used with this entry because one form of medullary cystic kidney disease (MCKD2) is caused by mutation in the gene encoding uromodulin (UMOD; 191845), which is also the site of mutations causing familial juvenile hyperuricemic nephropathy-1 (HNFJ1; 162000). | ||||||||||
| Description | ||||||||||
| For a phenotypic description and a discussion of genetic heterogeneity of medullary cystic kidney disease, see MCKD1 (174000). | ||||||||||
| 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. | ||||||||||
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