Mutations in the Hepatocyte Nuclear Factor-1β Gene Are Associated with Familial Hypoplastic Glomerulocystic Kidney Disease

Bingham, Coralie; Bulman, Michael P.; Ellard, Sian; Allen, Lisa; Lipkin, Graham; Hoff, William G. van’t; Woolf, Adrian S.; Rizzoni, Gianfranco; Novelli, Giuseppe; Nicholls, Anthony; Hattersley, Andrew T.

doi:10.1086/316945

Cited by 253 publications

(187 citation statements)

References 18 publications

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“…Given the predominantly glomerular origin of cysts in the Wwtr1 KO mice, we focused on genes linked to PKD types with a glomerular component. Glomerular cysts are found in juvenile patients with autosomal dominant PKD (16) and have also been reported for tuberous sclerosis complex (17,18), juvenile NPH (19), OFD1 (20), and hypoplastic familial GCKD linked to mutations in HNF1␤ (21). Glomerular cysts are also present in the jcpk (juvenile congenital polycystic kidney) mouse (22), a model for autosomal recessive PKD due to a mutation in the Bicc1 gene (24).…”

Section: Several Genes Linked To Glomerulocystic Kidney Disease (Gckdmentioning

confidence: 86%

Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1

Hossain¹,

Ali²,

Ko³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

259

249

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Wwtr1 is a widely expressed 14-3-3-binding protein that regulates the activity of several transcription factors involved in development and disease. To elucidate the physiological role of Wwtr1, we generated Wwtr1 ؊/؊ mice by homologous recombination. Surprisingly, although Wwtr1 is known to regulate the activity of Cbfa1, a transcription factor important for bone development, Wwtr1 ؊/؊ mice show only minor skeletal defects. However, Wwtr1 ؊/؊ animals present with renal cysts that lead to end-stage renal disease. Cysts predominantly originate from the dilation of Bowman's spaces and atrophy of glomerular tufts, reminiscent of glomerulocystic kidney disease in humans. A smaller fraction of cysts is derived from tubules, in particular the collecting duct (CD). The corticomedullary accumulation of cysts also shows similarities with nephronophthisis. Cells lining the cysts carry fewer and shorter cilia and the expression of several genes associated with glomerulocystic kidney disease (Ofd1 and Tsc1) or encoding proteins involved in cilia structure and/or function (Tg737, Kif3a, and Dctn5) is decreased in Wwtr1 ؊/؊ kidneys. The loss of cilia integrity and the down-regulation of Dctn5, Kif3a, Pkhd1 and Ofd1 mRNA expression can be recapitulated in a renal CD epithelial cell line, mIMCD3, by reducing Wwtr1 protein levels using siRNA. Thus, Wwtr1 is critical for the integrity of renal cilia and its absence in mice leads to the development of renal cysts, indicating that Wwtr1 may represent a candidate gene for polycystic kidney disease in humans.bone ͉ cilia ͉ cysts ͉ glomerulus ͉ gene expression

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Section: Several Genes Linked To Glomerulocystic Kidney Disease (Gckdmentioning

confidence: 86%

Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1

Hossain¹,

Ali²,

Ko³

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

259

249

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“…In the latter case, mutations of the hepatocyte nuclear factor-1␤ gene (HNF-1␤) have been reported. 59 Interestingly, a mutation in HNF-1␤ recently also was found in 1 family with atypical FJHN associated with renal cysts, urogenital malformations, and diabetes. 60 Unfortunately, the presence of cysts affecting glomeruli was not excluded in all patients in this kindred because glomerular cysts cannot be differentiated readily from those localized in tubuli by means of ultrasonography; a renal biopsy is required for a differential diagnosis.…”

