Alternative titles; symbols
ORPHA: 34149, 88950; DO: 0060062;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p12.3 | Tubulointerstitial kidney disease, autosomal dominant, 1 | 162000 | Autosomal dominant | 3 | UMOD | 191845 |
A number sign (#) is used with this entry because of evidence that autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1) is caused by heterozygous mutation in the gene encoding uromodulin (UMOD; 191845) on chromosome 16p12.
Autosomal dominant tubulointerstitial kidney disease-1 (ADTKD1) is an adult-onset slowly progressive renal disease characterized by elevated serum uric acid (hyperuricemia) due to low fractional excretion of uric acid, defective urinary concentrating ability, 'bland' urinary sediment, and progression to end-stage renal failure. Some patients may develop gouty arthritis, arterial hypertension, polydipsia/polyuria, or mild proteinuria. The onset of symptoms is usually in the third or fourth decade, although earlier and later onset have been reported. Renal ultrasound may show small or hyperechogenic kidneys. Renal biopsy shows variable abnormalities, including tubular atrophy, interstitial fibrosis, microcystic dilatation of the tubules, thickening of tubular basement membranes, medullary cysts, and secondary glomerulosclerotic or glomerulocystic changes with abnormal glomerular tufting. The median age at onset of end-stage renal disease (ESRD) is 56 years (range 50-65). There is significant inter- and intrafamilial variability, as well as incomplete penetrance, which hampers diagnosis (summary by Hart et al., 2002, Ayasreh et al., 2018, and Devuyst et al., 2019).
Genetic Heterogeneity of Autosomal Dominant Tubulointerstitial Kidney Disease
ADTKD2 (174000) is caused by mutation in the MUC1 gene (158340) on chromosome 1q22; ADTKD3 (137920) is caused by mutation in the HNF1B gene (189907) on chromosome 17q12; ADTKD4 (613092) is caused by mutation in the renin gene (REN; 179820) on chromosome 1q32; and ADTKD5 (617056) is caused by mutation in the SEC61A1 gene (609213) on chromosome 3q21.
See 614227 for a possibly distinct form of ADTKD tentatively mapped to chromosome 2p22.1-p21.
The terms 'familial juvenile hyperuricemic nephropathy' (FJHN, HNFJ), 'medullary cystic kidney disease' (MCKD), 'glomerulocystic kidney disease' (GCKD), 'tubulointerstitial nephritis,' and 'hereditary interstitial kidney disease,' among others, have all been used to describe this phenotype. In a review, Devuyst et al. (2019) noted that the use of these confusing and inconsistent terms has hampered the detection and study of this renal disorder, which is genetically heterogeneous. These authors proposed the adoption of a unifying terminology, namely 'autosomal dominant tubulointerstitial kidney disease' (ADTKD), to refer to these diseases. The usual clinical manifestations of ADTKD in general are adult onset, progressive loss of kidney function, and variable proteinuria or microscopic hematuria. Renal biopsy shows interstitial fibrosis and tubular atrophy with a thickening and lamellation of tubular membranes, sometimes with secondary glomerulosclerosis. There may be microcystic tubular dilatations or renal cysts, but these findings are not pathognomonic. Although renal biopsy is important, Devuyst et al. (2019) stated that it is not possible to make a diagnosis of ADTKD based solely on biopsy findings. Genetic testing using a candidate gene panel may be the most effective diagnostic method (see also Ayasreh et al., 2018). Due to the nonspecific nature of the clinical and pathologic findings, ADTKD is likely underdiagnosed (summary by Olinger et al., 2020).
Early Reports of Families With Unknown Mutations
Rosenbloom et al. (1967) described a family in which multiple males in 3 generations died from renal failure at a relatively early age. All had hyperuricemia early in the course of the disease and developed gout. No distinctive histologic findings were yielded by renal biopsy. Transmission from father to son excluded X-linked inheritance. See McKusick (1974) for pedigree of the family of Rosenbloom et al. (1967). Duncan and Dixon (1960), Van Goor et al. (1971), and Simmonds et al. (1980) reported families with hyperuricemia and gout associated with renal disease.
