Mutations in the Hepatocyte Nuclear Factor-1α Gene in MODY and Early-Onset NIDDM: Evidence for a Mutational Hotspot in Exon 4

Kaisaki, Pamela J.; Menzel, Stephan; Lindner, Tom H.; Oda, Naohisa; Rjasanowski, I; Sahm, Jürgen; Meincke, G.; Schulze, Jan; Schmechel, H; Petzold, C; Ledermann, H; Sachse, G.; Boriraj, V. Vicky; Menzel, R; Kerner, W.; Turner, R. C.; Yamagata, Kazuya; Bell, Graeme I.

doi:10.2337/diab.46.3.528

Cited by 124 publications

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“…Codon 291 is the most common site for mutations in the HNF-1␣ gene, and this is almost certainly due to slipped mispairing during DNA replication, causing this region to be a hotspot for mutations, rather than any founder effect (30,32). The type and distribution of HNF-1␣ mutations across the gene suggest that mutations in the transactivation domain are more likely to be protein-truncating, whereas missense mutations predominate in the DNA-binding domain.…”

Section: Discussionmentioning

confidence: 99%

“…We used two approaches to identify mutations in the known MODY genes and NeuroD1. First, a rapid length-polymorphism-based method was used to screen 210 probands (97% U.K.) for insertion/deletion mutations in the poly-C tract of exon 4 of HNF-1␣-a known mutation hotspot (31,32). Of these, 160 fulfilled the minimum criteria for MODY: two generations of diabetes with at least one member diagnosed under the age of 25 years.…”

Section: Methodsmentioning

confidence: 99%

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beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors.

et al. 2001

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␤-Cell transcription factor genes are important in the pathophysiology of the ␤-cell, with mutations in hepatocyte nuclear factor (HNF)-1␣, HNF-4␣, insulin promoter factor (IPF)-1, HNF-1␤, and NeuroD1/BETA2, all resulting in early-onset type 2 diabetes. We assessed the relative contribution of these genes to early-onset type 2 diabetes using linkage and sequencing analysis in a cohort of 101 families (95% U.K. Caucasian). The relative distribution of the 90 families fitting maturityonset diabetes of the young (MODY) criteria was 63% HNF-1␣, 2% HNF-4␣, 0% IPF-1, 1% HNF-1␤, 0% NeuroD1/ BETA2, and 20% glucokinase. We report the molecular genetic and clinical characteristics of these patients T ranscription factor genes play a crucial role in the normal development and function of the ␤-cell (1). This is highlighted by the identification of mutations in ␤-cell transcription factors as a cause of early-onset type 2 diabetes-most notably the distinct subtype maturity-onset diabetes of the young (MODY). MODY is characterized by an autosomal dominant mode of inheritance, ␤-cell dysfunction, and a young age of diagnosis (usually before 25 years) (2). Mutations in the transcription factors hepatocyte nuclear factor (HNF)-1␣ (3), HNF-4␣ (4), insulin promoter factor (IPF)-1 (5), HNF-1␤ (6), and NeuroD1 (7) all cause early-onset diabetes. These genes form crucial links in the cascade of transcription factors that control the appropriate expression of ␤-cell genes, such as insulin and GLUT2 (1,8,9).Mutations in different transcription factor genes appear to result in different clinical presentations. HNF-1␣ mutations are highly penetrant, with 63% of mutation carriers having diabetes by the age of 25 years, 78.6% by 35 years, and 95.5% by 55 years (10). Mutations in HNF-1␣ result in progressive ␤-cell dysfunction with increasing treatment requirements and greater risk of complications with age (11,12). Mutations in HNF-4␣ result in a similar progressive deterioration of ␤-cell function but appear to be associated with a later age of diagnosis (13-16). The predominant feature of patients with HNF-1␤ mutations appears to be renal dysfunction, which is often diagnosed before diabetes (6,(17)(18)(19). Mutations in IPF-1 (PDX-1) are not a common cause of MODY (20)(21)(22). Only one MODY family published to date has an IPF-1 mutation that clearly cosegregates with diabetes (5), although the average age at diagnosis in this family (35 years) was somewhat older than that in families with HNF mutations. The mutation in this family (P63fsdelC) had a severe dominant-negative effect in vitro (23). Two recent studies suggest that missense mutations in the coding region of the IPF-1 gene are more likely to represent predisposing alleles in more common forms of type 2 diabetes (24,25) rather than highly penetrant disease-causing alleles. Mutations in the NeuroD1/BETA2 gene have recently been reported as being associated with type 2 diabetes in two families, one of which meets MODY criteria (7). Studies of the HNF-3␤ (26-28) and NkX2.2 (29) ...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors.

et al. 2001

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“…All of them co-segregate with the MODY phenotype in the kindreds and are located in sites likely to play an important role in HNF-1a function. Three of the four missense mutations were C-to-T transitions occurring at CpG dinucleotides, as observed already in many other HNF-1a mutations [9,14,25,27]. These are known to be a hot spot for nucleotide substitutions in mammalian genes, presumably due to the deamination of methylated cytosine to thymidine [28].…”

