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

Abstract

␤-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) ...

Response to oral gliclazide in a pre-pubertal child with hepatic nuclear factor-1 alpha maturity onset diabetes of the young

“…The age of presentation was more suggestive of GCK MODY, as other MODY subtypes often present in adolescence and young adulthood; however, this condition did not explain the early retinopathy in his father from whom he inherited the diabetes. The absence of renal cysts and other extrapancreatic features ruled out the possibility of HNF-1a MODY 1112…”

Phenotypic heterogeneity between different mutations of MODY subtypes and within MODY pedigrees

“…To the Editor: Contrary to currently held views [1], different mutations within the same MODY gene may be associated with differences in phenotype in diabetic as well as non-diabetic carrier subjects. This is illustrated by studies of apolipoproteins in different MODY1 pedigrees with various mutations of the gene encoding hepatocyte nuclear factor 4α (HNF4A).…”

Increased hexosamine biosynthetic pathway flux dedifferentiates INS-1E cells and murine islets by an extracellular signal-regulated kinase (ERK)1/2-mediated signal transmission pathway

“…Downstream of ERK1/2 there are several factors that bind to the insulin gene promoter to enhance transcription in response to glucose [37]. Pancreatic and duodenal homeobox 1 (PDX1) and beta cell E-box transcriptional activator 2 (BETA2) synergistically activate insulin gene transcription [38]. v-Maf musculoaponeurotic fibrosarcoma oncogene family, protein A (avian) (MAFA) also contributes to glucose responsiveness [39].…”