Leumann (1972) and Leumann and Wegmann (1983) observed chronic interstitial nephropathy with disproportionate hyperuricemia in 2 girls and their mother. The mother suffered from gout beginning at age 20 years and required dialysis by age 34. The authors suggested that 'the severity of renal destruction by gout has been overestimated in the past and that families like the one described have been considered as gouty nephropathy.' Calabrese et al. (1990) and Cameron et al. (1990) reported further families. They emphasized the importance of investigating all sibs of such patients and of treatment with allopurinol of family members with a reduced fractional clearance of urate. Deterioration of renal function in patients who did not consistently take allopurinol and stability of renal function in compliers was the experience of Cameron et al. (1990) in 6 kindreds. Moro et al. (1991) found hyperuricemia associated with a grossly reduced fractional uric acid clearance in 2 children who did not yet have other signs of renal damage. They emphasized the usefulness of early recognition since allopurinol therapy in doses adjusted to the reduced renal function may ameliorate the progression of the renal lesion.
Saeki et al. (1995) found autosomal dominant inheritance in a Japanese family. They reported on 2 sisters who had gout and renal insufficiency.
McBride et al. (1997) stated that the Guy's Hospital group in London had identified 79 subjects with familial juvenile hyperuricemic nephropathy. They studied 36 children ranging in age from 3 to 17 years. Three were index cases. The other 33 were among 116 'healthy' relatives investigated from FJHN families in which the index case had presented initially with gout, renal disease, or both--generally with a strong family history spanning 2 or 3 generations (Moro et al., 1991). McBride et al. (1997) found a number of these children from kindreds who had hyperuricemia associated with a grossly reduced fractional uric acid clearance (FE(ur)) but normal renal function. (The FE(ur) is uric acid clearance factored by creatinine clearance x 100; mean for UK children = 18.4 +/- 5.1%.) The FE(ur) was 5.0 in affected children with normal or only mildly impaired renal function. These studies provided compelling evidence that hyperuricemia is a primary event in this type of nephropathy. The investigators underlined the importance of presymptomatic detection of the disorder, since in patients diagnosed before the onset of severe renal disease (creatinine clearance greater than 50 ml/min), allopurinol has ameliorated the hitherto rapid progression of the renal disease seen in earlier generations for up to 27 years (Moro et al., 1991).
Families with Mutations in the UMOD Gene
Massari et al. (1980) described a family in which 9 individuals had renal disease characterized mainly by hyperuricemia. Three had gouty arthritis. Renal biopsy showed focal global and segmental sclerosis of glomeruli, occasional hypercellularity, foci of atrophic tubules, chronic interstitial inflammation, and folding and wrinkling of the glomerular basement membrane without electron-dense deposits.
Hart et al. (2002) reported 4 unrelated families with a similar renal disease characterized by juvenile onset of hyperuricemia, polyuria, gout, and progressive renal insufficiency that was tubulointerstitial in origin. Family 4 had previously been reported by Massari et al. (1980). In all patients, the disorder was associated with impaired urinary concentrating ability, which was postulated to result in a compensatory increase in proximal tubular reabsorption of uric acid and hyperuricemia. Renal biopsies showed tubular atrophy and interstitial fibrosis. Global glomerulosclerosis was also observed, although there was no evidence of glomerulonephritis. Necroscopy showed sheathing of the renal tubules by dense acellular hyaline fibrous tissue that likely represented abnormal deposition of the UMOD protein. Three families (families 1, 2, and 4) had a clinical diagnosis of familial juvenile hyperuricemic nephropathy (FJHN, HNFJ). Medullary cysts were present in 1 family (family 3), consistent with a clinical diagnosis of medullary cystic kidney disease (MCKD).
