| Full gene name: | HNF1 homeobox A |
|---|---|
| Entrez Gene ID: | 6927 |
| Location: | 12q24.2 |
| Synonyms: | TCF-1, TCF1, HNF-1A, MODY3, IDDM20, LFB1, HNF1 |
| Type: | protein-coding |
SNPs given by the user that are near or inside this gene:
| SNP | Distance (bp) | Direction |
|---|---|---|
| rs7957197 | 20372 | downstream |
The protein encoded by this gene is a transcription factor required for the expression of several liver-specific genes. The encoded protein functions as a homodimer and binds to the inverted palindrome 5’-GTTAATNATTAAC-3’. Defects in this gene are a cause of maturity onset diabetes of the young type 3 (MODY3) and also can result in the appearance of hepatic adenomas. [provided by RefSeq, Mar 2009]
| OMIM ID: | `OMIM ID 142410 `_ |
|---|
Allelic Variants (Selected Examples)
.0001 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3
Maturity-Onset DIABETES of the Young
In a patient from an Edinburgh pedigree with MODY3 (600496), Yamagata et al. (1996) found in exon 4 of the TCF1 gene an insertion of a cytosine at codon 291 (pro), resulting in a frameshift and synthesis of a truncated mutant protein of 315 amino acids. This mutation was present in all affected members and no unaffected members of this family. It was not found on screening 55 healthy nondiabetic white subjects.
Using a rapid screening PCR method for frameshift mutations in the HNF1A gene in the screening of 60 MODY probands defined according to strict diagnostic criteria, Frayling et al. (1997) detected mutations in 11 (18%); the insertion mutation accounted for 13% of the MODY cases.
Ellard (2000) stated that the C insertion in the poly(C) tract of exon 4 had been reported in 22 of the 116 families with MODY3 worldwide who were identified by the finding of a mutation in the TCF1 gene. The total number of different mutations described was 65.
Bjorkhaug et al. (2003) found the P291fsinsC mutation in 9 families, 8 of Norwegian origin. Microsatellite analysis data suggested that in 7 of these families the mutant allele had a common origin.
Hepatic Adenoma
In studies of hepatic adenomas (142330) demonstrating biallelic inactivation of TCF1, Bluteau et al. (2002) observed the pro291fsX316 frameshift mutation (142410.0001) in heterozygous state in the tumor tissue of 2 individuals, one with multiple adenoma and the other with hepatocellular carcinoma (114550).
Renal Cell Carcinoma
In a 78-year-old man with clear cell renal carcinoma (see 144700), Rebouissou et al. (2005) identified heterozygosity for the 872insC mutation. Mutation screening of a tumor sample detected the germline mutation without mutation/deletion of the second allele. The man was diagnosed with DIABETES mellitus in his sixth decade that was controlled by diet and oral hypoglycemic agents. No relatives had a diagnosis of renal carcinoma or DIABETES.
Insulin-Dependent DIABETES Mellitus
In a Japanese subject with type 1 DIABETES mellitus (IDDM20; 612520) in whom Insulin treatment was begun when hyperglycemia and ketonuria were noticed at 15 years of age, Yamada et al. (1997) identified a heterozygous frameshift mutation of codon pro291 resulting from insertion of a C in a poly(C) tract. (They designated this mutation P291fsinsC.) The mutation was predicted to result in a mutant truncated protein of 340 amino acids. The same mutation had been observed in British, German, and Finnish MODY families (Byrne et al., 1996; Yamagata et al., 1996; Kaisaki et al., 1997). Thus, Yamada et al. (1997) concluded that this site in exon 4 of the HNF1A gene appears to be a mutation hotspot.
.0002 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3
In their family A, Yamagata et al. (1996) found that MODY3 (600496) was associated with a single amino acid substitution in exon 7 of the TCF1 gene: codon 447 was changed from CCG (pro) to CTG (leu).
Hansen et al. (1997) found this mutation in a glucose-tolerant lean male who had relatives with MODY. He showed a low Insulin secretion rate during oral glucose tolerance test (OGTT), but a 2-fold increase in pancreatic beta-cell response after intravenous glucose and a 2.5- to 4-fold increase in beta-cell response after either intravenous tolbutamide or intravenous glucagon loads. Hansen et al. (1997) concluded that early stages in the pathogenesis of MODY3 caused by the P447L mutation may be characterized by hyperexcitability of beta-cells to intravenous secretagogues.
.0003 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3
In a family in which 4 members of 3 generations had MODY3 (600496), Vaxillaire et al. (1997) found deletion of a guanine from codon glycine-292 (G292fsdelG) resulting in frameshift in the TCF1 gene.
