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Hepatocyte nuclear factor-1-beta (HNF1B), also known as transcription factor-2 (TCF2), is a member of the homeodomain-containing superfamily of transcription factors.

Expression

Early expression of TCF2 is seen in the kidney, liver, bile ducts, thymus, genital tract, pancreas, lung, and gut. It can act either as a homodimer or as a heterodimer with HNF1A (MIM.142410).

The transcription factor hepatocyte nuclear factor HNF1B (TCF2) is expressed from the earliest stages of development of the Wolffian duct, the mesonephros and metanephros, and the Mullerian ducts in the mouse.

Functions

Hepatocyte nuclear factor-1beta (HNF-1beta) is a critical transcription factor in pancreatic and renal development.

HNF1B is a widely distributed transcription factor which plays a critical role in embryonic development of the kidney, pancreas, liver, and Mullerian duct.

The transcription factor hepatocyte nuclear factor (HNF)-1beta (HNF1B) is expressed from the earliest stages of development of the Wolffian duct, the mesonephros and metanephros, and the Müllerian ducts in the mouse.

In adult mice, HNF-1beta is expressed in the kidney tubules, collecting ducts, and in the oviducts and uterus in the female (Müllerian duct derivatives) and in the epididymis, vas deferens and seminal vesicles (Wolffian duct derivatives) in the male.

Pathology

HNF-1beta mutations have been reported in families where affected members have renal abnormalities, female genital tract malformations and early-onset diabetes. Renal and uterine abnormalities have not been described in families without early-onset diabetes.

Thirty HNF-1beta mutations have been reported in patients with renal cysts and other renal developmental disorders, young-onset diabetes, pancreatic atrophy, abnormal liver function tests, and genital tract abnormalities.

Mutations: HNF1B-V61G, HNF1B-V110G, HNF1B-S148L, HNF1B-K156E, HNF1B-Q176X, HNF1B-R276Q, HNF1B-S281fsinsC, HNF1B-R295P, HNF1B-H324fsdelCA, HNF1B-Q470X. 30% of de novo mutations. (#15930087#)

Mutant phenotype (#15930087#)

 renal cysts
 glomerulocystic kidney disease (GCKD)
 diabetes

• maturity-onset diabetes of the young (MODY)
• renal cysts and diabetes (RCAD)

No clear genotype/phenotype relationships. (#15930087#)

Despite the original description of HNF-1beta as a MODY gene, a personal/family history of diabetes is often absent and the most common clinical manifestation is renal cysts. (#15930087#)

Molecular genetic testing for HNF-1beta mutations should be considered in patients with unexplained renal cysts (including GCKD), especially when associated with diabetes, early-onset gout, or uterine abnormalities. (#15930087#)

Pathology

 HNF1B germline mutation in

• MODY type V (MODY5) (MIM.604284)
  • MODY5 (MIM.604284) with mullerian aplasia (vaginal aplasia and rudimentary uterus) (MIM.158330)
  • MODY5 (MIM.604284) with nephron agenesis

• noninsulin-dependent type II diabetes (MIM.125853)
• neonatal paucity of intrahepatic bile ducts (neonatal biliary ductopenia) (#17307554#)
• renal cysts and diabetes syndrome (MIM.137920)

• fetal renal anomalies (#17267738#, #16971658#)
  • familial hypoplastic glomerulocystic kidney disease (MIM.137920)
  • renal hypodysplasia (#16971658#)
  • association cystic kidneys and genital tract malformations (#11918730#, #11317673#)
    • uterus bicornuate (uterus didelphys) (#11918730#, #11317673#)
    • hypospadias (#11918730#)

 HNF1B (TCF2) inactivation in tumors

• germline and somatic biallelic TCF2 (HNF1beta) inactivation in
  • chromophobe renal cell carcinoma (MIM.144700) (#15649945#)
    • germline 1-bp deletion at nucleotide 46 (46delC) of the HNF1B gene, resulting in a frameshift and premature truncation at codon 17

 epigenetic inactivation of TCF2 in ovarian cancer (#16479257#)

 HNF1B deletions

HNF-1beta mutations have been identified in 23/160 patients with unexplained renal disease. The most common phenotype is renal cysts, which is frequently associated with early-onset diabetes in the renal cysts and diabetes (RCAD) syndrome.

HNF-1beta gene deletions have recently been shown to cause renal malformations and early-onset diabetes. The phenotype associated with deletions or coding region/splicing mutations is very similar suggesting that haploinsufficiency is the underlying mechanism. (#17971380#)

See also

 pathology of transcription factors

• pathology of TCFs

References

 Solitary functioning kidney and diverse genital tract malformations associated with hepatocyte nuclear factor-1beta mutations. Bingham C, Ellard S, Cole TR, Jones KE, Allen LI, Goodship JA, Goodship TH, Bakalinova-Pugh D, Russell GI, Woolf AS, Nicholls AJ, Hattersley AT. Kidney Int. 2002 Apr;61(4):1243-51. PMID: #11918730#

 Hepatocyte nuclear factor-1beta gene deletions—a common cause of renal disease. Edghill EL, Oram RA, Owens M, Stals KL, Harries LW, Hattersley AT, Ellard S, Bingham C. Nephrol Dial Transplant. 2008 Feb;23(2):627-35. PMID: #17971380#