Stiburkova et al. (2003) studied 3 Belgian brothers (family BE2) who reportedly developed the first symptoms of hyperuricemia and gouty arthritis after the age of 30 years; allopurinol treatment was started at that time. They had onset of renal failure between 45 and 50 years of age, with renal echography showing small hyperechogenic kidneys. Between 55 and 60 years of age, they developed arterial hypertension and progressive preterminal renal failure with elevated creatinine levels. Linkage analysis was consistent with linkage to chromosome 16p11. Vylet'al et al. (2006) restudied family BE2 and reported that 2 of the 3 brothers had earlier onset of the disease at age 20 years. The eldest brother had undergone successful kidney transplantation at age 65 years, and the middle brother began hemodialysis at age 60 years.
Dahan et al. (2003) reported 11 unrelated families with ADTKD1, 10 of which were of European descent and 1 of Moroccan descent. The 2 largest families had 11 and 7 affected individuals, respectively. At the time of examination, 17 patients had reached end-stage renal failure between ages 25 and 64 years, and 15 had chronic renal failure. Seven had preserved renal function, all of whom were younger than 34 years. Eighteen individuals had a history of gout with onset between 8 and 38 years. Renal biopsy, available from 6 individuals from 3 families, showed chronic interstitial nephritis with tubular atrophy and marked thickening of the tubular basement membrane. Renal imaging showed small cysts in 12 individuals with renal failure. Laboratory studies showed variably decreased urinary excretion of uromodulin compared to controls.
Lens et al. (2005) reported 4 Spanish families with variable manifestations of ADTKD1, demonstrating the phenotypic heterogeneity of the disorder. Family 4 had previously been reported by Rezende-Lima et al. (2004) as having medullary cystic kidney disease, although those authors noted that cyst formation may be a nonspecific secondary effect. There were 9 individuals in family 1 of Lens et al. (2005) who had highly variable clinical manifestations. Most had onset of hyperuricemia between 27 and 52 years of age, sometimes associated with gout. Four developed renal insufficiency between 29 and 57 years, but only 2 of these had end-stage renal disease after age 64. Four patients had arterial hypertension. Renal ultrasound showed medullary cysts in 2 patients with end-stage renal disease; renal biopsy in 1 of these patients showed chronic interstitial nephritis with marked thickening of tubular membranes. Other mutation carriers in the family did not have renal cysts. Two patients, ages 28 and 32, had only borderline increased serum uric acid without other manifestations. The findings suggested a clinical diagnosis of medullary cystic kidney disease. A 54-year-old man in family 2 had onset of hyperuricemia and gout at 15 and 31 years of age, respectively, and developed renal insufficiency at 44 years. Two older family members had end-stage renal disease at 51 and 67 years, respectively. Renal cysts were not present in this family; they were diagnosed with hyperuricemic nephropathy. Two sisters in family 3 had onset of hyperuricemia and renal insufficiency as teenagers. Renal biopsy showed dilatation of Bowman space in most glomeruli with rudimentary glomerular tufts without tubular dilatations; these findings were consistent with a diagnosis of glomerulocystic kidney disease. Their father and his sister developed end-stage renal disease at 55 and 62 years of age, respectively.
Williams et al. (2009) reported 6 unrelated probands (families 5, 6, 9, 11, 15, and 20), ranging from 14 to 72 years of age, with ADTKD1 confirmed by genetic analysis. Including affected family members, 13 individuals were identified. All patients had low fractional excretion of uric acid, with hyperuricemia in 73% and gout in 31%. Small or atrophic kidneys were found in 23% of patients, and cysts in 8%. About half had renal insufficiency, and 39% had end-stage renal failure. Two patients, including the 72-year-old, had a renal transplant.
Ayasreh et al. (2018) reported 9 unrelated Spanish families in which 44 individuals had ADTKD1 confirmed by genetic analysis. The majority of patients (87%) had hyperuricemia with a mean age at onset of 36.6 years. Other common features included gout (24%), hypertension (63%), polyuria/polydipsia (30%/24%), and proteinuria (10%). End-stage renal disease developed at an average age of 56 years. In 1 consanguineous family (F36), 2 members with a homozygous mutation developed end-stage renal disease at a mean age of 38.5 years, earlier than usual. Renal ultrasound showed small hyperechogenic kidneys in about 50% of those studied; cysts were found in 2 patients. Two patients had renal biopsies that showed tubular atrophy and interstitial fibrosis; 1 also had microcystic dilatation of the tubules. There was marked inter- and intrafamilial phenotypic variability, and the authors emphasized that neither hyperuricemia nor cysts represent hallmarks of the disease. Late onset of the disorder, incomplete penetrance, environmental factors, and other genetic or epigenetic changes may partially explain the variability.
