␤-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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Familial glomerulocystic kidney disease (GCKD) is a dominantly inherited condition characterized by glomerular cysts and variable renal size and function; the molecular genetic etiology is unknown. Mutations in the gene encoding hepatocyte nuclear factor (HNF)-1beta have been associated with early-onset diabetes and nondiabetic renal disease-particularly renal cystic disease. We investigated a possible role for the HNF-1beta gene in four unrelated GCKD families and identified mutations in two families: a nonsense mutation in exon 1 (E101X) and a frameshift mutation in exon 2 (P159fsdelT). The family members with HNF-1beta gene mutations had hypoplastic GCKD and early-onset diabetes or impaired glucose tolerance. We conclude that there is genetic heterogeneity in familial GCKD and that the hypoplastic subtype is a part of the clinical spectrum of the renal cysts and diabetes syndrome that is associated with HNF-1beta mutations.

Phenotypic selection of subjects with gestational diabetes greatly increases the likelihood of detecting a mutation in the glucokinase gene as previous studies have suggested a prevalence of 2.5% (range 0-6%). Our study in gestational diabetes to successfully used clinical criteria to assist in the definition of a genetic subgroup.

These studies indicate that HNF-1 beta plays a central role in normal kidney development and pancreatic beta-cell function, and suggest that one mechanism by which HNF-1 beta gene mutations may cause renal dysfunction are by their effects on nephron development.

This study confirms an association between HNF-1beta mutations and renal and Müllerian anomalies. The hypospadias may be coincidental. This study describes the first HNF-1beta mutations that are associated with a single functioning kidney and the absence of diabetes. This study further reinforces the variability of the renal and non-renal phenotypes associated with HNF-1beta mutations.

OBJECTIVE -HNF-1␣ gene mutations (MODY3) present with marked hyperglycemia in lean young adults and may, therefore, be mistaken for type 1 diabetes, with implications for individual treatment and risk of diabetes in other family members. We examined the prevalence of HNF-1␣ mutations in families with three generations of diabetes identified in a populationbased study of childhood diabetes, representing a subpopulation in which misclassification was likely.RESEARCH DESIGN AND METHODS -In a study population of 1,470 families, 36 families (2.4%) with three affected generations were identified. In the 18 families in whom DNA samples were available, islet autoantibody testing, HLA class II genotyping, and HNF-1␣ sequencing were performed.RESULTS -At least one islet autoantibody was found in 13 of 14 probands, and diabetesassociated HLA class II haplotypes were found in 17 of 18. One proband, who had no islet autoantibodies and was homozygous for the protective HLA haplotype DRB1*02-DQB1*0602, had a novel HNF-1␣ heterozygous nonsense mutation (R54X). This mutation cosegregated with diabetes in the family. The proband, his brother, mother, and maternal grandmother were diagnosed with type 1 diabetes aged 14 -18 years and treated with insulin (0.39 -0.74 units/kg) from diagnosis. The mother has since been successfully transferred to sulfonylurea treatment.CONCLUSIONS -Family history alone is of limited value in identification of individuals with HNF-1␣ mutations, and we propose a stepwise approach that restricts sequencing of the HNF-1␣ gene to those with a family history of diabetes who also test negative for islet autoantibodies. Diabetes Care 26:333-337, 2003T ype 1 diabetes accounts for the vast majority cases of diabetes in young people, but there are other causes of diabetes in this age-group. Mutations in the hepatocyte nuclear factor (HNF) genes 1␣, 1␤, and 4␣, causing maturityonset diabetes of the young (MODY), typically present in lean individuals with progressive hyperglycemia and osmotic symptoms in adolescence or early adulthood; therefore, they may be misclassified as type 1 diabetes (1). Mutations in the HNF-1␣ gene account for 65% of MODY in U.K. populations (2) and make up the majority of cases that might be mistaken for type 1 diabetes. The distinction between MODY and type 1 diabetes is important because patients with HNF-1␣ mutations are not insulin dependent and are sensitive to sulfonylureas (3). There are also implications for other family members, since the lifetime incidence of type 1 diabetes in the offspring of an affected parent is estimated at 10% (4), whereas risk to the offspring of an affected parent with MODY is 50%.Type 1 diabetes is characterized by islet autoantibodies that are present at diagnosis in up to 97% of children (5) and by a predisposing HLA genotype. A diagnosis of MODY might therefore be suggested by the absence of islet autoantibodies or the coexistence of class II haplotypes known to confer protection against type 1 diabetes. Of 39 patients identified in a Danish popula...

The transmission disequilibrium test with use of trios (an affected proband with both parents) is a robust method for assessing the role of gene variants in disease that avoids the problem of population stratification that may confound conventional case/control studies and allows the detection of parent-of-origin effects. Trios have played a major role in defining genes in a number of polygenic conditions, including type 1 diabetes. We assessed the prevalence, clinical characteristics, and suitability for defining type 2 susceptibility genes of European type 2 diabetes trios. In a Caucasian population in the U.K., only 2.5% of type 2 patients had both parents alive. Using a nationwide strategy, we collected 182 trios defined by strict clinical criteria. Immunological and genetic testing resulted in the exclusion of 25 trios as a result of latent autoimmune diabetes (n = 13), inconsistent family relationships (n = 7), and maternally inherited diabetes and deafness (n = 5). The 157 remaining probands had similar treatment requirements to familial type 2 diabetic subjects but presented at a younger age, were more obese, and more frequently had affected parents. Using this resource, we have not found any evidence for linkage disequilibrium between type 2 diabetes and the glucokinase gene markers GCK1 and GCK2 and the chromosome 20 marker D20S197. We conclude that European type 2 diabetes trios are difficult to collect but provide an important additional approach to dissecting the genetics of type 2 diabetes.