Alternative titles; symbols
HGNC Approved Gene Symbol: HNF1B
SNOMEDCT: 128667008, 253864004, 44054006, 609572000, 733471003; ICD10CM: E11;
Cytogenetic location: 17q12 Genomic coordinates (GRCh38): 17:37,686,431-37,745,059 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q12 | {Renal cell carcinoma} | 144700 | 3 | |
| Renal cysts and diabetes syndrome | 137920 | Autosomal dominant | 3 | |
| Type 2 diabetes mellitus | 125853 | Autosomal dominant | 3 |
Hepatocyte nuclear factor-1-beta (HNF1B), also known as transcription factor-2 (TCF2), is a member of the homeodomain-containing superfamily of transcription factors (Bach et al., 1991). 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 (142410) (Edghill et al., 2006).
Abbott et al. (1990) isolated and partially sequenced a human clone corresponding to the HNF1B gene, which they called LFB3.
Bach et al. (1991) isolated a cDNA clone from a human liver library encoding a protein, designated HNF1B, that is highly homologous to HNF1A in 3 regions, including the homeodomain and the dimerization domain. They showed that this protein can heterodimerize with human HNF1A in vitro. Sequence comparison with a rat variant HNF1A identified the cDNA as the human homolog. HNF1B is a nuclear protein recognizing the same binding site as HNF1A. By Northern blot analysis, Bach et al. (1991) showed that the HNF1B transcripts are present in differentiated human HepG2 hepatoma cells as well as in rat liver and that this transcript level is 10- to 20-fold lower than that of HNF1A.
The HNF1B gene contains 9 exons (Horikawa et al., 1997).
By analysis of human/rodent somatic cell hybrids, Abbott et al. (1990) mapped the TCF2 gene to chromosome 17q between the centromere and the breakpoint of acute promyelocytic leukemia, i.e., proximal to 17q22.
Bach et al. (1991) assigned the HNF1B gene to human chromosome 17 and mouse chromosome 11. The HNF1A gene maps to human chromosome 12 and mouse chromosome 5.
Gudmundsson et al. (2007) noted that the HNF1B gene maps to chromosome 17q12.
Kolatsi-Joannou et al. (2001) detected TCF2 mRNA in liver, pancreas, stomach, and lung through 91 days' gestation in 6 terminated normal human fetuses. Renal metanephroi expressed the gene at preglomerular stages during metanephrogenesis. The expression was most prominent in medullary and cortical collecting duct branches, which are ureteric bud derivatives. TCF2 gene expression was not detected in mesenchymal tissues, suggesting that it plays a role in epithelial differentiation.
Using genomewide chromatin immunoprecipitation and DNA microarray analysis and microarray analysis of mRNA expression, Ma et al. (2007) identified Socs3 (604176) as an Hnf1b target gene in mouse kidney. Hnf1b bound to the Socs3 promoter and repressed Socs3 transcription. Expression of Socs3 increased in Hnf1b-knockout mice and in renal epithelial cells expressing dominant-negative mutant Hnf1b. Increased levels of Socs3 inhibited Hgf (142409)-induced tubulogenesis by decreasing phosphorylation of Erk (see MAPK1; 176948) and Stat3 (102582). Conversely, knockdown of Socs3 in renal epithelial cells expressing dominant-negative mutant Hnf1b rescued the defect in Hgf-induced tubulogenesis by restoring phosphorylation of Erk and Stat3. Ma et al. (2007) concluded that HNF1B regulates renal tubulogenesis by controlling expression of SOC3.
By time-lapse microscopy of IMCD3 mouse renal cells expressing fluorescence-tagged Hnf1b, Verdeguer et al. (2010) found that, unlike the classical behavior of transcription factors, such as Hnf4a (600281), a substantial fraction of Hnf1b remained associated with mitotic chromatin and traveled with condensed chromosomes throughout mitosis. From these observations and data they obtained following conditional knockout of Hnf1b in mice (see ANIMAL MODEL), Verdeguer et al. (2010) hypothesized that HNF1B functions as both a classic transcriptional activator and as a bookmarking factor that marks target genes for rapid transcriptional reactivation after mitosis.