.0004 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3
In a family with multiple members with MODY3 (600496) in 3 generations, Vaxillaire et al. (1997) found a TAC-to-TGC transition in codon 122 of the TCF1 gene, predicted to cause an amino acid change from tyrosine to cysteine (Y122C).
.0005 DIABETES MELLITUS, Insulin-DEPENDENT, 20
In a Japanese subject who developed IDDM (IDDM20; 612520) 1 year after the diagnosis of NIDDM at 8 years of age, Yamada et al. (1997) identified heterozygosity for an arg272-to-his (R272H) mutation in the DNA binding domain of the HNF1A gene.
.0006 DIABETES MELLITUS, Insulin-DEPENDENT, 20
In a Japanese patient with sudden-onset IDDM (IDDM20; 612520) at 20 years of age, Yamada et al. (1997) identified heterozygosity for an arg583-to-gly (R583G) mutation in the transactivation domain of HNF1A. When first diagnosed there was marked hyperglycemia and ‘absolute’ Insulin deficiency, prompting the initiation of Insulin therapy. Control of blood glucose levels by exogenous Insulin was poor, and complications of DIABETES (proliferative retinopathy, cataracts, and sensory-motor neuropathy) developed.
.0007 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3
Gragnoli et al. (1997) found an A-to-C substitution at nucleotide -58 of the promoter region of the HNF1A gene that cosegregated with MODY3 (600496). This mutation is located in a highly conserved region of the promoter and disrupted the binding site for the transcription factor HNF-4-alpha (600281), mutations in the gene encoding HNF-4-alpha being another cause of MODY (MODY1; 125850). This result demonstrated that decreased levels of HNF1-alpha per se can cause MODY. Moreover, it indicated that both the promoter and the coding regions of the HNF1A gene should be screened for mutations in subjects thought to have MODY.
.0008 DIABETES MELLITUS, TYPE II, SUSCEPTIBILITY TO
Hegele et al. (1999) identified a gly319-to-ser (G319S) variant in the HNF1A gene in Ontario Oji-Cree with maturity-onset DIABETES of the young type 3 (600496). G319S is in the proline II-rich domain of the trans-activation site of HNF1A and alters a glycine residue that is conserved throughout evolution. S319 was absent from 990 alleles from 6 other ethnic groups, suggesting that it is private for Oji-Cree. The S319 allele was more prevalent in diabetic than in nondiabetic Oji-Cree (0.209 vs 0.087; P = 0.000001). S319/S319 homozygotes and S319/G319 heterozygotes, respectively, had odds ratios for type II DIABETES of 4.00 (95% CI, 2.65-6.03) and 1.97 (95% CI, 1.44-2.70) compared with G319/G319 homozygotes. There was a significant difference in the mean age of onset of type II DIABETES, with G319/G319, S319/G319, and S319/S319 subjects being affected in the fifth, fourth, and third decades of life, respectively. Among nondiabetic subjects, S319/G319 heterozygotes had significantly lower plasma Insulin than G319/G319 homozygotes. The authors concluded that the G319S variant is associated with a distinct form of type II DIABETES, characterized by onset at an earlier age, lower body mass, and a higher postchallenge plasma glucose.
That the majority of Oji-Cree subjects with DIABETES did not have the HNF1A S319 variant suggested to Hegele et al. (2000) that there might be other genetic determinants of DIABETES susceptibility. In the course of sequencing candidate genes in diabetic subjects who were homozygous for HNF1A G319/G319, they found that some subjects had the PPARG A12 variant (601487.0002). PPARG A12 was strongly associated with type II DIABETES in women, but not in men. The authors concluded that, when taken together with the previously reported association of DIABETES with HNF1A in both men and women, the gender-specific association with PPARG A12 confirms that type II DIABETES is etiologically complex in the Oji-Cree and that at least 2 genes are involved in determining susceptibility to the disease in this population.
