Human Molecular Genetics

Human Molecular Genetics Advance Access published online on February 17, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi086

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© The Author 2005. Published by Oxford University Press. All rights reserved

Article

Relapsing diabetes can result from moderately activating mutations in KCNJ11

Anna L. Gloyn ¹, Frank Reimann ², Christophe Girard ³, Emma L. Edghill ⁴, Peter Proks ³, Ewan R. Pearson ⁴, I. Karen Temple ⁵, Deborah J.G. Mackay ⁶, Julian P.H. Shield ⁷, Debra Freedenberg ⁸, Kathryn Noyes ⁹, Sian Ellard ⁴, Frances M. Ashcroft ³, Fiona M. Gribble ², and Andrew T. Hattersley ^10*

¹ Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, EX2 5DW, UK; Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, OX3 7LJ, UK
² Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC building, Hills Road, Cambridge, CB2 2XY, UK
³ University Laboratory of Physiology, University of Oxford, OX1 4TP, UK
⁴ Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, EX2 5DW, UK
⁵ Wessex Clinical Genetics Service, NHS Trust, Southampton, S016 5YA, UK; Division of Human Genetics, Southampton University, Salisbury, SO16 6YD, UK
⁶ Division of Human Genetics, Southampton University, Salisbury, SO16 6YD, UK; Wessex Regional Genetics Labs, Salisbury District Hospital, Salisbury, SP2 8BJ, UK
⁷ The Royal Hospital for Children, Bristol, BS2 8AE, UK
⁸ Genetics Institute of Austin, Texas Department of Health, Austin, Texas, TX 78705, USA
⁹ Department of Diabetes Endocrinology & Diabetes, The Royal Hospital for Sick Children, Edinburgh, EH9 1LF, UK
¹⁰ Institute of Biomedical and Clinical Science, Peninsula Medical School, RD & E Hospital (Wonford), Barrack Road, Exeter, EX2 5DW, UK

^* To whom correspondence should be addressed.
Andrew T. Hattersley, E-mail: A.T.Hattersley{at}exeter.ac.uk

	Abstract

Neonatal diabetes can either remit and hence be transient or else may be permanent. These two phenotypes were considered to be genetically distinct. Abnormalities of 6q24 are the commonest cause of transient neonatal diabetes (TNDM). Mutations in KCNJ11, which encodes Kir6.2, the pore forming subunit of the ATP-sensitive potassium channel (K_ATP), are the commonest cause of permanent neonatal diabetes (PNDM). Some KCNJ11 mutations result in marked developmental delay and epilepsy in addition to diabetes. These mutations are more severe on functional characterisation. We investigated whether mutations in KCNJ11 could also give rise to transient neonatal diabetes (TNDM). We identified 3 novel heterozygous mutations (G53S, G53R, I182V) in 3 of 11 probands with clinically defined TNDM who did not have chromosome 6q24 abnormalities. The mutations co-segregated with diabetes within families and were not found in 100 controls. All probands had insulin treated diabetes diagnosed in the first four months and went into remission by 7-14 months. Functional characterisation of the TNDM associated mutations was performed by expressing the mutated Kir6.2 with SUR1 in Xenopus laevis oocytes. All 3 heterozygous mutations resulted in a reduction in the sensitivity to ATP compared to wild type (IC₅₀30 vs 7 µM, p all <0.01), however this was less profoundly reduced than with the PNDM associated mutations. In conclusion, mutations in KCNJ11 are the first genetic cause for remitting as well as permanent diabetes. This suggests a fixed ion channel abnormality can result in a fluctuating glycaemic phenotype. The multiple phenotypes associated with activating KCNJ11 mutations may reflect their severity in vitro.

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