Mosaic Paternal Uniparental Isodisomy and an <i>ABCC8</i> Gene Mutation in a Patient With Permanent Neonatal Diabetes and Hemihypertrophy

Shield, Julian P H; Flanagan, Sarah E.; Mackay, Deborah J G; Harries, Lorna W.; Proks, Peter; Girard, Christophe A.; Ashcroft, Frances M.; Temple, I. Karen; Ellard, Sian

doi:10.2337/db07-0999

Cited by 17 publications

(9 citation statements)

References 26 publications

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“…The absence of syndromic features in our patient is consis- tent with the absence of UPD across the BWS locus. We recently reported a patient with telomeric mosaic segmental paternal UPD (11p14 -11pter) that unmasked a recessive activating mutation in ABCC8 resulting in permanent neonatal diabetes in addition to syndromic features of BWS (12). To our knowledge, this is the first reported case of interstitial UPD at 11p15.1.…”

Section: Molecular Genetic Analysismentioning

confidence: 83%

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An ABCC8 Gene Mutation and Mosaic Uniparental Isodisomy Resulting in Atypical Diffuse Congenital Hyperinsulinism

et al. 2008

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OBJECTIVE-Congenital hyperinsulinism (CHI) may be due to diffuse or focal pancreatic disease. The diffuse form is associated with an increase in the size of ␤-cell nuclei throughout the whole of the pancreas and most commonly results from recessive ATP-sensitive K ϩ channel (K ATP channel) mutations. Focal lesions are the consequence of somatic uniparental disomy for a paternally inherited K ATP channel mutation with enlargement of the ␤-cell nuclei confined to the focal lesion. Some "atypical" cases defy classification and show pancreatic ␤-cell nuclear enlargement confined to discrete regions of the pancreas. We investigated an atypical case with normal morphology within the tail of the pancreas but occasional enlarged endocrine nuclei in parts of the body and head. RESEARCH DESIGN AND METHODS-The KCNJ11 andABCC8 genes encoding the K ATP channel subunits and microsatellite markers on chromosome 11 were analyzed in DNA samples from the patient and her parents.RESULTS-A mosaic ABCC8 nonsense mutation (Q54X) was identified in the proband. The paternally inherited mutation was present at 90% in lymphocytes and 50% in normal pancreatic sections but between 64 and 74% in abnormal sections. Microsatellite analysis showed mosaic interstitial paternal uniparental isodisomy (UPD) for chromosome 11p15.1.CONCLUSIONS-We report a novel genetic mechanism to explain atypical histological diffuse forms of CHI due to mosaic UPD in patients with dominantly inherited ABCC8 (or KCNJ11) gene mutations.

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Section: Molecular Genetic Analysismentioning

confidence: 83%

“…Microsatellite analysis. Mosaic paternal isodisomy was investigated with a panel of 20 microsatellite markers on chromosome 11, using DNA extracted from leukocytes from the proband and parents (12). Six of these markers were used to investigate UPD in the 10 sections of pancreatic tissue from the patient (15).…”

Section: Methodsmentioning

confidence: 99%

An ABCC8 Gene Mutation and Mosaic Uniparental Isodisomy Resulting in Atypical Diffuse Congenital Hyperinsulinism

et al. 2008

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“…24,25) It has been reported that Kir6.2 polymorphism (E23K) reduces ATP sensitivity of K ATP channels and is associated with type-2 diabetes, [26][27][28] and that mutations in SUR1 enhance K ATP currents and cause neonatal diabetes. [29][30][31] Mutations of SUR2A, which alter the sensitivity of K ATP channels on nucleotides, have been identified to be responsible for dilated cardiomyopathy. 32) PHHI is a genetic disorder characterized by inappropriate insulin secretion despite severe hypoglycemia.…”

