Neonatal Diabetes Caused by Activating Mutations in the Sulphonylurea Receptor

Proks, Peter

doi:10.4093/dmj.2013.37.3.157

Cited by 17 publications

(20 citation statements)

References 49 publications

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“…As such, glibenclamide, or other sulfonylureas, represents a potential pharmacotherapy for CS. However, there are multiple reports of neonatal diabetes mutations in the Kir6.2/SUR1 K ATP subunits that reduce sulfonylurea sensitivity (28,29) and, as we have recently demonstrated, the CS-associated mutation V65M in Kir6.1 profoundly reduces glibenclamide inhibition of recombinant channels (30). Therefore, it is important to assess the effect of SUR2 CS mutations on inhibitor sensitivity.…”

Section: Consequences For Sulfonylurea Sensitivitymentioning

confidence: 98%

Cantu syndrome–associated SUR2 (ABCC9) mutations in distinct structural domains result in KATP channel gain-of-function by differential mechanisms

McClenaghan¹,

Hanson²,

Sala-Rabanal³

et al. 2018

Journal of Biological Chemistry

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The complex disorder Cantu syndrome (CS) arises from gain-of-function mutations in either or, the genes encoding the Kir6.1 and SUR2 subunits of ATP-sensitive potassium (K) channels, respectively. Recent reports indicate that such mutations can increase channel activity by multiple molecular mechanisms. In this study, we determined the mechanism by which K function is altered by several substitutions in distinct structural domains of SUR2: D207E in the intracellular L0-linker and Y985S, G989E, M1060I, and R1154Q/R1154W in TMD2. We engineered substitutions at their equivalent positions in rat SUR2A (D207E, Y981S, G985E, M1056I, and R1150Q/R1150W) and investigated functional consequences using macroscopic rubidium (Rb) efflux assays and patch-clamp electrophysiology. Our results indicate that D207E increases K channel activity by increasing intrinsic stability of the open state, whereas the cluster of Y981S/G985E/M1056I substitutions, as well as R1150Q/R1150W, augmented Mg-nucleotide activation. We also tested the responses of these channel variants to inhibition by the sulfonylurea drug glibenclamide, a potential pharmacotherapy for CS. None of the D207E, Y981S, G985E, or M1056I substitutions had a significant effect on glibenclamide sensitivity. However, Gln and Trp substitution at Arg-1150 significantly decreased glibenclamide potency. In summary, these results provide additional confirmation that mutations in CS-associated SUR2 mutations result in K gain-of-function. They help link CS genotypes to phenotypes and shed light on the underlying molecular mechanisms, including consequences for inhibitory drug sensitivity, insights that may inform the development of therapeutic approaches to manage CS.

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Section: Consequences For Sulfonylurea Sensitivitymentioning

confidence: 98%

Cantu syndrome–associated SUR2 (ABCC9) mutations in distinct structural domains result in KATP channel gain-of-function by differential mechanisms

McClenaghan¹,

Hanson²,

Sala-Rabanal³

et al. 2018

Journal of Biological Chemistry

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show abstract

“…As such, glibenclamide, or other sulfonylureas, represents a potential pharmacotherapy for CS. However, there are multiple reports of neonatal diabetes mutations in the Kir6.2/SUR1 K ATP subunits which reduce sulfonylurea sensitivity [28,29], and as we have recently demonstrated, the CS-associated mutation V65M in Kir6.1 profoundly reduces glibenclamide inhibition of recombinant channels [30]. Therefore, it is important to assess the effect of SUR2 CS mutations on inhibitor sensitivity.…”

Section: Consequences For Sulfonylurea Sensitivitymentioning

confidence: 99%

“…In addition, the sensitivity of mutant channels to the sulfonylurea K ATP -inhibitor, glibenclamide was tested. Glibenclamide holds promise as a potential treatment for CS, however numerous K ATP GoF mutations which reduce sulfonylurea sensitivity have previously been reported [28][29][30]. Therefore, determining sulfonylurea sensitivity for specific mutations may be required for future individualized therapy.…”

Section: Introductionmentioning

confidence: 99%

Cantu syndrome-associated SUR2 (ABCC9) mutations in distinct structural domains result in K_ATP channel gain-of-function by differential mechanisms

