Atypical familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1β gene mutation

Bingham, Coralie; Ellard, Sian; Hoff, William G. van’t; Simmonds, H. Anne; Marinaki, Anthony M.; Badman, Michael K.; Winocour, Peter; Stride, Amanda; Lockwood, Christopher R.; Nicholls, Anthony; Owen, Katharine R.; Spyer, Ghislaine; Pearson, Ewan R.; Hattersley, Andrew T.

doi:10.1046/j.1523-1755.2003.00903.x

Cited by 143 publications

(116 citation statements)

References 33 publications

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“…A mutation in HNF1B gene was found in five probands, which displayed clinical features similar to those of patients with UMOD mutation, similarly to previously reported cases (14). Only one of them developed diabetes in the years after diagnosis of renal disease.…”

Section: Discussionsupporting

confidence: 83%

“…Recently, mutations in preprorenin signal peptide (1q32) were reported as a new cause of autosomal dominant TIN (13). Mutations in HNF1B gene were also shown to cause a wide variety of renal and extrarenal manifestations including renal cysts and, rarely, FJHN (14,15). Although the last decade has witnessed important advances into the understanding of the genetic substratum of hereditary TIN, other genes involved remain to be discovered.…”

Section: Introductionmentioning

confidence: 99%

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Phenotype and Outcome in Hereditary Tubulointerstitial Nephritis Secondary to UMOD Mutations

Bollée¹,

Dahan²,

Flamant³

et al. 2011

Clinical Journal of the American Society of Nephrology

115

134

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SummaryBackground UMOD mutations cause familial juvenile hyperuricemic nephropathy (FJHN) and medullary cystic kidney disease (MCKD), although these phenotypes are nonspecific.Design, setting, participants, & measurements We reviewed cases of UMOD mutations diagnosed in the genetic laboratories of Necker Hospital (Paris, France) and of Université Catholique de Louvain (Brussels, Belgium). We also analyzed patients with MCKD/FJHN but no UMOD mutation. To determine thresholds for hyperuricemia and uric-acid excretion fraction (UAEF) according to GFR, these parameters were analyzed in 1097 patients with various renal diseases and renal function levels.Results Thirty-seven distinct UMOD mutations were found in 109 patients from 45 families, all in exon 4 or 5 except for three novel mutations in exon 8. Median renal survival was 54 years. The type of mutation had a modest effect on renal survival, and intrafamilial variability was high. Detailed data available in 70 patients showed renal cysts in 24 (34.3%) of nonspecific localization in most patients. Uricemia was Ͼ75th percentile in 31 (71.4%) of 42 patients not under dialysis or allopurinol therapy. UAEF (n ϭ 27) was Ͻ75th percentile in 70.4%. Among 136 probands with MCKD/FJHN phenotype, UMOD mutation was found in 24 (17.8%). Phenotype was not accurately predictive of UMOD mutation. Six probands had HNF1B mutations.Conclusions Hyperuricemia disproportionate to renal function represents the hallmark of renal disease caused by UMOD mutation. Renal survival is highly variable in patients with UMOD mutation. Our data also add novel insights into the interpretation of uricemia and UAEF in patients with chronic kidney diseases.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Phenotype and Outcome in Hereditary Tubulointerstitial Nephritis Secondary to UMOD Mutations

Bollée¹,

Dahan²,

Flamant³

et al. 2011

Clinical Journal of the American Society of Nephrology

115

134

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“…Twelve patients with HNF1B mutation had early gout and/or hyperuricemia, a feature that has been reported in patients with HNF1B mutations (15), but this frequency must be underestimated because the uricemia dosage was not available for many patients in our cohort. Only one adult proband who presented with tubulointerstitial nephropathy and early hyperuricemia that was previously shown not to be associated with UMOD mutation was carrying an HNF1B mutation.…”

Section: Discussionmentioning

confidence: 79%

Spectrum of HNF1B Mutations in a Large Cohort of Patients Who Harbor Renal Diseases