Section: Discussionmentioning

confidence: 99%

Mutation screening in 18 Caucasian families suggest the existence of other MODY genes

et al. 1998

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Maturity-onset diabetes of the young (MODY) is a subtype of Type II (non-insulin dependent) diabetes mellitus characterised by early onset, usually before 25 years of age, an autosomal dominant mode of inheritance with high penetrance, and a primary defect of insulin secretion [1,2]. MODY is not an uncommon disorder and could account for about 2 to 5 % of all cases of Type II diabetes [3]. MODY is genetically heterogeneous and to date five MODY genes have been identified on chromosomes 20q12-q13.1 (MODY1) [4,5], 7p15-p13 (MODY2) [6,7], 12q24.2 (MODY3) [8,9], 13q12.1 (MODY4) [10,11] and 17cen-q21.3 (MODY5) [12]. The MODY2 gene encodes the glycolytic enzyme glucokinase which plays a major role in the regulation and integration of glucose metabolism in pancreatic beta cells and liver [13]. Recent studies have shown that mutations in three transcription factors, hepatocyte nuclear factor-4a (HNF-4a) [5] (gene symbol TCF14), hepatocyte nuclear factor-1a (HNF-1a) [9, 14] (TCF1) and insulin promoter factor-1 (IPF1) [10], are responsible for the MODY1, MODY3 and MODY4 subtypes, re- Diabetologia (1998) Summary Maturity-onset diabetes of the young (MODY) is a heterogeneous subtype of non-insulindependent diabetes mellitus characterised by early onset, autosomal dominant inheritance and a primary defect in insulin secretion. To date five MODY genes have been identified: hepatocyte nuclear factor-4 alpha (HNF-4a/MODY1/TCF14) on chromosome 20 q, glucokinase (GCK/MODY2) on chromosome 7 p, hepatocyte nuclear factor-1 alpha (HNF-1a/ MODY3/TCF1) on chromosome 12 q, insulin promoter factor-1 (IPF1/MODY4) on chromosome 13 q and hepatocyte nuclear factor-1 beta (HNF-1b/MODY5/ TCF2) on chromosome 17cen-q. We have screened the HNF-4a, HNF-1a and HNF-1b genes in members of 18 MODY kindreds who tested negative for glucokinase mutations. Five missense (G31D, R159W, A161T, R200W, R271W), one substitution at the splice donor site of intron 5 (IVS5nt + 2T®A) and one deletion mutation (P379fsdelT) were found in the HNF-1a gene, but no MODY-associated mutations were found in the HNF-4a and HNF-1b genes.

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“…[3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] MODY3 is clinically distinct from typical type 2 diabetes and probably results from defective pancreatic insulin secretion. [3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] However, the underlying mechanistic relationship with the dysfunctional HNF1A gene product is not fully understood for either MODY3 or type 2 diabetes in the Oji-Cree. [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]…”

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confidence: 99%

The Private Hepatocyte Nuclear Factor-1α G319S Variant Is Associated With Plasma Lipoprotein Variation in Canadian Oji-Cree

Hegele¹,

Cao²,

Harris³

et al. 2000

ATVB

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Abstract-We previously showed an extremely strong association between type 2 diabetes and a private polymorphism, namely G319S, in the hepatocyte nuclear transcription factor (HNF)-1␣. Because HNF-1␣ is involved in the transcription of several apolipoprotein genes, we tested for an association between the private HNF1A G319S variant and plasma lipoproteins in a sample of 55 unrelated Oji-Cree subjects with type 2 diabetes and 175 unrelated Oji-Cree subjects without type 2 diabetes. In Oji-Cree subjects with type 2 diabetes, we found that the HNF1A G319S genotype was significantly associated with lower plasma concentrations of total cholesterol, low density lipoprotein cholesterol, and apolipoprotein (apo) B. In Oji-Cree subjects without type 2 diabetes, we found that the HNF1A G319S genotype was significantly associated with higher plasma concentrations of high density lipoprotein cholesterol and apo AI. There were no associations with plasma triglycerides or lipoprotein(a). Regression analysis indicated that the HNF1A genotype accounted for Ϸ10% of the variation in the apo B-related traits in the diabetic subjects and for Ϸ5% of the variation in the apo AI-related traits in the nondiabetic subjects. Furthermore, the regression model indicated that the HNF1A S319 allele affected these traits in a dominant manner in subjects with and without type 2 diabetes. These findings provide the first evidence that a rare variant in a nuclear transcription factor is associated with variation in plasma lipoprotein traits.

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Mutations in the Hepatocyte Nuclear Factor-1α Gene in MODY and Early-Onset NIDDM: Evidence for a Mutational Hotspot in Exon 4

Cited by 124 publications

References 0 publications

beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors.

beta-cell genes and diabetes: molecular and clinical characterization of mutations in transcription factors.

Mutation screening in 18 Caucasian families suggest the existence of other MODY genes

The Private Hepatocyte Nuclear Factor-1α G319S Variant Is Associated With Plasma Lipoprotein Variation in Canadian Oji-Cree

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