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CMP
Credit: Jack Hobhouse

Peter Proks

Postdoctoral Research Assistant

Sub department

  • Condensed Matter Physics
peter.proks@physics.ox.ac.uk
Telephone: 72426
Clarendon Laboratory, room 071.4 & 071.7
  • About
  • Publications

A mouse model of neonatal diabetes caused by the K-ATP channel mutation Kir6.2-V59M

DIABETOLOGIA 51 (2008) S54-S54

Authors:

CA Girard, TF Wunderlich, K Shimomura, S Collins, S Kaizik, P Proks, F Abdulkader, A Clark, L Bentley, J Galvanovskis, R Cox, P Rorsman, JC Bruning, FM Ashcroft
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Alpha glucosidase inhibitor voglibose can prevent pioglitazone-induced body weight gain in Type 2 diabetic patients.

Br J Clin Pharmacol 66:2 (2008) 318-319

Authors:

Mayumi Negishi, Kenju Shimomura, Peter Proks, Yohnosuke Shimomura, Masatomo Mori
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A mutation (R826W) in nucleotide-binding domain 1 of ABCC8 reduces ATPase activity and causes transient neonatal diabetes.

EMBO Rep 9:7 (2008) 648-654

Authors:

Heidi de Wet, Peter Proks, Mathilde Lafond, Jussi Aittoniemi, Mark SP Sansom, Sarah E Flanagan, Ewan R Pearson, Andrew T Hattersley, Frances M Ashcroft

Abstract:

Activating mutations in the pore-forming Kir6.2 (KCNJ11) and regulatory sulphonylurea receptor SUR1 (ABCC8) subunits of the K(ATP) channel are a common cause of transient neonatal diabetes mellitus (TNDM). We identified a new TNDM mutation (R826W) in the first nucleotide-binding domain (NBD1) of SUR1. The mutation was found in a region that heterodimerizes with NBD2 to form catalytic site 2. Functional analysis showed that this mutation decreases MgATP hydrolysis by purified maltose-binding protein MBP-NBD1 fusion proteins. Inhibition of ATP hydrolysis by MgADP or BeF was not changed. The results indicate that the ATPase cycle lingers in the post-hydrolytic MgADP.P(i)-bound state, which is associated with channel activation. The extent of MgADP-dependent activation of K(ATP) channel activity was unaffected by the R826W mutation, but the time course of deactivation was slowed. Channel inhibition by MgATP was reduced, leading to an increase in resting whole-cell currents. In pancreatic beta cells, this would lead to less insulin secretion and thereby diabetes.
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How ATP inhibits the open K(ATP) channel.

J Gen Physiol 132:1 (2008) 131-144

Authors:

Tim J Craig, Frances M Ashcroft, Peter Proks

Abstract:

ATP-sensitive potassium (K(ATP)) channels are composed of four pore-forming Kir6.2 subunits and four regulatory SUR1 subunits. Binding of ATP to Kir6.2 leads to inhibition of channel activity. Because there are four subunits and thus four ATP-binding sites, four binding events are possible. ATP binds to both the open and closed states of the channel and produces a decrease in the mean open time, a reduction in the mean burst duration, and an increase in the frequency and duration of the interburst closed states. Here, we investigate the mechanism of interaction of ATP with the open state of the channel by analyzing the single-channel kinetics of concatenated Kir6.2 tetramers containing from zero to four mutated Kir6.2 subunits that possess an impaired ATP-binding site. We show that the ATP-dependent decrease in the mean burst duration is well described by a Monod-Wyman-Changeux model in which channel closing is produced by all four subunits acting in a single concerted step. The data are inconsistent with a Hodgkin-Huxley model (four independent steps) or a dimer model (two independent dimers). When the channel is open, ATP binds to a single ATP-binding site with a dissociation constant of 300 microM.
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Mosaic paternal uniparental isodisomy and an ABCC8 gene mutation in a patient with permanent neonatal diabetes and hemihypertrophy.

Diabetes 57:1 (2008) 255-258

Authors:

Julian PH Shield, Sarah E Flanagan, Deborah J Mackay, Lorna W Harries, Peter Proks, Christophe Girard, Frances M Ashcroft, I Karen Temple, Sian Ellard

Abstract:

OBJECTIVE: Activating mutations in the KCNJ11 and ABCC8 genes encoding the Kir6.2 and SUR1 subunits of the pancreatic ATP-sensitive K(+) channel are the most common cause of permanent neonatal diabetes. In contrast to KCNJ11, where only dominant heterozygous mutations have been identified, recessively acting ABCC8 mutations have recently been found in some patients with neonatal diabetes. These genes are co-located on chromosome 11p15.1, centromeric to the imprinted Beckwith-Wiedemann syndrome (BWS) locus at 11p15.5. We investigated a male with hemihypertrophy, a condition classically associated with neonatal hyperinsulinemia and hypoglycemia, who developed neonatal diabetes at age 5 weeks. RESEARCH DESIGN AND METHODS: The KCNJ11 and ABCC8 genes and microsatellite markers on chromosome 11 were analyzed in DNA samples from the patient and his parents. RESULTS: A paternally inherited activating mutation (N72S) in the ABCC8 gene was identified in the proband. The mutation was present at 70% in the patient's leukocytes and 50% in buccal cells. Microsatellite analysis demonstrated mosaic segmental paternal uniparental isodisomy (UPD) of 11pter-11p14 in the proband that encompassed the ABCC8 gene and the BWS locus. CONCLUSIONS: We report a patient with neonatal diabetes, hemihypertrophy, and relatively high birth weight resulting from telomeric segmental paternal UPD of chromosome 11, which unmasks a recessively acting gain-of-function mutation in the ABCC8 gene and causes deregulation of imprinted genes at the BWS locus on 11p15.5.
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