Kornfeld et al. (2013) found that inducible transgenic overexpression of Mir802 (616090) in mice caused impaired glucose tolerance and attenuated insulin sensitivity, whereas reduction of Mir802 expression improved glucose tolerance and insulin action. The authors identified Hnf1b as a target of Mir802-dependent silencing, and showed that short hairpin RNA (shRNA)-mediated reduction of Hnf1b in liver causes glucose intolerance, impairs insulin signaling, and promotes hepatic gluconeogenesis. In turn, hepatic overexpression of Hnf1b improves insulin sensitivity in Lepr (601007)(db/db) mice. Kornfeld et al. (2013) concluded that their study defined a critical role for deregulated expression of MIR802 in the development of obesity-associated impairment of glucose metabolism through targeting of HNF1B, and assigned HNF1B an unexpected role in the control of hepatic insulin sensitivity.
Renal Cysts and Diabetes Syndrome
In 2 Japanese sibs with a phenotype consistent with renal cysts and diabetes syndrome (RCAD; 137920), Horikawa et al. (1997) identified a heterozygous mutation in the TCF2 gene (189907.0001). The sibs developed diabetes mellitus at ages 10 and 15 years, respectively, consistent with a diagnosis of maturity-onset diabetes of the young (MODY5). Although there was no report of renal appearance or histology, a nonspecific nephropathy was described.
In affected members of a Norwegian family with renal cysts and diabetes syndrome, Lindner et al. (1999) identified a 75-bp deletion in exon 2 of the TCF2 gene (189907.0002). Bingham et al. (2000) identified a heterozygous 5-bp deletion in the TCF2 gene (189907.0003) in a woman with renal cysts and diabetes syndrome.
Bingham et al. (2001) identified 2 different heterozygous mutations in the TCF2 gene (189907.0004 and 189907.0005) in affected members of the families reported by Rizzoni et al. (1982) and Kaplan et al. (1989) as having familial hypoplastic glomerulocystic kidney disease. All of the patients eventually developed diabetes mellitus.
In 8 probands and 5 offspring with renal cysts and diabetes syndrome, Bellanne-Chantelot et al. (2004) identified 8 novel mutations in the TCF2 gene, all in the DNA-binding domain: 5 missense mutations (see, e.g., 189907.0014), 2 nonsense mutations, and 1 mutation in the splice donor site of intron 2 at the highly conserved +1 position. Cosegregation of the mutation and the phenotype was observed in 4 families; 2 mutations were de novo. The patients had various renal abnormalities and some also had genital tract abnormalities and pancreatic atrophy. Eleven patients had abnormal liver enzyme levels with normal liver function.
Barbacci et al. (2004) functionally characterized 5 missense mutations, 2 truncating mutations, and 1 frameshift deletion in different domains of the TCF2 protein. Truncation mutations, retaining the dimerization domain, displayed defective nuclear localization and weak dominant-negative activity when coexpressed with the wildtype protein. A frameshift mutation located within the C-terminal QSP-rich domain partially reduced transcriptional activity, whereas selective deletion of this domain abolished transactivation. All 5 missense mutations, which involved POU-specific and homeodomain residues, were correctly expressed and localized to the nucleus. Although having different effects on DNA-binding capacity that ranged from complete loss to mild reduction, these mutations exhibited severe reduction in transactivation capacity. The transcriptional impairment of mutations with weak or unaffected DNA-binding activity correlated with the loss of association with 1 of the histone-acetyltransferases CREBBP (600140) or PCAF (602303). In contrast to the transactivation potential of wildtype TCF2, which depends on the synergistic action of CREBBP and PCAF, the activity of these mutants was not increased by the synergistic action of these 2 coactivators or by treatment with a specific histone-deacetylase inhibitor. Barbacci et al. (2004) concluded that the complex syndrome associated with TCF2 mutations arises from either defective DNA-binding or decreased transactivation function through impaired coactivator recruitment.
Harries et al. (2005) investigated the susceptibility to nonsense-mediated decay (NMD) of 6 truncating HNF1B mutations. Four of the 6 mutations showed evidence of NMD; 2 mutations, 1 of which was P159fsdelT (189907.0005), produced transcripts unexpectedly immune to NMD. Harries et al. (2005) concluded that truncating mutant transcripts of the HNF1B gene do not conform to the known rules governing NMD susceptibility, but instead demonstrate a previously unreported 5-prime to 3-prime polarity. They hypothesized that this may be due to reinitiation of translation downstream of the premature termination codon, thus providing a mechanism for the evasion of NMD, but that other factors such as the distance from the native initiation codon may play a part.