Olinger et al. (2020) identified 303 patients from 216 families with ADTKD1 confirmed by genetic analysis. The families were ascertained from 2 large cohorts from Europe and the United States comprising 726 patients from 585 families, and thus represented 38.4% of families. The mean age at presentation was 42 years (range 27-53); most patients had hyperuricemia and gout. End-stage kidney disease occurred at a mean age of 46 years (range 39-57). Regarding pathogenesis, the authors noted that abnormal accumulation of UMOD in the endoplasmic reticulum (ER) of the distal renal tubules may induce ER stress and disrupt function. Defective urinary concentration resulting in polyuria and polydipsia most likely results from impaired activity of the thick ascending loop of Henle, which causes plasma volume contraction with compensatory reabsorption activity of the proximal tubule, including upregulation of Na(+)-coupled urate transporters. This results in hyperuricemia that is unique to ADTKD1. Olinger et al. (2020) provided a diagnostic algorithm based on simple scoring of clinical features, including urinary UMOD levels, hyperuricemia, and gout.
The transmission pattern of ADTKD1 in the families reported by Lens et al. (2005) and Ayasreh et al. (2018) was consistent with autosomal dominant inheritance with incomplete penetrance and variable expressivity.
By genomewide linkage mapping in a 4-generation Italian pedigree with adult-onset renal disease, Scolari et al. (1999) identified a disease locus, which they termed 'autosomal dominant medullary cystic disease-2' (MCKD2), on chromosome 16p12. The family fulfilled the typical diagnostic criteria of ADTKD1, 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 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 this disorder; UMOD was considered a candidate gene.
By linkage analysis of 2 families with ADTKD, Hart et al. (2002) identified a candidate region between 16p13.11 (D16S499) and 16p12.2 (D16S403). The authors noted that this region did not overlap with a region on 16p12 identified by Kamatani et al. (2000) in a large Japanese family (see below).
Stacey et al. (2003) pursued linkage studies in 7 European families with ADTKD and used 11 chromosome 16p13-p11 polymorphic loci. Cosegregation between these polymorphic loci and the disorder was observed in 5 of the families; linkage was established between ADTKD and 6 loci.
Vylet'al et al. (2006) performed linkage analysis in 19 families with variable manifestations of ADTKD and found linkage to chromosome 16p11.2 in 9 of the families. Quantitative analysis showed that UMOD excretion was significantly reduced in almost all affected individuals, regardless of which linkage group they belonged to; 1 family (CZ3), which did not link to any known loci, showed normal UMOD excretion.
Genetic Heterogeneity
Yokota et al. (1991) described a large Japanese family with autosomal dominant transmission of gouty arthritis with renal disease. At least 20 members of the family were affected. Kamatani et al. (2000) obtained DNA from 13 affected and 18 unaffected members. A genomewide search initially showed evidence of linkage for a marker on 16p. Subsequently, the same subjects were genotyped for 12 additional markers spanning approximately 30 cM on the short arm of chromosome 16. They obtained a maximum 2-point lod score of 6.04 at theta = 0.0 with the marker D16S401; multipoint linkage analysis yielded a maximum lod score of 6.14 with markers D16S401 and D16S3113, and established a minimum candidate interval of approximately 9 cM in the 16p12 region.
Stacey et al. (2003) excluded linkage to chromosome 16p13-p11 in 2 European families with ADTKD, thereby demonstrating genetic heterogeneity (see 614227).
