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Human Molecular Genetics Advance Access originally published online on June 21, 2007
Human Molecular Genetics 2007 16(16):2011-2019; doi:10.1093/hmg/ddm149
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Mechanism of action of a sulphonylurea receptor SUR1 mutation (F132L) that causes DEND syndrome

Peter Proks{dagger}, Kenju Shimomura{dagger}, Tim J. Craig, Christophe A.J. Girard and Frances M. Ashcroft*

University Laboratory of Physiology, Oxford University, Oxford OX1 3PT, UK

* To whom correspondenceshould be addressed. Tel: +44 1865285810; Fax: +44 1865285813; Email: frances.ashcroft{at}physiol.ox.ac.uk

Received April 23, 2007; Revised June 10, 2007; Accepted June 10, 2007

Activating mutations in the genes encoding the ATP-sensitive potassium (KATP) channel subunits Kir6.2 and SUR1 are a common cause of neonatal diabetes. Here, we analyse the molecular mechanism of action of the heterozygous mutation F132L, which lies in the first set of transmembrane helices (TMD0) of SUR1. This mutation causes severe developmental delay, epilepsy and permanent neonatal diabetes (DEND syndrome). We show that the F132L mutation reduces the ATP sensitivity of KATP channels indirectly, by altering the intrinsic gating of the channel. Thus, the open probability is markedly increased when Kir6.2 is co-expressed with mutant TMD0 alone or with mutant SUR1. The F132L mutation disrupts the physical interaction between Kir6.2 and TMD0, but does not alter the plasmalemma channel density. Our results explain how a mutation in an accessory subunit can produce enhanced activity of the KATP channel pore (formed by Kir6.2). They also provide further evidence that interactions between TMD0 of SUR1 and Kir6.2 are critical for KATP channel gating and identify a residue crucial for this interaction at both physical and functional levels.

{dagger} The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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