Nakayama et al. (2010) identified heterozygous pathogenic HNF1B mutations in 5 (10%) of 50 Japanese children with congenital anomalies of the kidney and urinary tract (CAKUT), including 2 with hypodysplastic kidneys and 3 with unilateral multicystic dysplastic kidneys. No mutations were found in 4 patients with a single kidney. There were 3 whole-gene deletions, 1 truncating mutation, and 1 missense mutation. The clinical spectrum of renal disease was variable, ranging in severity from unilateral disease and normal renal function to bilateral disease necessitating transplant. However, none of the patients had evidence of diabetes.
Susceptibility to Chromophobe Renal Cell Carcinoma
Rebouissou et al. (2005) screened 35 renal neoplasms for HNF1A and HNF1B inactivation. Biallelic HNF1B inactivation was found in 2 of 12 chromophobe renal carcinomas by association of 2 germline mutations (189907.0014 and 189907.0015, respectively) with somatic gene deletion. In these cases, expression of PKHD1 (606702) and uromodulin (UMOD; 191845), 2 genes regulated by HNF1B, was turned off. In normal and tumor renal tissues, there was a network of transcription factors differentially regulated in tumor subtypes. There was a related cluster of coregulated genes associating HNF1B, PKHD1, and UMOD. Rebouissou et al. (2005) suggested that germline mutations of HNF1B may predispose to renal tumors and proposed that HNF1B may function as a tumor suppressor gene in chromophobe renal cell carcinogenesis through control of PKHD1 expression.
Possible Association with Prostate Cancer
For information regarding a possible association of single-nucleotide polymorphisms (SNPs) in the HNF1B gene with susceptibility to prostate cancer, see HPC11 (611955).
Wild et al. (2000) reported that the 5-bp deletion in the TCF2 gene reported by Bingham et al. (2000) resulted in a truncated protein that retained the DNA-binding domain; 3 previously reported mutations lacked part of the DNA-binding domain. In transfection experiments, the 5-bp deletion was associated with nephron agenesis and acted as a gain-of-function mutation with increased transactivation potential. Expression of this mutated factor in Xenopus embryos led to defective development and agenesis of the pronephros, the first kidney form of amphibians. Very similar defects were generated by overexpression of wildtype HNF1B, consistent with the gain-of-function property of the mutant. In contrast, introduction of the human 75-bp deletion HNF1B mutant, which was associated with a reduced number of nephrons and hypertrophy of the remaining ones and had impaired DNA binding, showed only a minor effect on pronephros development in Xenopus. Thus, the overexpression of both human mutants had a different effect on renal development in Xenopus, reflecting the variation in renal phenotype seen with these mutations. The findings implied that HNF1B not only is an early marker of kidney development but also is functionally involved in morphogenetic events, and that these processes can be investigated in lower vertebrates.
During pancreatic organogenesis, endocrine cells arise from non-self-renewing progenitors that express Ngn3 (604882). Maestro et al. (2003) showed that from E13 to E18 (the embryonic stage during which the major burst of beta-cell neogenesis takes place) murine pancreatic duct cells express Hnf1b. Ngn3-positive cells at this stage invariably cluster with mitotically competent Hnf1b-positive cells and are often intercalated with these cells in the epithelium that lines the lumen of primitive ducts. Hnf1b expression is markedly reduced in early pancreatic epithelial cells of Hnf6 (ONECUT1; 604164)-deficient mice, in which formation of Ngn3-positive cells is defective. Maestro et al. (2003) suggested that Hnf1b plays a role in the genetic hierarchy regulating the generation of pancreatic endocrine cells.
Hiesberger et al. (2004) identified an evolutionarily conserved TCF2-binding site in the proximal promoter of the mouse Pkhd1 gene. Mutations in the human homolog (PKHD1; 606702) cause autosomal recessive polycystic kidney disease (see 263200). Wildtype Tcf2 and the structurally related Tcf1 were noted to bind specifically to the Pkhd1 promoter and activate gene transcription. Expression of a dominant-negative Tcf2 mutant inhibited Pkhd1 expression and produced renal cysts in transgenic mice. Pkhd1 transcripts were absent in the cells lining the cysts but were present in morphologically normal surrounding tubules. The authors concluded that TCF2 directly regulates the transcription of PKHD1 and that inhibition of PKHD1 gene expression may contribute to the formation of renal cysts in humans with MODY5.
