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Nonsense and Missense Mutations in the Human Hepatocyte Nuclear Factor-1ß Gene (TCF2) and Their Relation to Type 2 Diabetes in Japanese

The First Department of Medicine (H.F., M.F., K.E., T.H., M.N., H.S., K.N.) and Department of Clinical Laboratory Medicine (T.S.), Wakayama University of Medical Science, Wakayama 641-8509, Japan

Address all correspondence and requests for reprints to: Kishio Nanjo, M.D., Ph.D., The First Department of Medicine, Wakayama University of Medical Science, 811-1 Kimii-dera, Wakayama 641-8509, Japan. E-mail: . k-nanjo{at}wakayama-med.ac.jp

Abstract

Mutations in transcription factors expressed in the pancreatic ß-cell are a major cause of maturity-onset diabetes of the young (MODY). They have also been found in patients diagnosed with type 1 and type 2 diabetes mellitus, which may highlight the difficulty in diagnosing these forms of diabetes or perhaps indicate a direct role in the development of multiple forms of diabetes. We have screened the hepatocyte nuclear factor-1ß (HNF-1ß/MODY5) gene for mutations in a group of 126 unrelated Japanese patients with type 2 diabetes and a family history of at least one first degree relative with diabetes. We identified one patient with a nonsense mutation (R276X) and another with a missense mutation (S465R). These mutations were present in the heterozygous state and were not found in 132 nondiabetic subjects (264 normal alleles). We identified a second patient with the S465R mutation on screening a second group of 272 randomly selected type 2 diabetic patients but not in another 122 nondiabetic subjects. Functional studies indicated that R276X-HNF-1ß was inactive and S465R-HNF-1ß exhibited a 22% reduction in activity compared with the wild-type protein. The S465R mutation may function in a dominant-negative manner. The subject with the R276X mutation had MODY5 misdiagnosed as common type 2 diabetes. He was diagnosed with diabetes at 13 yr of age and also had small kidneys with multiple bilateral renal cysts and decreased urinary concentrating ability. The two subjects with the S465R mutation had typical late-onset type 2 diabetes and no evidence of kidney disease. We have identified two novel mutations in human HNF-1ß gene. The prevalence of MODY5 among our population of Japanese diabetes patients with a strong positive family of disease is 0.8%. The S465R mutation was found in 0.5% of our patients with common type 2 diabetes and thus may be a rare genetic risk factor contributing to the development of type 2 diabetes rather than MODY5.

MUTATIONS IN THE genes encoding the ß-cell transcription factors, hepatocyte nuclear factor (HNF)-1 (TCF1), -1ß (TCF2), and -4 (HNF4A), insulin promoter factor-1 (IPF1) and neurogenic differentiation-1 (NEUROD1), are associated with various subtypes of maturity-onset diabetes of the young (MODY), a monogenic form of diabetes mellitus characterized by early age at onset, autosomal dominant inheritance and ß-cell dysfunction (1, 2). Mutations in HNF-1 and -4, IPF-1, and NeuroD1 have also been found in a small fraction of patients diagnosed with type 1 and type 2 diabetes, which may indicate diagnostic uncertainty or a predisposing role for these genes in the development of polygenic forms of diabetes (1). We have also found patients with type 2 diabetes who have mutations in two other ß-cell transcription factors, islet-1 (ISL1) and Pax4 (PAX4), thus expanding the list of transcription factors that may play a role in the development of diabetes (3, 4).

To examine the role of sequence variation in HNF-1ß in the development of type 2 diabetes in Japanese, we have screened the gene encoding this transcription factor for mutations in a group of 126 unrelated type 2 diabetic subjects with a strong family history of diabetes.

