Medullary Cystic Kidney Disease 1
A number sign (#) is used with this entry because of evidence that autosomal dominant medullary cystic kidney disease-1 (MCKD1) is caused by heterozygous mutation in the MUC1 gene (158340) on chromosome 1q22.
DescriptionMedullary 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).
Although early reports suggested that medullary cystic kidney disease and familial juvenile nephronophthisis (NPHP1; 256100) represented the same disease entity because of the overlapping phenotype (Chamberlin et al., 1977), they are now considered to be distinct disorders. MCKD has adult onset and shows autosomal dominant inheritance, whereas NPHP1 has juvenile onset and shows autosomal recessive inheritance (Christodoulou et al., 1998). NPHP1 is caused by mutation in the nephrocystin gene (NPHP1; 607100) on chromosome 2q13.
Genetic Heterogeneity of Medullary Cystic Kidney Disease
See also MCKD2 (603860), which is caused by mutation in the UMOD gene (191845) on chromosome 16p.
Clinical FeaturesThorn et al. (1944) are credited with the first description of medullary cystic renal disease under the designation 'salt-losing nephritis.' They noted an association with red and blond hair. Rayfield and McDonald (1972) also recognized the association between medullary cystic disease and red and blond hair. Smith and Graham (1945) reported an isolated case.
Goldman et al. (1966) described a kindred with 17 affected members spanning 5 generations. Fifteen had died in the second decade of life with rapid clinical deterioration after the onset of symptoms. The kidneys showed thin cortices, prominent glomerular hyalinization, numerous corticomedullary and intramedullary cysts lined by low cuboidal epithelium, and increase in medullary connective tissue. The authors noted differences from polycystic kidney disease (see 173900), such as the absence of flank pain, and the presence of hypertension and small kidneys. Gardner (1971) reported 2 extensively affected sibships. The average age of onset of symptoms was 23 years in one and 35 years in the second. The average duration of illness was only 2.2 years. Wrigley et al. (1973) described a family with somewhat later onset of medullary cystic kidney disease. Whelton et al. (1974) reported another affected family. Giangiacomo et al. (1975) presented a family in which the onset of autosomal dominant MCKD was unusually early.
Stavrou et al. (1998) reported a large Cypriot family in which at least 23 members spanning 4 generations had interstitial nephropathy inherited in an autosomal dominant pattern. Ten patients were deceased. Clinical features were variable and included renal medullary cysts, hypertension, hyperuricemia, and gout. Urinalysis of 10 patients showed no hematuria, pyuria, or casts. The mean age at onset of end-stage renal disease (ESRD) was 62 years. Two renal biopsies showed interstitial fibrosis and severe tubular atrophy consistent with a primary tubulointerstitial process. There was also periglomerular fibrosis with a few sclerotic glomeruli. Linkage analysis excluded the NPHP1 locus on 2q13 and the PKD1 locus (601313) on 16p.
Ala-Mello et al. (1999) used the term 'nephronophthisis' for both the dominant disorder called medullary cystic disease and recessive juvenile nephronophthisis (NPHP1). The dominant form was characterized by later age at onset of first symptoms, at start of dialysis, and at transplantation. In a survey of 59 cases ascertained in Finland, 17 came from 4 families showing dominant inheritance and 37 came from apparently recessive families; 2 were considered new dominant mutations, and 3 sporadic cases could not be classified.
Parvari et al. (2001) studied a family of Jewish ancestry in which 15 members spanning 4 generations had chronic renal failure with onset between 18 and 38 years of age. Hypertension was often the presenting sign, followed by progressive renal insufficiency. No polyuria, anemia, gout, hematuria, or proteinuria were seen. An average of 4.5 years elapsed between diagnosis and end-stage renal disease. Renal pathology at early stages of the disease showed extensive tubulointerstitial fibrosis and global glomerulosclerosis.
Wolf et al. (2004) reported a Belgian kindred with MCKD. Age at presentation ranged from 29 to 53 years, and age at ESRD varied between 34 and 49 years. First symptoms included polyuria, polydipsia, and anemia. One patient had hypertension and 2 had hyperuricemia. Gout was not reported. Variable ultrasound findings included small kidneys and small medullary cysts.
Kiser et al. (2004) reported a large Native American kindred in which 12 living members had MCKD1 confirmed by linkage analysis. Age at onset of renal insufficiency ranged from 34 to 65 years and age at development of ESRD ranged from 35 to 66 years. No patient presented with polyuria, polydipsia, or urinary salt wasting; most presented with abnormal laboratory data obtained for other reasons. Other features included gout (61%), hypertension (55%), and anemia (39%). Ultrasound detected renal cysts in 44% of patients, and renal biopsies of 4 patients showed interstitial fibrosis, interstitial inflammation, tubular atrophy, and glomerulosclerosis. Only 2 patients had significant proteinuria on urinalysis.
