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

Morris Muzyamba, Tabasum Farzaneh, Phillip Behe, Alison Thomas, Henrik Thybo Christesen, Klaus Brusgaard, Khalid Hussain, Andrew Tinker

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

 
Udgivelsesdato: 2007-Jul
OriginalsprogEngelsk
TidsskriftClinical Endocrinology
Vol/bind67
Udgave nummer1
Sider (fra-til)115-124
Antal sider9
ISSN0300-0664
DOI
StatusUdgivet - 1. jul. 2007

Fingeraftryk

Congenital Hyperinsulinism
Mutation
DNA
Cell Membrane
Hypoglycemia
Fathers
Alleles
Mothers

Citer dette

Muzyamba, Morris ; Farzaneh, Tabasum ; Behe, Phillip ; Thomas, Alison ; Christesen, Henrik Thybo ; Brusgaard, Klaus ; Hussain, Khalid ; Tinker, Andrew. / Complex ABCC8 DNA variations in congenital hyperinsulinism: lessons from functional studies. I: Clinical Endocrinology. 2007 ; Bind 67, Nr. 1. s. 115-124.
@article{4e778670cb3a11dc8674000ea68e967b,
title = "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.",
keywords = "ATP-Binding Cassette Transporters, Adult, Animals, Blotting, Western, CHO Cells, Case-Control Studies, Cricetinae, Cricetulus, Gene Expression, Genotype, Humans, Infant, Newborn, Male, Mice, Mutagenesis, Site-Directed, Mutation, Persistent Hyperinsulinemia Hypoglycemia of Infancy, Phenotype, Potassium Channels, Potassium Channels, Inwardly Rectifying, Receptors, Drug, Staining and Labeling, Transfection",
author = "Morris Muzyamba and Tabasum Farzaneh and Phillip Behe and Alison Thomas and Christesen, {Henrik Thybo} and Klaus Brusgaard and Khalid Hussain and Andrew Tinker",
year = "2007",
month = "7",
day = "1",
doi = "10.1111/j.1365-2265.2007.02847.x",
language = "English",
volume = "67",
pages = "115--124",
journal = "Clinical Endocrinology",
issn = "0300-0664",
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Complex ABCC8 DNA variations in congenital hyperinsulinism: lessons from functional studies. / Muzyamba, Morris; Farzaneh, Tabasum; Behe, Phillip; Thomas, Alison; Christesen, Henrik Thybo; Brusgaard, Klaus; Hussain, Khalid; Tinker, Andrew.

I: Clinical Endocrinology, Bind 67, Nr. 1, 01.07.2007, s. 115-124.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Complex ABCC8 DNA variations in congenital hyperinsulinism: lessons from functional studies

AU - Muzyamba, Morris

AU - Farzaneh, Tabasum

AU - Behe, Phillip

AU - Thomas, Alison

AU - Christesen, Henrik Thybo

AU - Brusgaard, Klaus

AU - Hussain, Khalid

AU - Tinker, Andrew

PY - 2007/7/1

Y1 - 2007/7/1

N2 - 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.

AB - 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.

KW - ATP-Binding Cassette Transporters

KW - Adult

KW - Animals

KW - Blotting, Western

KW - CHO Cells

KW - Case-Control Studies

KW - Cricetinae

KW - Cricetulus

KW - Gene Expression

KW - Genotype

KW - Humans

KW - Infant, Newborn

KW - Male

KW - Mice

KW - Mutagenesis, Site-Directed

KW - Mutation

KW - Persistent Hyperinsulinemia Hypoglycemia of Infancy

KW - Phenotype

KW - Potassium Channels

KW - Potassium Channels, Inwardly Rectifying

KW - Receptors, Drug

KW - Staining and Labeling

KW - Transfection

U2 - 10.1111/j.1365-2265.2007.02847.x

DO - 10.1111/j.1365-2265.2007.02847.x

M3 - Journal article

VL - 67

SP - 115

EP - 124

JO - Clinical Endocrinology

JF - Clinical Endocrinology

SN - 0300-0664

IS - 1

ER -