McClenaghan

Hanson

Sala-Rabanal

et al. 2017

Preprint

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The complex cardiovascular disorder Cantu Syndrome arises from gain-of-function mutations in either KCNJ8 or ABCC9, the genes encoding the Kir6.1 and SUR2 subunits of ATP-sensitive potassium (K ATP ) channels. Recent reports indicate that such mutations can increase channel activity by multiple molecular mechanisms. In this study, we determine the mechanism by which K ATP function is altered by several mutations in distinct structural domains of SUR2: D207E in the intracellular L0-linker and Y985S, G989E, M1060I, and R1154Q/W in TMD2. Mutations were engineered at their equivalent position in rat SUR2A (D207E, Y981S, G985E, M1056I and R1150Q/W) and functional effects were investigated using macroscopic rubidium ( Mg-nucleotide activation. The response of mutant channels to inhibition by the sulfonylurea drug glibenclamide, a potential pharmacotherapy for CS, was also tested. There was no major effect on glibenclamide sensitivity for the D207E, Y981S, G985E or M1056I mutations, but glutamine and tryptophan substitution at R1150 resulted in significant decreases in potency.

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“…TNDM accounts for approximately for 50% cases of NDM, with an incidence of ~1/100,000 live births [9]. Its main clinical feature is that it may either spontaneously remit or be so mild as not to require treatment.…”

Section: Neonatal Diabetes -Definition and Clinical Formsmentioning

confidence: 99%

“…PNDM may be either isolated or form part of a syndrome associating diabetes and other extra-pancreatic manifestations, as briefly described in Table 1. The most common causes of isolated PNDM are represented by mutation in the genes that encode the K ATP channel components Kir6.2 (KCJN11 gene) and Sulphonylurea Receptor -SUR (ABCC8 gene) on chromosome 11p15.1 and insulin (INS gene) on chromosome 11p15.5 [9].…”

Section: Permanent Neonatal Diabetes Mellitusmentioning

confidence: 99%

Neonatal Diabetes – From Gene Discovery yo Clinical Practice Changes

Guja¹,

Guja²,

Ionescu-Tîrgovişte³

2013

Romanian Journal of Diabetes Nutrition and Metabolic Diseases

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Diabetes mellitus is one of the most common chronic diseases but also one of the most heterogeneous. Apart the common phenotypes of type 1 and type 2 diabetes, around 1-2% of all cases arise from a single gene mutation and are known as monogenic diabetes. Diabetes diagnosed within the first 6 months of life is known as neonatal diabetes and has been extensively studied during the last two decades. Unraveling the genetic cause and molecular mechanism of this rare diabetes phenotype led to a dramatic change in the treatment of these children who often can be switched from insulin to sulphonylurea treatment. The aim of this paper is to review the known genetic causes of neonatal diabetes and to highlight the most recent aspects of the disease caused by mutations in the KATP and insulin genes, with a special focus on the individualized treatment of these cases

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Neonatal Diabetes Caused by Activating Mutations in the Sulphonylurea Receptor

Cited by 17 publications

References 49 publications

Cantu syndrome–associated SUR2 (ABCC9) mutations in distinct structural domains result in KATP channel gain-of-function by differential mechanisms

Cantu syndrome–associated SUR2 (ABCC9) mutations in distinct structural domains result in KATP channel gain-of-function by differential mechanisms

Cantu syndrome-associated SUR2 (ABCC9) mutations in distinct structural domains result in K_ATP channel gain-of-function by differential mechanisms

Neonatal Diabetes – From Gene Discovery yo Clinical Practice Changes

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Neonatal Diabetes Caused by Activating Mutations in the Sulphonylurea Receptor

Cited by 17 publications

References 49 publications

Cantu syndrome–associated SUR2 (ABCC9) mutations in distinct structural domains result in KATP channel gain-of-function by differential mechanisms

Cantu syndrome–associated SUR2 (ABCC9) mutations in distinct structural domains result in KATP channel gain-of-function by differential mechanisms

Cantu syndrome-associated SUR2 (ABCC9) mutations in distinct structural domains result in KATP channel gain-of-function by differential mechanisms

Neonatal Diabetes – From Gene Discovery yo Clinical Practice Changes

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Cantu syndrome-associated SUR2 (ABCC9) mutations in distinct structural domains result in K_ATP channel gain-of-function by differential mechanisms