In affected members of 4 unrelated families with ADTKD1, Hart et al. (2002) identified 4 different heterozygous mutations in exon 4 of the UMOD gene (191845.0001-191845.0004). The mutations, which were found by a combination of linkage analysis and candidate gene sequencing, segregated with the disorder in the families. Three families (families 1, 2, and 4) had a clinical diagnosis of familial juvenile hyperuricemic nephropathy (FJHN, HNFJ), whereas family 3 was diagnosed clinically with medullary cystic kidney disease (MCKD). Family 4 had previously been reported by Massari et al. (1980). Functional studies of the variants and studies of patient cells were not performed, but the authors postulated that the mutations caused tertiary structural changes in the uromodulin protein that could alter cytokine binding and ultimately lead to fibrosis and progressive renal failure. The report established that the clinical entities of FJHN and MCKD not only share clinical features, but are also either allelic or variable manifestations of the same disease. Noting that hyperuricemia and medullary cysts are variable features and that the conditions result from mutations in the same gene, the authors suggested the designation 'uromodulin-associated kidney disease.'
In 5 unrelated kindreds with ADTKD1, 2 from Austria and 3 from Spain, Turner et al. (2003) identified 5 heterozygous missense mutations in the UMOD gene (191845.0005-191845.0009) that altered evolutionary conserved residues. These mutations were not found in 110 alleles from 55 unrelated normal individuals. Functional studies of the variants were not performed, but the authors postulated a loss-of-function effect. The families had previously been reported by Stacey et al. (2003).
In affected members of 4 unrelated Italian families with variable manifestations of ADTKD1, Rampoldi et al. (2003) identified heterozygous missense mutations in the UMOD gene (see, e.g., C315R, 191845.0010 and C148W, 191845.0015). All mutations affected highly conserved cysteine residues and were predicted to affect protein structure. Immunohistochemistry of kidney biopsies revealed dense intracellular accumulation of uromodulin in tubular epithelia of the thick ascending limb of Henle loop. Electron microscopy showed accumulation of dense fibrillar material within the endoplasmic reticulum, and patient urine samples consistently showed a severe reduction of excreted uromodulin. Experiments in transfected cells showed that all 4 mutations caused a delay in protein export to the plasma membrane due to a longer retention time in the ER. The protein maturation impairment and retention in the ER, which may trigger ubiquitination, suggested a pathogenetic mechanism leading to these kidney diseases. Rampoldi et al. (2003) postulated that hyperuricemia is a secondary effect of volume contraction resulting from UMOD dysfunction in the thick ascending loop of Henle. Three families had a clinical diagnosis of MCKD/FJHN (including a family previously reported by Scolari et al., 1999), and 1 family had a clinical diagnosis of glomerulocystic kidney disease (GCKD), thus demonstrating that these clinical entities are allelic and likely are different manifestations of the same disorder.
In patients from 11 families with ADTKD1, Dahan et al. (2003) identified 11 different heterozygous mutations in the UMOD gene, including 10 novel mutations (see, e.g., 191845.0012). There were 10 missense mutations and 1 in-frame deletion. All of the mutations occurred at highly conserved residues in exon 4, and 5 of the mutations affected a conserved cysteine residue. The families were ascertained from a larger group of 25 families with a similar phenotype; thus, UMOD mutations were found in 44% of families. Medullary cysts were identified in 9 patients from 8 families. Patient kidney samples showed abnormal uromodulin immunostaining within enlarged or cystic profiles in tubules in the thick ascending loop, and not at the apical membrane as observed in controls. Mutant UMOD was not found in proximal tubules. Patients also showed decreased urinary excretion of wildtype uromodulin. These findings indicated that mutant uromodulin accumulates within renal tubular cells in patients with UMOD mutations. Dahan et al. (2003) concluded that the clinical diagnoses of FJHN and MCKD2 represent 2 facets of the same disease entity.
In 14 affected members of a large consanguineous Spanish family with ADTKD1, Rezende-Lima et al. (2004) identified a C255Y mutation in the UMOD gene (191845.0008). Eleven family members were heterozygous for the mutation, whereas 3 were homozygous. The homozygous individuals had earlier disease onset than the heterozygous carriers, but the report demonstrated that homozygosity for UMOD mutations is not lethal. The clinical phenotype was consistent with medullary cystic kidney disease (MCKD), although the authors noted that cyst formation may be a nonspecific secondary effect. This family was also reported as family F4 by Lens et al. (2005).