Triggs-Raine et al. (2002) stated that Oji-Cree type 2 DIABETES does not resemble MODY, because affected Oji-Cree subjects are obese and Insulin-resistant with elevated plasma Insulin concentrations, which clearly were insufficient to prevent DIABETES onset. They evaluated the in vitro function of HNF1A G319S both to confirm that the mutation had a functional effect and to determine whether this effect was distinct from those of the complete loss-of-function or dominant-negative mutations seen in the MODY3 phenotype. They also evaluated the impact of the HNF1A G319S mutation on the dynamics of type 2 DIABETES onset in the whole Sandy Lake Oji-Cree community. They found that the G319S mutation reduced the in vitro ability of HNF1-alpha to activate transcription by approximately 50%, with no effect on DNA binding or protein stability. There was no evidence of a dominant-negative effect of the mutant protein. Disease onset showed significant differences according to G319S genotype when gauged by the age at which half the subjects had become diabetic. Each dose of G319S accelerated median disease onset by approximately 7 years. Thus, the transactivation-deficient HNF1A G319S mutation affects the dynamics of disease onset. The demonstration of a functional consequence for the G319S mutation provided a mechanistic basis for its strong association with Oji-Cree type 2 DIABETES and its unparalleled specificity for DIABETES prediction in these people, in whom DIABETES presents a significant public health problem. The finding also showed that HNF1A mutations can be associated with typical adult-onset Insulin-resistant obesity-related DIABETES in addition to maturity-onset DIABETES of the young. Triggs-Raine et al. (2002) stated that in the Oji-Cree, HNF1A G319S behaves as a susceptibility allele for type 2 DIABETES. Among nondiabetic Oji-Cree, fasting plasma Insulin concentration was reduced significantly in HNF1A G319S carriers, suggesting that the partial impairment of function is tolerated when there is no Insulin resistance. However, among Oji-Cree with type 2 DIABETES, both carriers and noncarriers of the mutation had elevated plasma Insulin concentration compared with nondiabetic Oji-Cree. The stress of obesity-induced Insulin resistance seemed to expose the partial defect in HNF1A G319S carriers, causing expression of the disease.
.0009 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3
Miedzybrodzka et al. (1999) described a family in which a thr620-to-ile substitution in transcription factor-1 was found in all members affected by MODY (600496). The mutation was not fully penetrant, as 2 family members aged 87 and 46 had the mutation but did not have DIABETES. The severity and age at diagnosis of DIABETES varied widely within the family, and most presented over the age of 25. Miedzybrodzka et al. (1999) suggested that TCF1 mutation screening should be considered in any family with autosomal dominant inheritance of DIABETES where one member has presented with DIABETES before the age of 25.
.0010 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3
Godart et al. (2000) observed a promoter mutation, -119delG, of the TCF1 gene that segregated with MODY3 (600496) in a diabetic family.
.0011 Insulin RESISTANCE, SUSCEPTIBILITY TO
Chiu et al. (2000) examined the relationship between the ile27-to-leu (I27L) polymorphism of HNF1-alpha and Insulin sensitivity (see 125853) and beta-cell function assessed by a hyperglycemic clamp. This study included 52 healthy glucose-tolerant and normotensive subjects (age, 19 to 40 years; body mass index, 17.58-35.61 kg/m2; waist/hip ratio, 0.65-1.03). Chiu et al. (2000) identified 19 LL subjects, 24 IL subjects, and 9 II subjects. The LL group had the highest postchallenge Insulin levels at 30 and 90 min (P = 0.038 and P = 0.015, respectively) and also the highest Insulin area under curve (P = 0.009) among the 3 genotypes. The LL group was more Insulin resistant than the IL and II groups (P = 0.042 for Insulin sensitivity index). After adjusting for age, gender, obesity, and ethnicity, the I27L polymorphism was an independent determinant of the Insulin sensitivity index (P = 0.001). However, it had no impact on either the first or second phase Insulin response. The authors concluded that the I27L polymorphism is associated with Insulin resistance, but not beta-cell function. The mechanism of this association is unclear, but HNF1-alpha may play a role in regulating hepatic glucose metabolism.
Babaya et al. (2003) studied the relationship of the HNF1A gene polymorphism I27L with lipid parameters, in particular with serum HDL cholesterol level, in 356 unrelated Japanese men. Though no significant difference was observed in total cholesterol and triglyceride levels among the 3 genotypes, the serum HDL cholesterol level was significantly associated with the genotype (P less than 0.01). Subjects with the II genotype had low serum HDL cholesterol levels, and those with the LL genotype had high serum HDL cholesterol levels. The authors concluded that the HNF1A gene locus is associated with serum HDL cholesterol level and suggested that the I27 allele is a risk marker for atherosclerosis.
.0012 DIABETES MELLITUS, Insulin-DEPENDENT, 20
Yoshiuchi et al. (2001) identified a 142delG frameshift mutation in the TCF1 gene in a family with a strong history of type I DIABETES (IDDM20; 612520). The expression of the mutant protein was not detected in COS-7 cells by Western blot analysis after transfection of the mutant cDNA. According to the authors, this was the first case of an unstable mutant HNF1-alpha protein. Reporter gene analysis indicated that the mutant protein had no transactivation activity in HeLa and other cells. Haploinsufficiency for the TCF1 gene may lead to severe forms of DIABETES resembling type I DIABETES.
