| Full gene name: | HNF1 homeobox B |
|---|---|
| Entrez Gene ID: | 6928 |
| Location: | 17q12 |
| Synonyms: | TCF-2, TCF2, FJHN, HNF1beta, HNF-1B, HPC11, VHNF1, MODY5, HNF2, LFB3, LF-B3 |
| Type: | protein-coding |
SNPs given by the user that are near or inside this gene:
| SNP | Distance (bp) | Direction |
|---|---|---|
| rs757210 | 0 | within |
This gene encodes a member of the homeodomain-containing superfamily of transcription factors. The protein binds to DNA as either a homodimer, or a heterodimer with the related protein hepatocyte nuclear factor 1-alpha. The gene has been shown to function in nephron development, and regulates development of the embryonic pancreas. Mutations in this gene result in renal cysts and diabetes syndrome and noninsulin-dependent diabetes mellitus, and expression of this gene is altered in some types of cancer. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]
| OMIM ID: | `OMIM ID 189907 `_ |
|---|
Allelic Variants (Selected Examples)
.0001 RENAL CYSTS AND DIABETES SYNDROME
In 2 Japanese sibs with renal disease and DIABETES syndrome (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.
.0002 RENAL CYSTS AND DIABETES SYNDROME
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.
.0003 RENAL CYSTS AND DIABETES SYNDROME
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 truncation 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.
.0004 RENAL CYSTS AND DIABETES SYNDROME
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.
.0005 RENAL CYSTS AND DIABETES SYNDROME
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.
.0006 RENAL CYSTS AND DIABETES SYNDROME
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.
.0007 DIABETES MELLITUS, NONINSULIN-DEPENDENT
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, 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 type II diabetic patients, 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 II DIABETES examined, may thus be a rare genetic risk factor contributing to the development of type II DIABETES rather than MODY5.
.0008 RENAL CYSTS AND DIABETES SYNDROME
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 truncation 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.
.0009 RENAL CYSTS AND DIABETES SYNDROME
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.
.0010 RENAL CYSTS AND DIABETES SYNDROME
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.
.0011 RENAL CYSTS AND DIABETES SYNDROME
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.
.0013 RENAL CYSTS AND DIABETES SYNDROME
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.
.0014 RENAL CYSTS AND DIABETES SYNDROME
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.
.0015 RENAL CELL CARCINOMA, CHROMOPHOBE
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 truncation 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.
Recent articles:
Top Pubmed articles linked to gene HNF1B matching any search term: