Clinical characteristics of recessive and dominant congenital hyperinsulinism due to mutation(s) in the ABCC8/KCNJ11 genes encoding the ATP-sensitive potasium channel in the pancreatic beta cell

AbstractGene expression is tightly regulated with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function. This silencing is largely controlled by non-coding elements and their disruption might cause human disease. We performed gene-agnostic screening of the non-coding regions to discover new molecular causes of congenital hyperinsulinism. This identified 14 non-coding de novo mutations affecting a 42bp conserved region encompassed by a regulatory element in intron 2 of Hexokinase 1 (HK1), a pancreatic beta-cell disallowed gene. We demonstrated that these mutations resulted in expression of HK1 in the pancreatic beta-cells causing inappropriate insulin secretion and congenital hyperinsulinism. These mutations identify a regulatory region critical for cell-specific silencing. Importantly, this has revealed a new disease mechanism for non-coding mutations that cause inappropriate expression of a disallowed gene.

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From congenital hyperinsulinism to diabetes mellitus: the role of pancreatic beta-cell KATP channels

Pediatric Diabetes ◽

10.1111/j.1399-543x.2005.00109.x ◽

2005 ◽

Vol 6 (2) ◽

pp. 103-113 ◽

Cited By ~ 15

Author(s):

Khalid Hussain ◽

Karen E Cosgrove

Keyword(s):

Diabetes Mellitus ◽

Beta Cell ◽

Pancreatic Beta Cell ◽

Katp Channels ◽

Congenital Hyperinsulinism

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Mapping to Chromosomes 1 and 12 of mouse homologs of human protein tyrosine phosphatase, receptor-type, related genes encoding pancreatic beta cell autoantigens

Mammalian Genome ◽

10.1007/s003359900619 ◽

1997 ◽

Vol 8 (12) ◽

pp. 949-950 ◽

Cited By ~ 5

Author(s):

Edward H. Leiter ◽

Hideki Tsumura ◽

David V. Serreze ◽

Harold D. Chapman ◽

Daniel U. Rabin ◽

...

Keyword(s):

Beta Cell ◽

Protein Tyrosine Phosphatase ◽

Tyrosine Phosphatase ◽

Pancreatic Beta Cell ◽

Human Protein ◽

Receptor Type ◽

Protein Tyrosine ◽

Genes Encoding

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Faculty Opinions recommendation of Large-scale association studies of variants in genes encoding the pancreatic beta-cell KATP channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) confirm that the KCNJ11 E23K variant is associated with type 2 diabetes.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1012670.186910 ◽

2003 ◽

Author(s):

David Altshuler

Keyword(s):

Type 2 Diabetes ◽

Beta Cell ◽

Katp Channel ◽

Large Scale ◽

Association Studies ◽

Pancreatic Beta Cell ◽

Genes Encoding

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Pancreatic beta-cell stimulation tests in transient and persistent congenital hyperinsulinism

Acta Paediatrica ◽

10.1111/j.1651-2227.2001.tb03239.x ◽

2007 ◽

Vol 90 (10) ◽

pp. 1116-1120 ◽

Cited By ~ 6

Author(s):

HBT Christesen ◽

N Feilberg-Jørgensen ◽

Brock Jacobsen

Keyword(s):

Beta Cell ◽

Pancreatic Beta Cell ◽

Congenital Hyperinsulinism ◽

Cell Stimulation ◽

Stimulation Tests

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NIDDM is associated with loss of pancreatic beta-cell L-type Ca2+ channel activity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1996.270.1.e133 ◽

1996 ◽

Vol 270 (1) ◽

pp. E133-E140 ◽

Cited By ~ 8

Author(s):

M. W. Roe ◽

J. F. Worley ◽

Y. Tokuyama ◽

L. H. Philipson ◽

J. Sturis ◽

...

Keyword(s):

Insulin Secretion ◽

Beta Cell ◽

Pancreatic Beta Cell ◽

Substantial Reduction ◽

Insulin Dependent Diabetes Mellitus ◽

Dependent Diabetes Mellitus ◽

Expression Of Genes ◽

Zucker Diabetic Fatty Rats ◽

Genes Encoding ◽

Glucose Stimulated Insulin Secretion

Development of non-insulin-dependent diabetes mellitus (NIDDM) is associated with defects in glucose-stimulated insulin secretion. We have investigated Zucker diabetic fatty rats (ZDF), an animal model of NIDDM, and found that, compared with control islets, the expression of mRNA encoding C- and D-isoforms of alpha 1-subunits of beta-cell L-type voltage-dependent Ca2+ channels (VDCC) was significantly reduced in islets isolated from ZDF rats. This correlated with a substantial reduction of L-type Ca2+ currents (ICa) in ZDF beta-cells. Intracellular Ca2+ concentration responses in ZDF islets after glucose, KCI, or BAY K 8644 stimulation were markedly attenuated, whereas responses evoked by carbachol were unimpaired, consistent with a specific decrease in ICa in the diabetic islets. This reduction was accompanied by loss of pulsatile insulin secretion from ZDF islets treated with oscillatory increases of external glucose concentration. Our findings suggest that the attenuation of ICa in diabetic islets may contribute to the abnormal glucose-dependent insulin secretory responses associated with NIDDM and indicate that this defect is caused by decreased expression of genes encoding beta-cell VDCC alpha 1-subunits.

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