Section: Glomerulocystic Kidney Diseasementioning

confidence: 98%

Uromodulin storage diseases: Clinical aspects and mechanisms

Scolari

Caridi

Rampoldi

et al. 2004

American Journal of Kidney Diseases

124

100

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• The recent discovery of mutations in the uromodulin gene (UMOD) in patients with medullary cystic kidney disease type 2 (MCKD2), familial juvenile hyperuricemic nephropathy (FJHN), and glomerulocystic kidney disease (GCKD) provides the opportunity for a revision of pathogenic aspects and puts forth the basis for a renewed classification. This review focuses on clinical, pathological, and cell biology advances in UMOD-related pathological states, including a review of the associated clinical conditions described to date in the literature. Overall, 31 UMOD mutations associated with MCKD2 and FJHN (205 patients) and 1 mutation associated with GCKD (3 patients) have been described, with a cluster at exons 4 and 5. Most are missense mutations causing a cysteine change in uromodulin sequence. No differences in clinical symptoms between carriers of cysteine versus polar residue changes have been observed; clinical phenotypes invariably are linked to classic MCKD2/FJHN. A common motif among all reports is that many overlapping symptoms between MCKD2 and FJHN are present, and a separation between these 2 entities seems unwarranted or redundant. Cell experiments with mutant variants indicated a delay in intracellular maturation and export dynamics, with consequent uromodulin storage within the endoplasmic reticulum (ER). Patchy uromodulin deposits in tubule cells were found by means of immunohistochemistry, and electron microscopy showed dense fibrillar material in the ER. Mass spectrometry showed only unmodified uromodulin in urine of patients with UMOD mutations. Lack of uromodulin function(s) is associated with impairments in tubular function, particularly the urine-concentrating process, determining water depletion and hyperuricemia. Intracellular uromodulin trapping within the ER probably has a major role in determining tubulointerstitial fibrosis and renal failure. We propose the definition of uromodulin storage diseases for conditions with proven UMOD mutations. Am J Kidney Dis 44:987-999.

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“…2 This disease was therefore renamed renal cysts and diabetes syndrome in 2001. 3 However, it now seems to be a clinical entity with a more broad and variable phenotype. Moreover, not all patients with an HNF1B mutation actually have renal cysts and/or diabetes.…”

mentioning

confidence: 99%

Hepatocyte Nuclear Factor 1β–Associated Kidney Disease

Verhave

Bech

Wetzels

et al. 2016

Journal of the American Society of Nephrology

130

121

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Hepatocyte nuclear factor 1b (HNF1b)-associated disease is a recently recognized clinical entity with a variable multisystem phenotype. Early reports described an association between HNF1B mutations and maturity-onset diabetes of the young. These patients often presented with renal cysts and renal function decline that preceded the diabetes, hence it was initially referred to as renal cysts and diabetes syndrome. However, it is now evident that many more symptoms occur, and diabetes and renal cysts are not always present. The multisystem phenotype is probably attributable to functional promiscuity of the HNF1b transcription factor, involved in the development of the kidney, urogenital tract, pancreas, liver, brain, and parathyroid gland. Nephrologists might diagnose HNF1b-associated kidney disease in patients referred with a suspected diagnosis of autosomal dominant polycystic kidney disease, medullary cystic kidney disease, diabetic nephropathy, or CKD of unknown cause. Associated renal or extrarenal symptoms should alert the nephrologist to HNF1b-associated kidney disease. A considerable proportion of these patients display hypomagnesemia, which sometimes mimics Gitelman syndrome. Other signs include early onset diabetes, gout and hyperparathyroidism, elevated liver enzymes, and congenital anomalies of the urogenital tract. Because many cases of this disease are probably undiagnosed, this review emphasizes the clinical manifestations of HNF1b-associated disease for the nephrologist.

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Mutations in the Hepatocyte Nuclear Factor-1β Gene Are Associated with Familial Hypoplastic Glomerulocystic Kidney Disease

Cited by 253 publications

References 18 publications

Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1

Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1

Uromodulin storage diseases: Clinical aspects and mechanisms

Hepatocyte Nuclear Factor 1β–Associated Kidney Disease

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