 Mefford HC, Clauin S, Sharp AJ, Moller RS, Ullmann R, Kapur R, Pinkel D, Cooper GM, Ventura M, Ropers HH, Tommerup N, Eichler EE, Bellanne-Chantelot C. Recurrent reciprocal genomic rearrangements of 17q12 are associated with renal disease, diabetes, and epilepsy. Am J Hum Genet. 2007 Nov;81(5):1057-69. PMID: #17924346#

 Decramer S, Parant O, Beaufils S, Clauin S, Guillou C, Kessler S, Aziza J, Bandin F, Schanstra JP, Bellanne-Chantelot C. Anomalies of the TCF2 Gene Are the Main Cause of Fetal Bilateral Hyperechogenic Kidneys. J Am Soc Nephrol. 2007 Mar;18(3):923-33. PMID: #17267738#

 Beckers D, Bellanne-Chantelot C, Maes M. Neonatal cholestatic jaundice as the first symptom of a mutation in the hepatocyte nuclear factor-1beta gene (HNF-1beta). J Pediatr. 2007 Mar;150(3):313-4. PMID: #17307554#

 Decramer S, Parant O, Beaufils S, Clauin S, Guillou C, Kessler S, Aziza J, Bandin F, Schanstra JP, Bellanne-Chantelot C. Anomalies of the TCF2 Gene Are the Main Cause of Fetal Bilateral Hyperechogenic Kidneys. J Am Soc Nephrol. 2007 Mar;18(3):923-33. PMID: #17267738#

 Weber S, Moriniere V, Knuppel T, Charbit M, Dusek J, Ghiggeri GM, Jankauskiene A, Mir S, Montini G, Peco-Antic A, Wuhl E, Zurowska AM, Mehls O, Antignac C, Schaefer F, Salomon R. Prevalence of mutations in renal developmental genes in children with renal hypodysplasia: results of the ESCAPE study. J Am Soc Nephrol. 2006 Oct;17(10):2864-70. PMID: #16971658#

 Woolf AS. Renal hypoplasia and dysplasia: starting to put the puzzle together. J Am Soc Nephrol. 2006 Oct;17(10):2647-9. PMID: #16959822#

 Lebrun G, Vasiliu V, Bellanne-Chantelot C, Bensman A, Ulinski T, Chretien Y, Grunfeld JP. Cystic kidney disease, chromophobe renal cell carcinoma and TCF2 (HNF1 beta) mutations. Nat Clin Pract Nephrol. 2005 Dec;1(2):115-9. PMID: #16932376#

 Mutations in hepatocyte nuclear factor-1beta and their related phenotypes. Edghill EL, Bingham C, Ellard S, Hattersley AT. J Med Genet. 2006 Jan;43(1):84-90. PMID: #15930087#

 Haumaitre C, Fabre M, Cormier S, Baumann C, Delezoide AL, Cereghini S. Severe pancreas hypoplasia and multicystic renal dysplasia in two human fetuses carrying novel HNF1beta/MODY5 mutations. Hum Mol Genet. 2006 Aug 1;15(15):2363-75. PMID: #16801329#

 Woolf AS. Unilateral multicystic dysplastic kidney. Kidney Int. 2006 Jan;69(1):190-3. PMID: #16374443#

 Ulinski T, Lescure S, Beaufils S, Guigonis V, Decramer S, Morin D, Clauin S, Deschenes G, Bouissou F, Bensman A, Bellanne-Chantelot C. Renal phenotypes related to hepatocyte nuclear factor-1beta (TCF2) mutations in a pediatric cohort. J Am Soc Nephrol. 2006 Feb;17(2):497-503. PMID: #16371430#

 Haumaitre C, Barbacci E, Jenny M, Ott MO, Gradwohl G, Cereghini S. Lack of TCF2/vHNF1 in mice leads to pancreas agenesis. Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1490-5. PMID: #15668393#

 Rebouissou S, Vasiliu V, Thomas C, Bellanne-Chantelot C, Bui H, Chretien Y, Timsit J, Rosty C, Laurent-Puig P, Chauveau D, Zucman-Rossi J. Germline hepatocyte nuclear factor 1alpha and 1beta mutations in renal cell carcinomas. Hum Mol Genet. 2005 Mar 1;14(5):603-14. PMID: #15649945#

 Bingham C, Hattersley AT. Renal cysts and diabetes syndrome resulting from mutations in hepatocyte nuclear factor-1beta. Nephrol Dial Transplant. 2004 Nov;19(11):2703-8. PMID: #15496559#

 Fischer E, Gresh L, Reimann A, Pontoglio M. Cystic kidney diseases: learning from animal models. Nephrol Dial Transplant. 2004 Nov;19(11):2700-2. PMID: #15496558#

 Wu G, Bohn S, Ryffel GU. The HNF1beta transcription factor has several domains involved in nephrogenesis and partially rescues Pax8/lim1-induced kidney malformations. Eur J Biochem. 2004 Sep;271(18):3715-28. PMID: #15355349#