Verdeguer et al. (2010) found that conditional knockout of Hnf1b expression in young mice led to the development of polycystic kidneys, whereas knockout on postnatal day 10 or later significantly delayed cyst development. Experiments with ischemia-reperfusion injury of adult wildtype and Hnf1b-knockout kidneys suggested that cyst formation following Hnf1b knockout required a background of rapid cell proliferation. In both developing kidney and regenerating adult kidney, Hnf1b knockout enhanced cell proliferation and distorted the orientation and synchronization of tubule cells required for tubule elongation, resulting in tubule dilation and cyst formation. Verdeguer et al. (2010) concluded that HNF1B is required to rapidly reactivate crucial target genes that orient rapidly proliferating cells toward tubule elongation.
In 2 Japanese sibs with renal disease and diabetes syndrome (RCAD; 137920), Horikawa et al. (1997) identified a heterozygous C-to-T transition in the TCF2 gene, resulting in an arg177-to-ter (R177X) substitution. The R177X mutation generated a truncated 176-residue protein with the NF2-dimerization and POU domains. This truncated protein did not stimulate transcription of a rat albumin promoter-linked reporter gene or inhibit the activity of wildtype TCF2, consistent with a loss of function. The 2 sibs had onset of diabetes at ages 10 and 15, respectively, consistent with a diagnosis of maturity-onset diabetes of the young type 5 (MODY5). Although both parents had late-onset diabetes, only the mother carried the TCF2 mutation. Horikawa et al. (1997) postulated that the early onset in the children reflected bilineal inheritance of 2 different diabetes susceptibility genes.
In affected members of a Norwegian family with renal cysts and diabetes syndrome (137920), Lindner et al. (1999) identified a 75-bp deletion spanning nucleotides 409 to 483 in exon 2 of the TCF2 gene (189907.0002), resulting in the synthesis of a protein lacking amino acids arg137 to lys161. This deletion was located in the pseudo-POU region of TCF2, a region implicated in the specificity of DNA binding. Functional studies of the mutant TCF2 protein showed that it could not bind a TCF1 target sequence or stimulate transcription of the reporter gene, indicating that this was a loss-of-function mutation. Two of 4 female mutation carriers had vaginal aplasia and rudimentary uterus (mullerian aplasia; 277000) in addition to diabetes and renal disease. The presence of internal genital malformations suggested that additional clinical features may be associated with TCF2 mutations.
In a woman with renal cysts and diabetes syndrome (137920), Bingham et al. (2000) identified a heterozygous 5-bp deletion in the TCF2 gene, which the authors designated P328L329fsdelCCTCT, resulting in a frameshift and premature termination of the protein. Her first pregnancy was terminated at 17 weeks following an ultrasound diagnosis of bilateral nonfunctioning cystic kidneys. Her first-born child had small multicystic, dysplastic kidneys with no normal nephrogenesis.
Wild et al. (2000) demonstrated that the 5-bp deletion reported by Bingham et al. (2000) resulted in a truncated protein that retained the DNA-binding domain; 3 previously reported mutations lacked part of the DNA-binding domain. Transfection experiments showed that the 5-bp deletion was associated with nephron agenesis and acted as a gain-of-function mutation with increased transactivation potential. Expression of this mutated factor in Xenopus embryos led to defective development and agenesis of the pronephros, the first kidney form of amphibians. Very similar defects were generated by overexpression of wildtype TCF2, consistent with the gain-of-function property of the mutant.
In 3 affected members of an Italian family with renal cysts and diabetes syndrome (137920), Bingham et al. (2001) identified a heterozygous mutation in exon 1 of the TCF2 gene, resulting in a glu101-to-ter (E101X) substitution. The family was originally described by Rizzoni et al. (1982) as having familial hypoplastic glomerulocystic kidney disease.
In affected members of a family with renal cysts and diabetes syndrome (137920), Bingham et al. (2001) identified a heterozygous 1-bp deletion (delT) in exon 2 of the TCF2 gene, predicted to result in a frameshift and premature termination of the protein at codon 160. The family had originally been reported by Kaplan et al. (1989) as having familial hypoplastic glomerulocystic kidney disease.
Furuta et al. (2002) screened the HNF1B gene for mutations in a group of 126 unrelated Japanese patients with type II diabetes (125853) and a family history of at least 1 first-degree relative with diabetes. In a patient with diabetes diagnosed at 13 years of age, they found a C-to-T transition in exon 4 of the HNF1B gene, which resulted in an arg276-to-ter (R276X) amino acid substitution in the protein product. This patient had MODY5 (137920) misdiagnosed as common type II diabetes. He had small kidneys with multiple bilateral renal cysts and decreased urinary concentrating ability. Functional studies indicated that the mutant hepatocyte nuclear factor-1-beta was inactive.