.0013 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3
This mutation was found by Collet et al. (2002) to be prevalent in African individuals with DIABETES (600496).
In an individual who had had a liver-tumor resection and had familial DIABETES, Bluteau et al. (2002) found a gly574-to-ser (G574S) mutation in the TCF1 gene. The hepatocellular carcinoma in this case had developed in an adenoma (142330).
.0014 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3
Bluteau et al. (2002) found a heterozygous germline mutation, arg583 to gln (R583Q), in an individual with a hyperplastic liver tumor (142330) who had had liver-tumor resection and had familial DIABETES (600496). The substitution involved a highly conserved amino acid.
.0015 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3
In a 3-generation Norwegian family with MODY3 (600496), Bjorkhaug et al. (2000) found a C-to-T transition at nucleotide 358 in exon 2 of the HNF1A gene, leading to a pro112-to-leu (P112L) amino acid substitution, in all 3 affected members. The phenotype in this family was mild with mild fasting and postprandial hyperglycemia easily controlled by diet only. DIABETES-associated late complications were not observed. P112L mutant protein demonstrated a significantly reduced ability to bind a high affinity HNF1 binding site and to activate transcription. Immunolocalization studies in HeLa cells showed that P112L mutant protein was correctly targeted to the nucleus. Bjorkhaug et al. (2000) concluded that the P112L mutation seems to impair pancreatic beta-cell function by loss-of-function mechanisms.
Xu et al. (2002) found the HNF1A P112L mutation in a southern Chinese MODY family.
Bjorkhaug et al. (2003) found evidence for possible founder effect of the P112L mutation in the Norwegian population.
.0016 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3
Bjorkhaug et al. (2003) found a C-to-T transition in exon 2 of the HNF1A gene, resulting in an arg131-to-trp (R131W) amino acid substitution, in 5 Norwegian families with MODY3 (600496). This mutation had been reported in families from North America and Great Britain. Haplotype analysis indicated possible founder effect for the Norwegian families. Immunofluorescence studies demonstrated incorrect localization and accumulation of protein in both cytoplasm and nucleus. The R131W mutant protein displayed 10 to 15% of binding activity of wildtype and levels of transcription activation close to 50% of wildtype.
.0017 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3
In a Norwegian family with MODY3 (600496), Bjorkhaug et al. (2003) detected a novel 4-bp deletion in exon 3 of the HNF1A gene (T196fsdelCCAA).
.0018 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3
In a Norwegian proband with MODY3 (600496), Bjorkhaug et al. (2003) found a novel splice site mutation in intron 3 of the HNF1A gene, IVS3-1G-A.
.0019 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3
In a Norwegian proband with MODY3 (600496), Bjorkhaug et al. (2003) detected a novel C-to-A transversion in exon 4 of the HNF1A gene resulting in an arg276-to-asp (A276D) amino acid substitution. Mutant protein was targeted to both nucleus and cytoplasm of transfected cells in immunofluorescence assays. DNA binding ability of 30 to 40% of wildtype could be detected; no significant reduction in transcription activation could be demonstrated.
.0020 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3
In 3 members of a Norwegian family with MODY3 (600496), Bjorkhaug et al. (2003) found a novel 2-bp deletion in exon 7 of the HNF1A gene (S445fsdelAG). Mutant protein was targeted to both nucleus and cytoplasm of transfected cells in immunofluorescence assays. DNA binding ability of 30 to 40% of wildtype could be detected; no significant reduction in transcription activation could be demonstrated.
.0021 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3
In a Norwegian proband with MODY3 (600496), Bjorkhaug et al. (2003) detected a novel G-to-C transversion in exon 8 of the HNF1A gene, leading to a ser531-to-thr (S531T) amino acid substitution.
.0022 MATURITY-ONSET DIABETES OF THE YOUNG, TYPE 3
–MODY3
In a French family with MODY3 (600496), Chevre et al. (1998) identified heterozygosity for a 92G-A transition in exon 1 of the HNF1A gene, resulting in a gly31-to-asp (G31D) substitution in the dimerization domain of the protein.
–Renal Cell Carcinoma
In a 76-year-old woman with both clear cell and chromophobe renal carcinomas (see 144700), Rebouissou et al. (2005) identified heterozygosity for the G31D mutation. Mutation screening of the tumor samples detected only the germline G31D mutation. The renal carcinomas manifested in the same kidney with a single renal cyst in the other kidney. None of her relatives had a history of DIABETES or renal carcinoma.
Recent articles:
Top Pubmed articles linked to gene HNF1A matching any search term: