Alternative titles; symbols
SNOMEDCT: 726017001; ORPHA: 34149, 88949;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q22 | Tubulointerstitial kidney disease, autosomal dominant, 2 | 174000 | Autosomal dominant | 3 | MUC1 | 158340 |
A number sign (#) is used with this entry because of evidence that autosomal dominant tubulointerstitial kidney disease-2 (ADTKD2) is caused by heterozygous mutation in the MUC1 gene (158340) on chromosome 1q22.
Autosomal dominant tubulointerstitial kidney disease-2 (ADTKD2) is characterized by adult onset of impaired renal function and salt wasting resulting in chronic renal insufficiency and end-stage renal failure by the sixth decade. Renal biopsy shows tubulointerstitial nephropathy, sometimes with the formation of renal cysts at the corticomedullary junction, although cysts are not pathognomonic for the disease and are not an essential criterion for the diagnosis. More variable features may include anemia, hypertension, hyperuricemia, and gout; urinary sediment is bland. The features are nonspecific and there is significant inter- and intrafamilial variability, as well as incomplete penetrance, which may hinder the clinical diagnosis (summary by Stavrou et al., 2002, Wolf et al., 2004; review by Devuyst et al., 2019).
For a discussion of genetic heterogeneity of ADTKD and a discussion of the revised nomenclature of these disorders, see ADTKD1 (162000).
Thorn et al. (1944) are credited with the first description of this disorder under the designation 'salt-losing nephritis.' They noted an association with red and blond hair. Rayfield and McDonald (1972) also recognized an association between medullary cystic renal 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 (CY4901) 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.
Stavrou et al. (2002) reported 6 Cypriot families with ADTKD2. One of the families (CY4901) had previously been reported by Stavrou et al. (1998) and 2 families (CY4901 and CY4903) by Christodoulou et al. (1998). The age at disease onset was difficult to determine because symptoms were essentially absent until chronic renal failure developed in adulthood. The mean age at onset of end-stage renal disease was 53.7 years, although there was great inter- and intrafamilial variability. Hypertension and hyperuricemia were observed in about 50% of patients; only a few had gout. Other features included decreased creatinine clearance, anemia, and increased fractional excretion of sodium. Kidney biopsy showed tubulointerstitial changes with tubular atrophy, interstitial lymphocytic infiltration, interstitial fibrosis, tubular basement membrane thickening, and tubular dilation. Less common findings included glomerulosclerosis, periglomerular fibrosis, and thickening of the Bowman capsule. Renal cysts, found in 40.3% of patients, were of variable size, location, and numbers, although most were corticomedullary or medullary. The authors noted that histopathologic features, while helpful, are not pathognomonic for the disease. None of the patients had extrarenal manifestations, such as red or blonde hair, spastic quadriparesis, or ocular abnormalities.
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 an affected Belgian kindred. 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. Renal biopsy in 1 patient showed atrophic tubules, thickened basement membranes, microcysts, and glomerulosclerosis.
Kiser et al. (2004) reported a large Native American kindred in which 12 living members had ADTKD2 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 ADTKD2, 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.
Ayasreh et al. (2018) reported 90 patients from 16 Spanish families with ADTKD2 confirmed by genetic analysis. The features were highly variable, even within families. Hyperuricemia occurred in about 54% of patients at a mean age of 36.8 years. Other common features included hypertension (65%) and proteinuria (23%), whereas gout (7%), polyuria (11%), and polydipsia (7%) were less common. End-stage renal disease occurred at a mean of 51 years. Renal ultrasound identified normal kidney size with cysts in 26% of patients, small hyperechogenic kidneys in 30%, and hyperechogenic kidneys with cortical cysts in 11%. Renal biopsies showed tubular atrophy and interstitial fibrosis, microcystic dilatation of the tubules, and nonspecific findings such as glomerular sclerosis. Late onset of the disorder, incomplete penetrance, environmental factors, and other genetic or epigenetic changes may partially explain the clinical variability.
Olinger et al. (2020) reported 93 families from Europe or the United States with ADTKD2. Although the average age of presentation was noted to be 47 years (range 37 to 57), end-stage kidney disease occurred at an average age of 36 years (range 30 to 46). Some patients had increased serum uric acid, but only about 26% developed gout.
Kiser et al. (2004) noted that the diagnosis of this disease 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.
Differential Diagnosis
Although early reports suggested that the phenotypes previously referred to as medullary cystic kidney disease (MCKD) and familial juvenile nephronophthisis (NPHP1; 256100) represented the same disease entity because of phenotypic overlap (Chamberlin et al., 1977), they are now considered to be distinct disorders. ADTKD2 has adult onset and shows autosomal dominant inheritance, whereas NPHP1 has juvenile onset and shows autosomal recessive inheritance (Christodoulou et al., 1998). NPHP results from mutations in genes expressed by the primary cilia and thus is considered to be a ciliopathy.
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.
The transmission pattern of ADTKD2 in the families reported by Kirby et al. (2013) was consistent with autosomal dominant inheritance. Ayasreh et al. (2018) noted incomplete penetrance.
By genomewide linkage analysis of 2 Cypriot families (CY4901 and CY4903) with adult-onset autosomal dominant renal disease, including the family reported by Stavrou et al. (1998), Christodoulou et al. (1998) identified a candidate disease locus 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. The locus was designated MCKD1.
Parvari et al. (2001) found linkage to chromosome 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 an affected British kindred, Fuchshuber et al. (2001) refined the 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 affected families, 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 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. By analysis of an affected Belgian kindred, Wolf et al. (2004) further refined the 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; see 162000) that had previously been linked to bipolar disorder and schizophrenia.
In affected members of 6 unrelated families with ADTKD2, 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 colocalization 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.
Olinger et al. (2020) reported 93 families from Europe or the United States with ADTKD2. Four different MUC1 mutations in the VNTR domain of MUC1 were detected (27dupC, 28dupA, 26_27insG, and 23delinsAT). All were predicted to lead to the same frameshift and premature stop codon (MUC1fs). This truncated protein accumulates in intracellular vesicles and causes tubulointerstitial damage.
In a review article on the pathogenesis of ADTKD2, Devuyst et al. (2019) concluded that the disorder results from a toxic gain-of-function effect due to abnormal intracellular accumulation of mutant MUC1fs.
In a genetic study of 56 Spanish families with a clinical diagnosis of ADTKD, Ayasreh et al. (2018) found that 25 (45%) carried pathogenic mutations in either the UMOD gene (9 families, 36%) or MUC1 gene (16 families, 64%). These findings suggested that MUC1 mutations are the most common cause of the disorder in that population. No pathogenic mutations were identified in REN (179820) or HNF1B (189907).
In a genetic study of 2 large cohorts from Europe and the United States comprising 726 patients from 585 families with ADTKD, Olinger et al. (2020) found that 104 patients from 93 families (21%) had mutations in the MUC1 gene. Mutations in the UMOD gene were found in 303 patients from 216 families (38.4%).
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