In a group of 126 unrelated Japanese patients with type 2 diabetes (T2D; 125853) and a family history of at least 1 first-degree relative with diabetes, Furuta et al. (2002) identified a C-to-G translation in exon 7 of the HNF1B gene, resulting in a ser465-to-arg (S465R) amino acid substitution, in a 50-year-old female diagnosed at 49 years of age. On screening a second group of 272 randomly selected patients with type 2 diabetes, they identified a second patient with the S465R mutation, a 68-year-old male whose diabetes was well controlled with diet therapy. Neither patient with the S465R mutation showed evidence of kidney disease. Functional studies indicated that the mutant protein exhibited a 22% reduction in activity compared with the wildtype protein. The S465R mutation may function in a dominant-negative manner. The authors concluded that the S465R mutation, found in 0.5% of patients with common type 2 diabetes examined, may thus be a rare genetic risk factor contributing to the development of type 2 diabetes rather than MODY5.
In a mother and son with renal cysts and diabetes syndrome (137920), Kolatsi-Joannou et al. (2001) identified a heterozygous 1-bp insertion (1055insA) in exon 5 of the TCF2 gene, resulting in a frameshift and premature termination of the protein at codon 352. The son had congenital cystic kidneys and was normoglycemic at age 12 years; his mother developed gestational diabetes at age 24 years and later developed renal cysts. The mutant TCF2 protein was predicted to retain dimerization and DNA-binding domains, but to lack most of the transactivation domain.
In a mother and 2 daughters with renal cysts and diabetes syndrome (137920), Iwasaki et al. (2001) identified a heterozygous G-to-A transition in intron 2 of the TCF2 gene, resulting in a splice site mutation. The mother developed diabetes at age 27 years and the children at ages 11 years. All had renal cysts, the mother had a bicornuate uterus, and 1 of the daughters had hyperuricemia. The mutation was not identified in 100 control chromosomes.
In affected members of a family with renal cysts and diabetes syndrome (137920), Bingham et al. (2003) identified a heterozygous splice site mutation in the TCF2 gene. The patients also showed juvenile hyperuricemic nephropathy and early-onset gout. Bingham et al. (2003) concluded that hyperuricemia is a consistent feature of the disorder. A G-to-A transition in the same splice site position had been reported by Iwasaki et al. (2001); see 189907.0009.
In 2 sibs with discordant phenotypes of the renal cysts and diabetes syndrome (137920), Yorifuji et al. (2004) reported recurrence of a missense mutation in TCF2 in 2 sibs, ser148 to trp (S148W), caused by a C-to-G transversion at nucleotide 443 in exon 2. The first sib had neonatal diabetes mellitus and kidneys with only a few small cysts and normal renal function. The second had neonatal polycystic, dysplastic kidneys leading to early renal failure but only a transient episode of hyperglycemia, which resolved spontaneously. Both parents were clinically unaffected, and RFLP analysis showed that the mother was a low-level mosaic of normal and mutant TCF2, which suggested that the recurrence was caused by germline mosaicism.
In 3 affected members of a French family with renal cysts and diabetes syndrome (137920), Carette et al. (2007) identified duplication of exon 5 (gly349_M402dup) of the TCF2 gene. There was wide intrafamilial variability of the phenotype. The proband had hyperuricemic nephropathy and early gout, chronic renal failure, renal morphologic abnormalities, abnormal liver tests, and diabetes. His son had almost no clinical expression of the disease, whereas his grandson had a restricted but severe renal phenotype present from birth.
In 54-year-old woman with renal cysts and diabetes syndrome (137920), Bellanne-Chantelot et al. (2004), identified heterozygosity for a 494G-A transition in the HNF1B gene, resulting in an arg165-to-his (R165H) substitution. She was diagnosed with MODY5 at age 20 years and had renal cysts, reduced kidney size, and bicornuate uterus. At age 54, she was diagnosed with chromophobe renal carcinoma (144700). By mutation screening of tumor samples, Rebouissou et al. (2005) identified biallelic inactivation resulting from the R165H mutation and a somatic gene deletion.
In a 37-year-old woman with chromophobe renal cell carcinoma (144700), Rebouissou et al. (2005) identified a germline 1-bp deletion at nucleotide 46 (46delC) of the HNF1B gene, resulting in a frameshift and premature termination at codon 17. Mutation screening of tumor samples identified biallelic inactivation resulting from the 1-bp deletion and a somatic gene deletion. Following partial nephrectomy of the primary tumor, local recurrence of 5 renal tumors required radical nephrectomy. In the recurrent tumor specimens, HNF1B alterations were identical to the primary tumor. When evaluated for MODY5, the patient had no liver test abnormality or diabetes, but CT scan detected absence of the body and tail of the pancreas. Renal abnormalities were observed in 2 of her children, but no other relatives exhibited findings suggestive of MODY5.
Abbott, C., Piaggio, G., Ammendola, R., Solomon, E., Povey, S., Gounari, F., De Simone, V., Cortese, R. Mapping of the gene TCF2 for the transcription factor LFB3 to human chromosome 17 by polymerase chain reaction. Genomics 8: 165-167, 1990. [PubMed: 2081590] [Full Text: https://doi.org/10.1016/0888-7543(90)90239-q]
Bach, I., Mattei, M.-G., Cereghini, S., Yaniv, M. Two members of an HNF1 homeoprotein family are expressed in human liver. Nucleic Acids Res. 19: 3553-3559, 1991. [PubMed: 1677179] [Full Text: https://doi.org/10.1093/nar/19.13.3553]
Barbacci, E., Chalkiadaki, A., Masdeu, C., Haumaitre, C., Lokmane, L., Loirat, C., Cloarec, S., Taliandis, I., Bellanne-Chantelot, C., Cereghini, S. HNF1-beta/TCF2 mutations impair transactivation potential through altered co-regulator recruitment. Hum. Molec. Genet. 13: 3139-3149, 2004. [PubMed: 15509593] [Full Text: https://doi.org/10.1093/hmg/ddh338]
Bellanne-Chantelot, C., Chauveau, D., Gautier, J.-F., Dubois-Laforgue, D., Clauin, S., Beaufils, S., Wilhelm, J.-M., Boitard, C., Noel, L.-H., Velho, G., Timsit, J. Clinical spectrum associated with hepatocyte nuclear factor-1B mutations. Ann. Intern. Med. 140: 510-517, 2004. [PubMed: 15068978] [Full Text: https://doi.org/10.7326/0003-4819-140-7-200404060-00009]
Bingham, C., Bulman, M. P., Ellard, S., Allen, L. I. S., Lipkin, G. W., van't Hoff, W. G., Woolf, A. S., Rizzoni, G., Novelli, G., Nicholls, A. J., Hattersley, A. T. Mutations in the hepatocyte nuclear factor-1-beta gene are associated with familial hypoplastic glomerulocystic kidney disease. Am. J. Hum. Genet. 68: 219-224, 2001. [PubMed: 11085914] [Full Text: https://doi.org/10.1086/316945]
Bingham, C., Ellard, S., Allen, L., Bulman, M., Shepherd, M., Frayling, T., Berry, P. J., Clark, P. M., Lindner, T., Bell, G. I., Ryffel, G. U., Nicholls, A. J., Hattersley, A. T. Abnormal nephron development associated with a frameshift mutation in the transcription factor hepatocyte nuclear factor-1-beta. Kidney Int. 57: 898-907, 2000. [PubMed: 10720943] [Full Text: https://doi.org/10.1046/j.1523-1755.2000.057003898.x]
Bingham, C., Ellard, S., van't Hoff, W. G., Simmonds, A., Marinaki, A. M., Badman, M. K., Winocour, P. H., Stride, A., Lockwood, C. R., Nicholls, A. J., Owen, K. R., Spyer, G., Peason, E. R., Hattersley, A. T. Atypical familial juvenile hyperuricemic nephropathy associated with a hepatocyte nuclear factor-1-beta gene mutation. Kidney Int. 63: 1645-1651, 2003. [PubMed: 12675839] [Full Text: https://doi.org/10.1046/j.1523-1755.2003.00903.x]
