HNF-1β Regulates Transcription of the PKD Modifier Gene Kif12

Gong, Yimei; Ma, Zhendong; Patel, Vishal; Fischer, Evelyne; Hiesberger, Thomas; Pontoglio, Marco; Igarashi, Peter

doi:10.1681/asn.2008020238

Cited by 54 publications

(48 citation statements)

References 22 publications

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“…33 Recently, chromatin immunoprecipitation array experiments were used to seek gene targets for Hnf1b in mouse kidneys. 34 Consistent with our observation of HNF1-binding sites in human FXYD2, the mouse im- Three different splice variants are recognized for human FXYD2 (Figure 3A), the main ones being variants a and b. 35 An immunohistochemical study of rat kidneys reported that TALs in the inner medullary stripe expressed both Fxyd2a and b isoforms, whereas Fxyd2a was predominant in proximal tubules and Fxyd2b in DCTs, connecting tubules, and other TAL.…”

Section: Discussionsupporting

confidence: 86%

HNF1B Mutations Associate with Hypomagnesemia and Renal Magnesium Wasting

Adalat

Woolf

Johnstone

et al. 2009

Journal of the American Society of Nephrology

240

238

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Mutations in hepatocyte nuclear factor 1B (HNF1B), which is a transcription factor expressed in tissues including renal epithelia, associate with abnormal renal development. While studying renal phenotypes of children with HNF1B mutations, we identified a teenager who presented with tetany and hypomagnesemia. We retrospectively reviewed radiographic and laboratory data for all patients from a single center who had been screened for an HNF1B mutation. We found heterozygous mutations in 21 (23%) of 91 cases of renal malformation. All mutation carriers had abnormal fetal renal ultrasonography. Plasma magnesium levels were available for 66 patients with chronic kidney disease (stages 1 to 3). Striking, 44% (eight of 18) of mutation carriers had hypomagnesemia (Ͻ1.58 mg/dl) compared with 2% (one of 48) of those without mutations (P Ͻ 0.0001). The median plasma magnesium was significantly lower among mutation carriers than those without mutations (1.68 versus 2.02 mg/dl; P Ͻ 0.0001). Because hypermagnesuria and hypocalciuria accompanied the hypomagnesemia, we analyzed genes associated with hypermagnesuria and detected highly conserved HNF1 recognition sites in FXYD2, a gene that can cause autosomal dominant hypomagnesemia and hypocalciuria when mutated. Using a luciferase reporter assay, we demonstrated HNF1B-mediated transactivation of FXYD2. These results extend the phenotype of HNF1B mutations to include hypomagnesemia. HNF1B regulates transcription of FXYD2, which participates in the tubular handling of Mg 2ϩ , thus describing a role for HNF1B not only in nephrogenesis but also in the maintenance of tubular function.

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Section: Discussionsupporting

confidence: 86%

HNF1B Mutations Associate with Hypomagnesemia and Renal Magnesium Wasting

Adalat

Woolf

Johnstone

et al. 2009

Journal of the American Society of Nephrology

240

238

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“…Cys1 is responsible for congenital polycystic kidney (CPK) disease (Tao et al, 2009) and is involved in ciliogenesis and polarization of cholangiocytes (Raynaud et al, 2011), whereas Glis3 is implicated in polycystic disease in both kidney (Kang et al, 2009a) and pancreas (Kang et al, 2009b). Among these genes, Kif12, Pkhd1, Pkd2 and Bicc1 were identified as direct Hnf1b targets in the kidney (Gong et al, 2009;Gresh et al, 2004;Verdeguer et al, 2010). Thus, we analyzed whether Hnf1b could be a major regulator of these genes in the pancreas by ChIP experiments on E12.5 pancreata (Fig.…”

Section: Hnf1b Controls Duct Morphogenesis By Regulating Cystic Diseamentioning

confidence: 99%

Hnf1b controls pancreas morphogenesis and the generation of Ngn3+ endocrine progenitors

et al. 2015

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Heterozygous mutations in the human HNF1B gene are associated with maturity-onset diabetes of the young type 5 (MODY5) and pancreas hypoplasia. In mouse, Hnf1b heterozygous mutants do not exhibit any phenotype, whereas the homozygous deletion in the entire epiblast leads to pancreas agenesis associated with abnormal gut regionalization. Here, we examine the specific role of Hnf1b during pancreas development, using constitutive and inducible conditional inactivation approaches at key developmental stages. Hnf1b early deletion leads to a reduced pool of pancreatic multipotent progenitor cells (MPCs) due to decreased proliferation and increased apoptosis. Lack of Hnf1b either during the first or the secondary transitions is associated with cystic ducts. Ductal cells exhibit aberrant polarity and decreased expression of several cystic disease genes, some of which we identified as novel Hnf1b targets. Notably, we show that Glis3, a transcription factor involved in duct morphogenesis and endocrine cell development, is downstream Hnf1b. In addition, a loss and abnormal differentiation of acinar cells are observed. Strikingly, inactivation of Hnf1b at different time points results in the absence of Ngn3 + endocrine precursors throughout embryogenesis. We further show that Hnf1b occupies novel Ngn3 putative regulatory sequences in vivo. Thus, Hnf1b plays a crucial role in the regulatory networks that control pancreatic MPC expansion, acinar cell identity, duct morphogenesis and generation of endocrine precursors. Our results uncover an unappreciated requirement of Hnf1b in endocrine cell specification and suggest a mechanistic explanation of diabetes onset in individuals with MODY5.

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“…During kidney development, the gene is expressed in the ureteric bud, in the comma-and S-shaped bodies, and then in the proximal and distal tubules but not in the glomerulus (9). Kidney-specific inactivation of Hnf1B in the mouse leads to cystic disease, and HNF1␤ was shown to bind directly DNA elements that regulate the expression of genes whose mutations are responsible for cystic kidney diseases (Nphp1, polaris, Umod, Pkhd1, and Pkd2) (10) or of a gene identified as a candidate modifier in a mouse model of cystic kidney disease (Kif12) (11). Here we report on HNF1B mutation screening in a series of 377 unrelated patients who presented with various kidney phenotypes, giving special attention to the prenatal renal phenotypes.…”

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confidence: 99%

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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HNF-1β Regulates Transcription of the PKD Modifier Gene Kif12

Cited by 54 publications

References 22 publications

HNF1B Mutations Associate with Hypomagnesemia and Renal Magnesium Wasting

HNF1B Mutations Associate with Hypomagnesemia and Renal Magnesium Wasting

Hnf1b controls pancreas morphogenesis and the generation of Ngn3+ endocrine progenitors

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

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