Complex ABCC8 DNA variations in congenital hyperinsulinism: lessons from functional studies.

Abstract

OBJECTIVE:

Congenital hyperinsulinism (CHI) is a cause of persistent and severe hypoglycaemia in infancy. Mutations in the genes ABCC8 and KCNJ11 encoding SUR1 and Kir6.2, respectively, are the commonest cause of CHI. We investigated whether the possession of two DNA variants leading to coding changes in a single allele of ABCC8 can affect the potential mechanism of disease pathogenesis.

DESIGN AND PATIENTS:

We studied two patients with complex mutations in the ABCC8 gene with CHI and used in vitro studies to explore the potential disease mechanism and the contribution of the various mutant allelles.

RESULTS:

The first case had diffuse disease and was homozygous for the mutations D1193V and R1436Q in SUR1. Channel complexes containing the D1193V mutant were delivered to the plasma membrane and were functional and those containing R1436Q were also present at the plasma membrane but were nonfunctional. Combining the two mutations (SUR1D1193V/R1436Q) led to intracellular retention of the channel complex. In a second family, the patient had histologically focal disease and was heterozygous for two mutations from his father (G228D and D1471N) and one from his mother (V1572I). SUR1 G228D and D1471N singly or in combination led to intracellular retention of the channel complex and loss of function. By contrast, V1572I is trafficked appropriately and is functional, consistent with a mechanism of reduction to hemizygosity of paternal ABCC8 in focal disease. V1572I is likely to be a benign DNA variant.

CONCLUSION:

In one patient the combination of two coding variants led to intracellular retention of channel complex. In a second patient, functional studies allowed us to unravel the DNA variants likely to be causing the abrogation of ATP-sensitive K(+) channel function.

• Authors: Morris Muzyamba, Tabasum Farzaneh, Phillip Behe, Alison Thomas, Henrik B T Christesen, Klaus Brusgaard, Khalid Hussain, Andrew Tinker
• Journal: Clinical endocrinology (Clin Endocrinol (Oxf)) Vol. 67 Issue 1 Pg. 115-24 (Jul 2007) ISSN: 0300-0664 [Print] England
• PMID: 17466004 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ABCC8 protein, human
• ATP-Binding Cassette Transporters
• Abcc8 protein, mouse
• Kir6.2 channel
• Potassium Channels
• Potassium Channels, Inwardly Rectifying
• Receptors, Drug
• Sulfonylurea Receptors

Topics

• ATP-Binding Cassette Transporters (genetics, metabolism)
• Adult
• Animals
• Blotting, Western
• CHO Cells
• Case-Control Studies
• Congenital Hyperinsulinism (genetics)
• Cricetinae
• Cricetulus
• Gene Expression
• Genotype
• Humans
• Infant, Newborn
• Male
• Mice
• Mutagenesis, Site-Directed
• Mutation
• Phenotype
• Potassium Channels (genetics, metabolism)
• Potassium Channels, Inwardly Rectifying (genetics, metabolism)
• Receptors, Drug (genetics, metabolism)
• Staining and Labeling
• Sulfonylurea Receptors
• Transfection (methods)