Carette, C., Vaury, C., Barthelemy, A., Clauin, S., Grunfeld, J.-P., Timsit, J., Bellanne-Chantelot, C. Exonic duplication of the hepatocyte nuclear factor-1-beta gene (transcription factor 2, hepatic) as a cause of maturity onset diabetes of the young type 5. J. Clin. Endocr. Metab. 92: 2844-2847, 2007. [PubMed: 17440011] [Full Text: https://doi.org/10.1210/jc.2007-0286]
Edghill, E. L., Bingham, C., Ellard, S., Hattersley, A. T. Mutations in hepatocyte nuclear factor-1-beta and their related phenotypes. J. Med. Genet. 43: 84-90, 2006. [PubMed: 15930087] [Full Text: https://doi.org/10.1136/jmg.2005.032854]
Furuta, H., Furuta, M., Sanke, T., Ekawa, K., Hanabusa, T., Nishi, M., Sasaki, H., Nanjo, K. Nonsense and missense mutations in the human hepatocyte nuclear factor-1-beta gene (TCF2) and their relation to type 2 diabetes in Japanese. J. Clin. Endocr. Metab. 87: 3859-3863, 2002. [PubMed: 12161522] [Full Text: https://doi.org/10.1210/jcem.87.8.8776]
Gudmundsson, J., Sulem, P., Steinthorsdottir, V., Bergthorsson, J. T., Thorleifsson, G., Manolescu, A., Rafnar, T., Gudbjartsson, D., Agnarsson, B. A., Baker, A., Sigurdsson, A., Benediktsdottir, K. R., and 63 others. Two variants on chromosome 17 confer prostate cancer risk, and the one in TCF2 protects against type 2 diabetes. Nature Genet. 39: 977-983, 2007. [PubMed: 17603485] [Full Text: https://doi.org/10.1038/ng2062]
Harries, L. W., Bingham, C., Bellanne-Chantelot, C., Hattersley, A. T., Ellard, S. The position of premature termination codons in the hepatocyte nuclear factor--1 beta gene determines susceptibility to nonsense-mediated decay. Hum. Genet. 118: 214-224, 2005. [PubMed: 16133182] [Full Text: https://doi.org/10.1007/s00439-005-0023-y]
Hiesberger, T., Bai, Y., Shao, X., McNally, B. T., Sinclair, A. M., Tian, X., Somlo, S., Igarashi, P. Mutation of hepatocyte nuclear factor-1-beta inhibits Pkhd1 gene expression and produces renal cysts in mice. J. Clin. Invest. 113: 814-825, 2004. [PubMed: 15067314] [Full Text: https://doi.org/10.1172/JCI20083]
Horikawa, Y., Iwasaki, N., Hara, M., Furuta, H., Hinokio, Y., Cockburn, B. N., Lindner, T., Yamagata, K., Ogata, M., Tomonaga, O., Kuroki, H., Kasahara, T., Iwamoto, Y., Bell, G. I. Mutation in hepatocyte nuclear factor-1-beta gene (TCF2) associated with MODY. (Letter) Nature Genet. 17: 384-385, 1997. [PubMed: 9398836] [Full Text: https://doi.org/10.1038/ng1297-384]
Iwasaki, N., Okabe, I., Momoi, M. Y., Ohashi, H., Ogata, M., Iwamoto, Y. Splice site mutation in the hepatocyte nuclear factor-1-beta gene, IVS2nt+1G-A, associated with maturity-onset diabetes of the young, renal dysplasia and bicornuate uterus. (Letter) Diabetologia 44: 387-391, 2001. [PubMed: 11317673] [Full Text: https://doi.org/10.1007/s001250051631]
Kaplan, B. S., Gordon, I., Pincott, J., Barratt, T. M. Familial hypoplastic glomerulocystic kidney disease: a definite entity with dominant inheritance. Am. J. Med. Genet. 34: 569-573, 1989. [PubMed: 2624270] [Full Text: https://doi.org/10.1002/ajmg.1320340423]
Kolatsi-Joannou, M., Bingham, C., Ellard, S., Bulman, M. P., Allen, L. I. S., Hattersley, A. T., Woolf, A. S. Hepatocyte nuclear factor-1-beta: a new kindred with renal cysts and diabetes and gene expression in normal human development. J. Am. Soc. Nephrol. 12: 2175-2180, 2001. [PubMed: 11562418] [Full Text: https://doi.org/10.1681/ASN.V12102175]
Kornfeld, J.-W., Baitzel, C., Konner, A. C., Nicholls, H. T., Vogt, M. C., Herrmanns, K., Scheja, L., Haumaitre, C., Wolf, A. M., Knippschild, U., Seibler, J., Cereghini, S., Heeren, J., Stoffel, M., Bruning, J. C. Obesity-induced overexpression of miR-802 impairs glucose metabolism through silencing of Hnf1b. Nature 494: 111-115, 2013. [PubMed: 23389544] [Full Text: https://doi.org/10.1038/nature11793]