Section: Cooperative Nucleotide Binding Of Surmentioning

confidence: 99%

ATP-Binding Cassette Proteins Involved in Glucose and Lipid Homeostasis

Matsuo¹

2010

Bioscience, Biotechnology, and Biochemistry

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Glucose and lipids are essential to the body, but excess glucose or lipids lead to metabolic syndrome. ATP-binding cassette (ABC) proteins are involved in the homeostasis of glucose and lipid in that they regulate insulin secretion and remove excess cholesterol from the body. Sulfonylurea receptor (SUR) is a subunit of the ATP-sensitive potassium channels, which regulate insulin secretion from pancreatic -cells by sensing cellular metabolic levels. ABCG1 removes excess cholesterol from peripheral tissues and functions in reverse cholesterol transport to the liver. ABCG5 and ABCG8 suppress the absorption of cholesterol in the intestine and exclude cholesterol from the liver to the bile duct. ABCG1 and ABCG4, expressed in the central nervous system, play roles in lipid metabolism in the brain. These ABC proteins are targets of drugs and functional foods to cure and prevent diabetes, hyperlipidemia, and neurodegenerative diseases. In this review, recent knowledge of the physiological function and regulation of ABC proteins in the homeostasis of glucose and lipids is discussed.

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“…Hypoglycemia is also elicited by administration of oral or intravenous infusions of a single amino acid, leucine. However most reported defects of the ABCC8 transporters are associated with different forms of glycemic disorders such as familial hyperinsulinemic hypoglycemia type 1 (HHF1) [6], permanent neonatal diabetes mellitus (PNDM) [7], and transient neonatal diabetes mellitus type 2 (TNDM2) [8]. Some papers reports that defects in ABCC8 may contribute also to non-insulindependent diabetes mellitus (NIDDM) [8,9], also known as diabetes mellitus type 2, in Northern European Caucasians.…”

Section: Sur1/abcc8 Transportersmentioning

confidence: 99%

“…Activating mutations in either the Kir6.2 or the SUR1 subunit of the K-ATP channel are frequent causes for permanent and sometimes also for transient neonatal diabetes [7,15,16,17,18,19,20,21,22,23], with the majority of permanent neonatal diabetes being caused by mutations in Kir6.2. Mildly activating mutations leading to transient neonatal diabetes are more frequently found in SUR1.…”

Section: Mutations In the Abcc8 Gene Encoding The Sur1 Subunit Of Thementioning

confidence: 99%

Multiple Drug Resistance Associated with Function of ABC-Transporters in Diabetes Mellitus: Molecular Mechanism and Clinical Relevance

Koehn

Fountoulakis²,

Krapfenbauer

2008

IDDT

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ATP-binding cassette (ABC) transporters are involved in a variety of physiological processes such as lipid metabolism, ion homeostasis and immune functions. A large number of these proteins have been causatively linked to rare and common human genetic diseases including familial high-density lipoprotein deficiency, retinopathies, cystic fibrosis, diabetes and cardiomyopathies. Furthermore, genetic variations in ABC transporter genes and deregulated expression patterns significantly contribute to drug resistance in human cancer and pancreatic beta cells and alter the pharmacokinetic properties of a variety of drugs. Up-to-date 15 ABC transporters have been identified in human pancreatic beta cells, however only a few of them are identified to date as proteins/genes associated with multidrug resistance (MDR) in diabetes mellitus. Prominent members include the multidrug resistance protein 1 (MRP1/ABCC1), sulfonylurea receptor 1 (SUR1/ABCC8), the multi drug transporter TAP2 and member of the ATP-binding cassette transporter subfamily A (ABCA1). ABCC8 is a subunit of the pancreatic beta-cell K(ATP) channel and plays a key role in the regulation of glucose-induced insulin secretion. Although the physiological role of these transporters to MDR is not yet fully understood, they play an important role in the blood-membrane barrier in pancreatic beta cells. The aim of this article is to provide an overview and to present few examples of drug treatment in MDR in diabetes mellitus associated with function of ABC-transporters.

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Mosaic Paternal Uniparental Isodisomy and an ABCC8 Gene Mutation in a Patient With Permanent Neonatal Diabetes and Hemihypertrophy

Cited by 17 publications

References 26 publications

An ABCC8 Gene Mutation and Mosaic Uniparental Isodisomy Resulting in Atypical Diffuse Congenital Hyperinsulinism

An ABCC8 Gene Mutation and Mosaic Uniparental Isodisomy Resulting in Atypical Diffuse Congenital Hyperinsulinism

ATP-Binding Cassette Proteins Involved in Glucose and Lipid Homeostasis

Multiple Drug Resistance Associated with Function of ABC-Transporters in Diabetes Mellitus: Molecular Mechanism and Clinical Relevance

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