In affected members of 2 apparently unrelated Spanish families with ADTKD1, Lens et al. (2005) identified the same heterozygous 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. Family 1 had a clinical phenotype consistent with MCKD, and family 2 had a clinical phenotype consistent with FJHN. The demonstration of the same mutation in both families further supported that MCKD and FJHN are the same disease entity. A third Spanish family (family 3), with a clinical phenotype consistent with GCKD, carried a different heterozygous missense mutation (C300G; 191845.0009).
Vylet'al et al. (2006) sequenced the UMOD gene in 19 families with variable manifestations of ADTKD1 and identified heterozygous mutations in 6 families, 5 of which had been previously reported (kindred 6 from McBride et al., 1998; kindreds A and B from Stiburkova et al., 2000; Fairbanks et al., 2002; and family BE2 from Stiburkova et al., 2003) (see, e.g., 191845.0006 and 191845.0011).
In 6 of 17 probands with ADTKD who were studied for UMOD mutations, Williams et al. (2009) identified 6 different heterozygous missense mutations in the UMOD gene (see, e.g., D196N, 191845.0016). In vitro functional studies of some of the mutations expressed in HeLa cells showed that the mutant uromodulins had significantly delayed maturation compared to wildtype, with abnormal protein retention in the ER and reduced or absent expression at the plasma membrane. There were different effects allowing the identification of 2 mutation groups: group A (including mutants C32W, D196N, and G488R) had 50% maturation compared to wildtype with some expression at the plasma membrane, whereas group B (including mutants C126R, 191845.0006; N128S, 191845.0007; and C223R) had 25% maturation compared to wildtype and absence of expression at the plasma membrane. There were no phenotypic differences between patients with group A and group B mutations. The findings suggested that abnormal folding of the mutant proteins resulted in protein retention in the ER, which may trigger apoptosis and underlie the mechanism for disease pathogenesis.
In affected members of 10 unrelated families with ADTKD1, Zaucke et al. (2010) identified 7 novel and 3 previously reported heterozygous missense mutations in the UMOD gene (see, e.g., 191845.0009 and 191845.0013). Most of the mutations affected conserved cysteine residues. The number of UMOD-positive primary cilia in renal biopsy samples from 2 of the patients was significantly decreased compared to control samples. The authors suggested that this defect may contribute to cyst formation. The families were ascertained from a cohort of 44 families with nephropathy from western Europe and the United States who underwent direct sequencing of the UMOD gene.
Olinger et al. (2020) identified 106 unique heterozygous mutations in the UMOD gene in 303 patients from 216 families with ADTKD1. The families were ascertained from 2 large cohorts from Europe and the United States comprising 726 patients from 585 families, and thus represented 38.4% of families. The majority (95.3%) of the mutations were missense, and most occurred in exon 3. About half involved cysteine bonds.
In a review article on the pathogenesis of ADTKD1, Devuyst et al. (2019) concluded that the disorder results from a toxic gain-of-function effect due to abnormal accumulation of mutant UMOD in the ER, where it is believed to stimulate the unfolded protein response and activate pathways of ER stress.
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 303 patients from 216 families (38.4%) had mutations in the UMOD gene. MUC1 mutations were found in 104 patients from 93 families (21%).
Bernascone et al. (2010) generated a transgenic mouse model for the UMOD-associated kidney diseases HNFJ and MCKD. The transgenic mice, which had a Umod C147W mutation corresponding to the human UMOD C148W mutation (191845.0015), recapitulated most of the features observed in patients with UMOD kidney disease, with urinary concentrating defect of renal origin and progressive renal injury, i.e., tubulointerstitial fibrosis with inflammatory cell infiltration, tubule dilation, and specific damage of the thick ascending limb of the loop of Henle (TAL), leading to mild renal failure. As observed in patients with the C148W mutation, the mutant mice showed a marked reduction in urinary uromodulin excretion. Mutant uromodulin was retained in the endoplasmic reticulum (ER) of expressing cells, leading to ER hyperplasia. The authors suggested that impaired TAL function is a consequence of a gain-of-function effect of UMOD mutations.
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