Kirby et al. (2013) reported 6 unrelated families with MCKD1, including the families previously reported by Kiser et al. (2004) and Kimmel et al. (2005). Affected individuals had slowly progressive kidney dysfunction beginning in adulthood, absent or low grade proteinuria with bland urinary sediments, decreased glomerular filtration rate, and absence of other association signs or symptoms of systemic disease. Hypertension tended to occur only after onset of chronic renal failure. Hematuria was typically not present. Renal biopsies showed tubulointerstitial fibrosis and tubular atrophy, and renal ultrasounds occasionally showed cortical cysts, but cysts were often not present.
DiagnosisKiser et al. (2004) noted that the diagnosis of MCKD is difficult because initial signs and symptoms may be mild or vague, symptoms of frank renal failure occur late, renal cysts may be absent in over 50% of patients, and renal histologic abnormalities are nonspecific.
InheritanceThe transmission pattern of MCKD1 in the families reported by Kirby et al. (2013) was consistent with autosomal dominant inheritance.
MappingBy genomewide linkage analysis of 2 Cypriot families with adult-onset autosomal dominant MCKD, including the family reported by Stavrou et al. (1998), Christodoulou et al. (1998) identified a candidate disease locus, MCKD1, on chromosome 1q21 (2-point lod score of 6.45 and multipoint lod score of 9.41 at marker D1S1595). Analysis of haplotypes and of critical recombinants refined the locus to an 8-cM interval between D1S498 and D1S2125. The 2 families shared the same disease haplotype, suggesting a common ancestor.
Parvari et al. (2001) found linkage to the MCKD1 locus on 1q21 (maximum 2-point lod score of 3.82 at D1S394) in a family of Jewish ancestry in which 15 members spanning 4 generations had chronic renal failure. The report established a relationship between an autosomal dominant nephropathy characterized by hypertension and progressive renal failure and autosomal dominant medullary cystic kidney disease associated with macroscopic corticomedullary cysts, salt-losing tubulointerstitial nephropathy, and anemia.
By haplotype analysis of a British kindred with MCKD, Fuchshuber et al. (2001) refined the MCKD1 locus to a 4-cM (3.3-Mb) interval between D1S305 and D1S2635. Molecular analysis excluded mutations in the HAX1 gene (605998) in 1 family.
By high-resolution haplotype analysis of 3 families with MCKD, including the original Arizona kindred reported by Gardner (1971), the Welsh family reported by Fuchshuber et al. (2001), and a family from the Dutch/German border, Wolf et al. (2003) detected extensive haplotype sharing across the MCKD1 critical gene region. The data enabled refinement of the disease interval to less than 650 kb. Genealogy of the Arizona kindred showed that they originated from Germany in the 17th century, thereby providing historical data for haplotype sharing by descent at the MCKD1 locus. By analysis of an affected Belgian kindred, Wolf et al. (2004) further refined the MCKD1 critical region to a 2.1-Mb interval on 1q21 with a telomeric marker at D1S2624.
Kimmel et al. (2005) reported a large family in which bipolar disorder (MAFD1; 125480) appeared to cosegregate with autosomal dominant medullary cystic kidney disease. Of the 7 members with kidney disease, 5 had bipolar I disorder, one had unipolar depression, and 1 had a hyperthymic phenotype. The authors noted that the 2 known loci of medullary cystic kidney disease are in regions of chromosome 1 (MCKD1) and 16 (MCDK2; 603860) that had previously been linked to bipolar disorder and schizophrenia.
Molecular GeneticsIn 16 kindreds with MCKD, Wolf et al. (2006) failed to identify pathogenic sequence changes in 37 genes within the MCKD1 critical region.
In affected members of 6 unrelated families with autosomal dominant medullary cystic kidney disease-1, Kirby et al. (2013) identified a heterozygous 1-bp insertion of a cytosine in 1 copy of an extremely long (1.5-5.0 kb) GC-rich coding variable number tandem repeat (VNTR) sequence in the MUC1 gene (158340.0001). The insertion was within a stretch of 7 cytosines occurring at positions 53-59 in a single copy of the canonical 60-mer repeat. The insertion of cytosine occurred in a different VNTR size in each family, indicating independent occurrence of the mutations. Some of the families had previously been reported (e.g., by Kiser et al., 2004). The insertion was predicted to cause a frameshift, resulting in a mutant protein with many copies of a novel repeat sequence, but lacking a downstream self-cleavage module and both the transmembrane and intracellular domains characteristic of the wildtype MUC1 precursor protein. Full genotyping of this region showed that the mutation segregated with the risk-associated haplotype in each family, but was not found in over 500 controls from various populations. A similar cytosine insertion was found in 13 of 21 additional families with the disorder who were studied, consistent with it being a fully penetrant cause of disease. Antibodies against a peptide synthesized to correspond to the predicted mutant VNTR sequence showed specific intracellular staining in epithelial cells from the loop of Henle, distal tubule, and collecting duct of patients that was not seen in controls. The mutant MUC1 showed partial colcalization with wildtype MUC1 in the collecting duct of a patient. Kirby et al. (2013) emphasized that the mutation was missed by massively parallel sequencing and was found only by diligent analysis of the linked region using cloning, Southern blot analysis, long-range PCR, and reconstruction of the VNTR allele in patients and controls.