Materials and Methods

Subjects

We carried out mutation analysis in 126 unrelated Japanese subjects with type 2 diabetes and a family history of at least one first degree relative with diabetes. All subjects were recruited from patients attending the outpatient clinic of Wakayama University of Medical Science Hospital. This group consisted of 60 men and 66 women. The average age was 56.5 ± 13.2 yr (range 14–81), body mass index (BMI) 23.4 ± 3.3 kg/m² (range 16.7–30.9), age at diagnosis was 36.7 ± 12.9 yr (range 10–66) and 8.7% were treated with diet, 42.1% with oral agents and 49.2% with insulin. The control group consisted of 132 nondiabetic Japanese subjects (56 men and 76 women) with no family history of diabetes. All of them were over 60 yr of age and without severe obesity (BMI less than 30 kg/m² ). We also studied a second group of 272 unrelated Japanese type 2 diabetic subjects and 122 nondiabetic subjects. The diabetic subjects consisted of 149 men and 123 women. One hundred forty subjects of this group had a family history of at least one diabetic subject within third degree relative and 132 subjects were without it. The average age was 65.3 ± 10.9 yr (range 22–90), BMI 22.1 ± 2.5 kg/m² (range 14.6– 26.0), age at diagnosis was 48.7 ± 10.9 yr (range 17–81) and 16.4% were treated with diet, 43.9% with oral agents and 39.7% with insulin. The nondiabetic subjects, who were selected as same criteria stated above, consisted of 52 men and 70 women. Diabetes was diagnosed using the criteria of the World Health Organization. This study was approved by the local ethics committee and informed consent was obtained from each subject.

Genetic analyses

We screened the nine exons, flanking introns, and minimal promoter region of the human HNF-1ß gene for mutations using PCR with fluorescence-labeled specific primers (5, 6) and single-stranded conformational polymorphism (SSCP) analysis. In SSCP analysis, the denatured PCR product was separated on 0.5x the Mutation Detection Enhancement gel (BMA, Rockland, ME) at two different temperatures (12 C and 22 C), and fluorescence signals were detected with an ALFred DNA sequencer (Amersham Pharmacia Biotech, Piscataway, NJ). When additional bands were observed, the PCR product was sequenced directly on both strands using a BIG Dye Terminator Cycle Sequencing Kit and an Applied Biosystems Prism 310 Gene Analyzer (Applied Biosystems, Foster City, CA). The mutations were confirmed by cloning the PCR product into pGEM-T vector (Promega Corp., Madison, WI) and sequencing individual clones. We screened the diabetic subjects and the nondiabetic subjects for the R276X and S465R mutations by PCR-SSCP.

Functional studies of normal and mutant human HNF-1ß

The human wild-type HNF-1ß mammalian expression vector pcDNA3.1-HisB-HNF-1ß and the rat albumin promoter-firefly luciferase reporter gene construct pGL3-RA (7) were a kind gift from Y. Horikawa and G. Bell (The University of the Chicago). The R276X and S465R mutations were introduced by site-directed mutagenesis (QuickChange Mutagenesis Kit, Stratagene, La Jolla, CA) to generate pcDNA3.1-HisB-HNF-1ß-R276X and pcDNA3.1-HisB-HNF-1ß-S465R, respectively. The Xpress-epitope-tagged wild-type and mutant constructs of HNF-1ß were transfected into HeLa cells using Lipofectamine (Life Technologies, Inc., Gaithersburg, MD) along with 500 ng of pGL3-RA, 25 ng of pRL-SV40 (to control for efficiency of transfection). The final amount of DNA in each transfection was adjusted to 2 µg by adding the appropriate amount of pcDNA3.1(+)-HisB DNA. After 24 h, the transactivation activity of the normal and mutant HNF-1ß proteins was measured using the Dual-Luciferase Reporter Assay System (Promega Corp.). At the same time, whole cell extracts prepared by lysing the transfected cells with RIPA buffer (Roche Molecular Biochemicals, Mannheim, Germany) were subjected to Western blot analysis using Anti-Xpress antibody (Invitrogen, The Netherlands).