Lindner, T. H., Njolstad, P. R., Horikawa, Y., Bostad, L., Bell, G. I., Sovik, O. A novel syndrome of diabetes mellitus, renal dysfunction and genital malformation associated with a partial deletion of the pseudo-POU domain of hepatocyte nuclear factor-1-beta. Hum. Molec. Genet. 8: 2001-2008, 1999. [PubMed: 10484768] [Full Text: https://doi.org/10.1093/hmg/8.11.2001]
Ma, Z., Gong, Y., Patel, V., Karner, C. M., Fischer, E., Hiesberger, T., Carroll, T. J., Pontoglio, M., Igarashi, P. Mutations of HNF-1-beta inhibit epithelial morphogenesis through dysregulation of SOCS-3. Proc. Nat. Acad. Sci. 104: 20386-20391, 2007. [PubMed: 18077349] [Full Text: https://doi.org/10.1073/pnas.0705957104]
Maestro, M. A., Boj, S. F., Luco, R. F., Pierreux, C. E., Cabedo, J., Servitja, J. M., German, M. S., Rousseau, G. G., Lemaigre, F. P., Ferrer, J. Hnf6 and Tcf2 (MODY5) are linked in a gene network operating in a precursor cell domain of the embryonic pancreas. Hum. Molec. Genet. 12: 3307-3314, 2003. [PubMed: 14570708] [Full Text: https://doi.org/10.1093/hmg/ddg355]
Menzel, R., Kaisaki, P. J., Rjasanowski, I., Heinke, P., Kerner, W., Menzel, S. A low renal threshold for glucose in diabetic patients with a mutation in the hepatocyte nuclear factor-1-alpha (HNF-1-alpha) gene. Diabet. Med. 15: 816-820, 1998. [PubMed: 9796880] [Full Text: https://doi.org/10.1002/(SICI)1096-9136(199810)15:10<816::AID-DIA714>3.0.CO;2-P]
Nakayama, M., Nozu, K., Goto, Y., Kamei, K., Ito, S., Sato, H., Emi, M., Nakanishi, K., Tsuchiya, S., Iijima, K. HNF1B alterations associated with congenital anomalies of the kidney and urinary tract. Pediat. Nephrol. 25: 1073-1079, 2010. [PubMed: 20155289] [Full Text: https://doi.org/10.1007/s00467-010-1454-9]
Nishigori, H., Yamada, S., Kohama, T., Tomura, H., Sho, K., Horikawa, Y., Bell, G. I., Takeuchi, T., Takeda, J. Frameshift mutation, A263fsinsGG, in the hepatocyte nuclear factor-1-beta gene associated with diabetes and renal dysfunction. Diabetes 47: 1354-1355, 1998. [PubMed: 9703339] [Full Text: https://doi.org/10.2337/diab.47.8.1354]
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 1-alpha and 1-beta mutations in renal cell carcinomas. Hum. Molec. Genet. 14: 603-614, 2005. [PubMed: 15649945] [Full Text: https://doi.org/10.1093/hmg/ddi057]
Rizzoni, G., Loirat, C., Levy, M., Milanesi, C., Zachello, G., Mathieu, H. Familial hypoplastic glomerulocystic kidney: a new entity? Clin. Nephrol. 18: 263-268, 1982. [PubMed: 7151342]
Verdeguer, F., Le Corre, S., Fischer, E., Callens, C., Garbay, S., Doyen, A., Igarashi, P., Terzi, F., Pontoglio, M. A mitotic transcriptional switch in polycystic kidney disease. (Letter) Nature Med. 16: 106-110, 2010. [PubMed: 19966811] [Full Text: https://doi.org/10.1038/nm.2068]
Wild, W., Pogge von Strandmann, E., Nastos, A., Senkel, S., Lingott-Frieg, A., Bulman, M., Bingham, C., Ellard, S., Hattersley, A. T., Ryffel, G. U. The mutated human gene encoding hepatocyte nuclear factor 1-beta inhibits kidney formation in developing Xenopus embryos. Proc. Nat. Acad. Sci. 97: 4695-4700, 2000. [PubMed: 10758154] [Full Text: https://doi.org/10.1073/pnas.080010897]
Yorifuji, T., Kurokawa, K., Mamada, M., Imai, T., Kawai, M., Nishi, Y., Shishido, S., Hasegawa, Y., Nakahata, T. Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys: phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1-beta gene due to germline mosaicism. J. Clin. Endocr. Metab. 89: 2905-2908, 2004. [PubMed: 15181075] [Full Text: https://doi.org/10.1210/jc.2003-031828]