Heidet¹,

Decramer²,

Pawtowski³

et al. 2010

Clinical Journal of the American Society of Nephrology

255

261

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Background and objectives: Hepatocyte nuclear factor 1␤ (HNF1␤) is a transcription factor that is critical for the development of kidney and pancreas. In humans, mutations in HNF1B lead to congenital anomalies of the kidney and urinary tract, pancreas atrophy, and maturity-onset diabetes of the young type 5 and genital malformations.Design, setting, participants, & measurements: We report HNF1B screening in a cohort of 377 unrelated cases with various kidney phenotypes (hyperechogenic kidneys with size not more than ؉3 SD, multicystic kidney disease, renal agenesis, renal hypoplasia, cystic dysplasia, or hyperuricemic tubulointerstitial nephropathy not associated with UMOD mutation).Results: We found a heterozygous mutation in 75 (19.9%) index cases, consisting of a deletion of the whole gene in 42, deletion of one exon in one, and small mutations in 32. Eighteen mutations were novel. De novo mutations accounted for 66% of deletions and 40% of small mutations. In patients who carried HNF1B mutation and for whom we were able to study prenatal ultrasonography (56 probands), isolated hyperechogenic kidneys with normal or slightly enhanced size were the more frequent (34 of 56) phenotype before birth. Various other prenatal renal phenotypes were associated with HNF1B mutations, at a lesser frequency. Diabetes developed in four probands. Hyperuricemia and hypomagnesemia, although not systematically investigated, were frequently associated.Conclusions: This large series showed that the severity of the renal disease associated with HNF1B mutations was extremely variable (from prenatal renal failure to normal renal function in adulthood) and was not correlated with the genotype.

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“…It is interesting that a mutation in the HNF-1␤ gene was recently identified in a family with FJHN (32).…”

Section: Discussionmentioning

confidence: 99%

A Cluster of Mutations in the UMOD Gene Causes Familial Juvenile Hyperuricemic Nephropathy with Abnormal Expression of Uromodulin

Dahan¹,

Devuyst²,

Smaers³

et al. 2003

Journal of the American Society of Nephrology

201

170

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Abstract. Familial juvenile hyperuricemic nephropathy (FJHN [MIM 162000]) is an autosomal-dominant disorder characterized by abnormal tubular handling of urate and late development of chronic interstitial nephritis leading to progressive renal failure. A locus for FJHN was previously identified on chromosome 16p12 close to the MCKD2 locus, which is responsible for a variety of autosomal-dominant medullary cystic kidney disease (MCKD2). UMOD, the gene encoding the Tamm-Horsfall/uromodulin protein, maps within the FJHN/MCKD2 critical region. Mutations in UMOD were recently reported in nine families with FJHN/ MCKD2 disease. A mutation in UMOD has been identified in 11 FJHN families (10 missense and one in-frame deletion)-10 of which are novel-clustering in the highly conserved exon 4. The consequences of UMOD mutations on uromodulin expression were investigated in urine samples and renal biopsies from nine patients in four families. There was a markedly increased expression of uromodulin in a cluster of tubule profiles, suggesting an accumulation of the protein in tubular cells. Consistent with this observation, urinary excretion of wild-type uromodulin was significantly decreased. The latter findings were not observed in patients with FJHN without UMOD mutations. In conclusion, this study points to a mutation clustering in exon 4 of UMOD as a major genetic defect in FJHN. Mutations in UMOD may critically affect the function of uromodulin, resulting in abnormal accumulation within tubular cells and reduced urinary excretion.Familial juvenile hyperuricemic nephropathy (FJHN) is an autosomal-dominant disorder characterized by hyperuricemia and decreased urinary excretion of urate, followed by the development of chronic interstitial nephritis most often leading to progressive renal failure (1,2). The link between early hyperuricemia and subsequent progression of renal disease remains unclear.Urate is the end product of purine metabolism in humans, who have lost the expression of the uricase gene during evolution (3). Urate is freely filtered by the glomerulus and essentially reabsorbed, because only 10% of the filtered load is present in the final urine (4). The transport mechanisms of urate are localized in the proximal tubule (PT), whereas no experimental evidence supports urate permeability in the more distal segments of the nephron (5). URAT1, the long-hypothesized apical urate-anion exchanger involved in the reabsorption of urate by PT cells, was recently identified (6). Inactivating mutations of URAT1 located on 11q13 are responsible

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Atypical familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1β gene mutation

Cited by 143 publications

References 33 publications

Phenotype and Outcome in Hereditary Tubulointerstitial Nephritis Secondary to UMOD Mutations

Phenotype and Outcome in Hereditary Tubulointerstitial Nephritis Secondary to UMOD Mutations

Spectrum of HNF1B Mutations in a Large Cohort of Patients Who Harbor Renal Diseases

A Cluster of Mutations in the UMOD Gene Causes Familial Juvenile Hyperuricemic Nephropathy with Abnormal Expression of Uromodulin

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