The results are presented as mean ± SD and the significance of differences was calculated by one-way ANOVA. A P value of less than 0.05 was considered statistically significant.

Results

Mutations in the HNF-1ß gene

We screened 126 patients with type 2 diabetes and a strong family history of diabetes for mutations in the HNF-1ß gene. In additional to a previously reported polymorphism in intron 8 (IVS8nt-22C/T) (5), we found one patient who was heterozygous for a nonsense mutation in exon 4, codon 276 (CGA (Arg) to TGA (OP); R276X) and another who was heterozygous for a missense mutation in exon 7, codon 465 (AGC (Ser) to AGG (Arg); S465R). These mutations were detected at 22 C and 12 C in PCR-SSCP analysis, respectively. Neither mutation was found in 132 nondiabetic subjects (264 normal chromosomes), although we did find one nondiabetic subject who was heterozygous for a silent mutation in exon 7, codon 466 [CTG (Leu) to TTG (Leu)]. To investigate the frequency of the S465R mutation, we screened a second group of 272 subjects with type 2 diabetes and 122 nondiabetic subjects and found this mutation in 1/272 type 2 diabetic patient in the heterozygous state but in 0/122 controls.

Clinical features of patients with HNF-1ß mutations

The patient with the R276X mutation is a male diagnosed with diabetes at 13 yr of age (present age, 24 yr). He has an older sister (present age, 28 yr) who does not have diabetes (or any evidence of kidney disease) and does not carry this mutation. His mother has diabetes (age at diagnosis, 32 yr; present age, 50 yr; treatment, insulin). However, she does not carry the R276X mutation. His mother also has severe diabetic complications including diabetic retinopathy, neuropathy, and chronic renal failure (renal cysts were not observed). The chronic renal failure is believed to be a consequence of diabetic nephropathy. The patient’s father is deceased. Review of his medical records indicates that he did not have diabetes and that his renal function was normal. Thus, the patient with the R276X mutation has MODY5 that was misdiagnosed as common type 2 diabetes. The origin of the R276X mutation in this family is unclear. One possibility is that the mutation arose de novo in the gametes of one of the parents, because the absence of the mutation in the proband’s mother and the absence of diabetes and renal dysfunction in his father. The R276X mutation is not the only cause of diabetes in this family, because the mother has diabetes but does not carry the R276X mutation. We have screened the mother for mutations in other MODY genes (HNF-1, HNF-4, IPF-1, and glucokinase genes), but no mutations were found. The cause of her diabetes is unknown.

We have had an opportunity to study the evolution of diabetes in the patient with the R276X mutation. He was admitted to our hospital on three occasions at 13, 21, and 24 yr of age because of poor diabetic control [hemoglobin A1c (HbA1c) values of 13.2%, 11.3% and 11.5%, respectively] (Fig. 1A). Intensive diet therapy at 13 and 21 yr of age and associated weight loss improved blood glucose levels: 13 yr of age BMI of 23.2 and 21.3 kg/m², HbA1c values of 13.2 and 5.8%, before and after treatment; and 21 yr of age BMI of 21.3 and 19.7 kg/m², HbA1c values of 11.3 and 6.3%, before and after treatment, respectively. The fasting plasma glucose concentration, fasting serum insulin level and homeostasis model assessment of insulin resistance (HOMA-IR) values (8) were 7.3 mmol/liter, 54 pmol/liter and 2.9 before diet therapy at 13 yr, 5.8 mmol/liter, 38.4 pmol/liter and 1.7 after diet therapy at 13 yr, and 5.8 mmol/liter, 12 pmol/liter and 0.5 after diet therapy at 21 yr, respectively. We also performed a 75 g oral glucose tolerance test (OGTT) at 13 yr (before and after normalization of blood glucose levels) and at 21 yr (after normalization of blood glucose levels) (Fig. 1B). At 13 yr of age, glucose tolerance and insulinogenic index calculated by [insulin (30 min-0 min)]/[glucose (30 min-0 min)] as a measure of early insulin secretory response were markedly improved following 1 month of diet therapy, although insulin secretion at 30 min was still reduced compared with nondiabetic subjects (Fig. 1A). At 21 yr of age, the insulinogenic index during the OGTT declined in spite of the fasting glucose concentration being the same as it after therapy at 13 yr of age. His fasting serum insulin concentration and HOMA-IR value also declined. These findings suggest that increased insulin sensitivity may account for the improvement in blood glucose levels in the presence of impaired insulin secretion at this time. There has been a continuing decline in ß-cell function in this patient and he is now treated with insulin. Microalbuminuria is present, but diabetic retinopathy and neuropathy are absent.

View larger version (20K): [in this window] [in a new window]   Figure 1. Clinical course (A) and OGTT studies (B) of the patient with the R276X mutation. The patient was hospitalized three times for poor control of diabetes. The HbA1c, BMI, HOMA-IR, fasting plasma glucose (FPG) and fasting immunoreactive insulin (fIRI) are shown. A 75-g OGTT was given before and after hospitalization at 13 and 21 yr of age and the insulinogenic index is indicated in Fig. 1A. The mean value of seven normal control subjects is represented by the dotted line.

We found the S465R mutation in two patients. The first is 50-yr-old female diagnosed with diabetes at 49 yr of age. She is currently treated with oral agents. There is no evidence of renal cysts or other renal abnormalities. She is insulin resistant (HOMA-IR value, 6.1; fasting glucose 7.5 mmol/liter; fasting insulin 109.8 pmol/liter). However, she is not obese (BMI of 22.4 kg/m² ), and the reason for her insulin resistance is unknown. She has a brother and mother with diabetes. However, the brother was not found to carry same mutation and the mother is deceased (as had the father). We have seen no differences in the natural history of diabetes and its complications (especially kidney disease) between the proband and her noncarrier brother to date. The second patient with the S465R mutation is a 68-yr-old male without a family history of diabetes. He is well controlled on diet therapy (HbA1c, 6.0%). His renal ultrasound and serum creatinine levels were normal and there is no proteinuria. These two patients appear to have common type 2 diabetes and not MODY5.

Functional characteristics of mutant human HNF-1ß

We examined the effect of the R276X and S465R mutations on the ability of HNF-1ß to stimulate transcription of a rat albumin reporter gene in HeLa cells. The R276X mutation is located in the middle of the homeodomain and would result in the synthesis of a truncated protein of 275 amino acids with an intact dimerization and pseudo-POU domain but interrupting the homeodomain and lacking a transactivation domain. The S465R mutation is located in the transactivation domain. The S465 is highly conserved: codon 465 is Ser in human, pig, rat, mouse, and Xenopus HNF-1ß and the corresponding residue in human HNF-1 is also Ser suggesting that this residue is functionally important.

The wild-type HNF-1ß was able to stimulate transcription of a rat albumin promoter-linked luciferase reporter gene up to 35-fold in HeLa cells with increasing amounts of an expression construct (Fig. 2). In contrast, the R276X mutant was inactive in this assay and the S465R mutant exhibited a 22% reduction in activity compared with wild type. Western blotting using an anti-Xpress antibody indicated that there were no differences in the expression of the wild-type and mutant proteins in these studies. We also examined the possibility that the R276X and S465R mutants may function in a dominant-negative manner as observed for some HNF-1ß mutations (9). We observed no effect of adding an equal amount or 2-fold excess of the R276X construct on the transactivation activity of the wild-type protein (Fig. 2). Cotransfection of 0.5 µg each of S465R and wild-type constructs exhibited a 75% activity compared with 1.0 µg of wild type alone and cotransfection of 1.0 µg of S465R and 0.5 µg of wild-type construct exhibited a 82% activity compared with 1.0 µg wild type alone. (The S465R mutant alone exhibited a 78% activity compared with wild type.) These results suggest that R276X is a loss-of-function mutation and S465R might be a dominant negative mutation.

