Molecular and biochemical analysis of the MODY syndromes

Winter, William E.

doi:10.1034/j.1399-5448.2000.010206.x

Cited by 29 publications

(21 citation statements)

References 88 publications

(105 reference statements)

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“…Heterozygous mutations in the Pdx-1 gene in humans have been shown to result in Maturity Onset Diabetes of the Young type 4 (MODY-4), a rare monogenic form of diabetes characterized by a loss of insulin production [50]. Our data suggest that a reduction in Pdx-1 levels will result in a reduction in Slc30a8 gene expression, which may contribute to the phenotype observed in individuals with MODY-4.…”

Section: Discussionmentioning

confidence: 74%

The pancreatic islet β-cell-enriched transcription factor Pdx-1 regulates Slc30a8 gene transcription through an intronic enhancer

Pound

Hang

Sarkar

et al. 2010

Biochemical Journal

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Synopsis The SLC30A8 gene encodes the zinc transporter ZnT-8, which provides zinc for insulin-hexamer formation. Genome-wide association studies have shown that a polymorphic variant in SLC30A8 is associated with altered susceptibility to type 2 diabetes and we recently reported that glucose-stimulated insulin secretion is decreased in islets isolated from Slc30a8 knockout mice. The present study examines the molecular basis for the islet-specific expression of Slc30a8. VISTA analyses identified two conserved regions in Slc30a8 introns 2 and 3, designated enhancers A and B, respectively. Transfection experiments demonstrated that enhancer B confers elevated fusion gene expression in both βTC-3 cells and αTC-6 cells. In contrast, enhancer A confers elevated fusion gene expression selectively in βTC-3 and not αTC-6 cells. These data suggest that enhancer A is an islet beta cell-specific enhancer and that the mechanisms controlling Slc30a8 expression in alpha and beta cells are overlapping but distinct. Gel retardation and chromatin immunoprecipitation (ChIP) assays revealed that the islet-enriched transcription factor Pdx-1 binds enhancer A in vitro and in situ, respectively. Mutation of two Pdx-1 binding sites in enhancer A markedly reduces fusion gene expression suggesting that this factor contributes to Slc30a8 expression in beta cells, a conclusion consistent with developmental studies showing that restriction of Pdx-1 to pancreatic islet beta cells correlates with the induction of Slc30a8 gene and ZnT-8 protein expression in vivo.

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Section: Discussionmentioning

confidence: 74%

The pancreatic islet β-cell-enriched transcription factor Pdx-1 regulates Slc30a8 gene transcription through an intronic enhancer

Pound

Hang

Sarkar

et al. 2010

Biochemical Journal

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“…76 The differential diagnosis of childhood or adolescent diabetes includes classic type 1 diabetes, maturity onset diabetes of the young (MODY), typical type 2 diabetes, and the atypical diabetes seen in African Americans. [77][78][79][80] Typical type 1 diabetes is associated with islet cell autoantibodies and often presents with diabetic ketoacidosis (DKA). Classic MODY occurs predominantly in white youth, under the age of 25 years.…”

Section: Childrenmentioning

confidence: 99%

Diabetes in African Americans

Marshall

2005

Postgraduate Medical Journal

128

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African Americans have a high risk for type 2 diabetes. Genetic traits, the prevalence of obesity, and insulin resistance all contribute to the risk of diabetes in the African American community. African Americans have a high rate of diabetic complications, because of poor glycaemic control and racial disparities in health care in the USA. African Americans with diabetes may have an atypical presentation that simulates type 1 diabetes, but then their subsequent clinical course is typical of type 2 diabetes. Culturally sensitive strategies, structured disease management protocols, and the assistance of nurses, diabetic educators, and other health care professionals are effective in improving the outcome of diabetes in the African American community.

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“…14 Additionally, HNF1a rare variants have been associated with maturity onset diabetes of the young (MODY3). 23 The effect of HNF1a genetic variation on its mRNA expression in human liver, as well as its association with the expression of UGTs known to be regulated by HNF1a, has never been studied.…”

Section: Introductionmentioning

confidence: 99%

Hepatocyte nuclear factor-1 alpha is associated with UGT1A1, UGT1A9 and UGT2B7 mRNA expression in human liver

et al. 2007

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Experimental evidence suggests HNF1alpha regulates UGT expression. This study investigates (1) whether the variability in HNF1alpha expression is associated with the variability in UGT1A1, UGT1A9 and UGT2B7 expression in human livers and (2) the functionality of 12 HNF1alpha variants using mRNA expression as phenotype. Controlling for known UGT variation in cis-acting elements known to affect UGT expression, we demonstrate that a combination of HNF1alpha mRNA levels and UGT genotype predicts variance in UGT expression to a higher extent than UGT genotype alone. None of the HNF1alpha polymorphisms studied, however, seem to have an effect on HNF1alpha, UGT1A1, UGT1A9 and UGT2B7 expression, ruling out their functional role. Our data provide evidence for HNF1alpha being a determinant of UGT1A1, UGT1A9 and UGT2B7 mRNA expression. However, the amount of UGT intergenotype variability explained by HNF1alpha expression appears to be modest, and further studies should investigate the role of multiple transcription factors.

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Molecular and biochemical analysis of the MODY syndromes

Cited by 29 publications

References 88 publications

The pancreatic islet β-cell-enriched transcription factor Pdx-1 regulates Slc30a8 gene transcription through an intronic enhancer

The pancreatic islet β-cell-enriched transcription factor Pdx-1 regulates Slc30a8 gene transcription through an intronic enhancer

Diabetes in African Americans

Hepatocyte nuclear factor-1 alpha is associated with UGT1A1, UGT1A9 and UGT2B7 mRNA expression in human liver

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