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Human Molecular Genetics Advance Access originally published online on April 13, 2006
Human Molecular Genetics 2006 15(11):1793-1800; doi:10.1093/hmg/ddl101
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

A heterozygous activating mutation in the sulphonylurea receptor SUR1 (ABCC8) causes neonatal diabetes

Peter Proks1,{dagger}, Amanda L. Arnold2,{dagger}, Jan Bruining3,{dagger}, Christophe Girard1, Sarah E. Flanagan2, Brian Larkin1, Kevin Colclough2, Andrew T. Hattersley2, Frances M. Ashcroft1 and Sian Ellard2,*

1University Laboratory of Physiology, Oxford University, Oxford, UK, 2Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK and 3Sophia Children's Hospital, Rotterdam, The Netherlands

* To whom correspondence should be addressed at: Department of Molecular Genetics, Royal Devon and Exeter NHS Foundation Trust, Barrack Road, Exeter EX2 5DW, UK. Tel: +44 1392402910; Fax: +44 1392402946; Email: s.ellard{at}exeter.ac.uk

Received February 10, 2006; Revised March 21, 2006; Accepted April 5, 2006

Neonatal diabetes is a genetically heterogeneous disorder with nine different genetic aetiologies reported to date. Heterozygous activating mutations in the KCNJ11 gene encoding Kir6.2, the pore-forming subunit of the ATP-sensitive potassium (KATP) channel, are the most common cause of permanent neonatal diabetes. The sulphonylurea receptor (SUR) SUR1 serves as the regulatory subunit of the KATP channel in pancreatic beta cells. We therefore hypothesized that activating mutations in the ABCC8 gene, which encodes SUR1, might cause neonatal diabetes. We identified a novel heterozygous mutation, F132L, in the ABCC8 gene of a patient with severe developmental delay, epilepsy and neonatal diabetes (DEND syndrome). This mutation had arisen de novo and was not present in 150 control chromosomes. Residue F132 shows evolutionary conservation across species and is located in the first set of transmembrane helices (TMD0) of SUR1, which is proposed to interact with Kir6.2. Functional studies of recombinant KATP channels demonstrated that F132L markedly reduces the sensitivity of the KATP channel to inhibition by MgATP and this increases the whole-cell KATP current. The functional consequence of this ABCC8 mutation mirrors that of KCNJ11 mutations causing neonatal diabetes and provides new insights into the interaction of Kir6.2 and SUR1. As SUR1 is expressed in neurones as well as in beta cells, this mutation can account for both neonatal diabetes and the neurological phenotype. Our results demonstrate that SUR1 mutations constitute a new genetic aetiology for neonatal diabetes and that they act by reducing the KATP channel's ATP sensitivity.

{dagger} The authors wish it to be known that, in their opinion, the first 3 authors should be regarded as joint First Authors.


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