View larger version (36K): [in this window] [in a new window]   Figure 2. Transactivation activity of wild-type (WT) and mutant (R276X and S465R) HNF-1ß. Data are shown as mean ± SD of six independent experiments. **, P < 0.01; *, P < 0.05; n.s., not significant.

Here, we report two novel mutations in the HNF-1ß gene on screening a group of 126 Japanese patients with type 2 diabetes and a strong positive family history of diabetes. The R276X mutation is a complete loss-of-function mutation. The patient with this mutation had MODY5 rather than typical type 2 diabetes. He had early-onset diabetes as well as kidney abnormalities that characterize MODY5. We have followed this patient for more than 10 yr, and clinical studies have shown that his diabetes could be easily controlled at the beginning by reducing insulin resistance such as decreasing body weight and improving blood glucose level (decreasing glucose toxicity) by diet therapy. However, continuing deterioration in ß-cell function led to diabetes and requirement for insulin treatment. The studies of this patient highlight the importance of insulin resistance in the development of MODY and suggest that insulin resistance due to weight gain, puberty, infection, stress, or other causes unmasks an underlying defect in ß-cell function.

The patient with R276X mutation also has kidney abnormalities, characterized by small kidneys with multiple bilateral renal cysts. Furthermore, hyposthenuria and poor urinary concentrating ability due to collecting duct dysfunction were observed. However, we did not observe any evidence for aminoaciduria or lower renal glucose threshold, which have been noted in patients with HNF-1/MODY3 mutations and associated with renal tubular dysfunction (10). HNF-1ß and HNF-1 are structurally related and coexpressed in many tissues including the proximal and distal tubules of the kidney (11). However, HNF-1 appears to be expressed at low levels in the collecting duct (11) and thus may not be able to compensate for the deficiency of HNF-1ß in this region of the nephron. In the patient with the R276X, the serum creatinine level was within the normal range, and creatinine clearance was only slightly decreased. The presence of hyposthenuria and poor urinary concentrating ability but not aminoaciduria or lower renal glucose threshold such that abnormal collecting duct function could be a feature of MODY5.

The second mutation that we found, S465R, was associated with a small (22%) reduction in HNF-1ß activity and acted as dominant-negative mutation. The two patients in whom we found this mutation appear to have typical type 2 diabetes rather than MODY5 because they had no evidence of kidney abnormalities. We speculate that mutations such as this (i.e. mutations having decreased but nonetheless significant activity) contribute to the development of diabetes but they are neither necessary nor sufficient to cause disease. Diabetes only develops in the presence of other genetic and environmental risk factors.

In summary, we have found that patients with MODY5 may be misdiagnosed as having type 2 diabetes. We have also found that mutations in HNF-1ß may be a rare contributing factor in the development of type 2 diabetes in Japanese.

Acknowledgments

A special thanks to Drs. Graeme I. Bell (The University of the Chicago) and Shinya Ohagi (Wakayama University of Medical Science) for their scientific advice. We also thank Ms. Ayako Ito and Naoko Ogami for their careful technical assistance.

Footnotes

This work was supported in by a Grant-in-Acid for creative scientific research (10NP0201) from the Japan Society for the Promotion of Science and from the Ministry of Education, Culture, Sports, Science and Technology.

Abbreviations: BMI, Body mass index; HOMA-IR, homeostasis model assessment of insulin resistance; HNF, hepatocyte nuclear factor; IPF1, insulin promoter factor-1; MODY, maturity-onset diabetes of the young; NEUROD1, neurogenic differentiation-1; OGTT, oral glucose tolerance test; SSCP, single-stranded conformational polymorphism; TCF1, HNF-1 gene; TCF2, HNF-1ß gene.

Received January 9, 2002.

Accepted May 7, 2002.

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