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Diabetes Publish Ahead of Print published online ahead of print April 19, 2007
DOI: 10.2337/db07-0043
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Original Research

Mutations in KATP Channel Genes cause Transient Neonatal Diabetes and Permanent Diabetes in Childhood or Adulthood.

Sarah E. Flanagan, BSc1, Ann-Marie Patch, PhD1, Deborah J.G. Mackay, PhD2,,3, Emma L. Edghill, MSc1, Anna L. Gloyn, DPhil1,,4, David Robinson, PhD2, Julian P.H. Shield, MD5, Karen Temple, FRCP3,,6, Sian Ellard, PhD1, and Andrew T. Hattersley, DM1

1Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK
2Wessex Regional Genetics Labs, Salisbury District Hospital, Salisbury, UK
3Division of Human Genetics, Southampton University, Southampton, UK
4Diabetes Research Laboratories, Oxford Centre for Diabetes Endocrinology & Metabolism, University of Oxford, UK
5The Royal Hospital for Children, Bristol, UK
6Wessex Clinical Genetics Service, NHS Trust, Southampton, UK

Correspondence: A.T.Hattersley{at}exeter.ac.uk

Objective: Transient neonatal diabetes mellitus (TNDM) is diagnosed in the first 6 months of life with remission in infancy or early childhood. For approximately 50% of patients their diabetes will relapse in later life. The majority of cases result from anomalies of the imprinted region on chromosome 6q24 and 14 patients have been reported with KATP channel gene mutations.

Research Design and Methods: We determined the 6q24 status in 97 patients with TNDM. In patients where no abnormality was identified the KCNJ11 gene and/or ABCC8 gene which encode the Kir6.2 and SUR1 subunits of the pancreatic beta-cell ATP sensitive potassium (KATP) channel were sequenced.

Results: KATP channel mutations were found in 25/97 (26%) TNDM probands (12 KCNJ11, 13 ABCC8) while 69/97 (71%) had chromosome 6q24 abnormalities. The phenotype associated with KCNJ11 and ABCC8 mutations was similar, but markedly different from 6q24 patients who had a lower birth weight, and were diagnosed and remitted earlier (all p <0.001). KATP channel mutations were identified in 26 additional family members, 17 had diabetes. Of the 42 diabetic patients, 91% diagnosed before 6 months remitted, but those diagnosed after 6 months had permanent diabetes (p<0.0001).

Conclusion: KATP channel mutations account for 89% of patients with non-6q24 TNDM and result in a discrete clinical subtype which includes biphasic diabetes that can be treated with sulphonylureas. Remitting neonatal diabetes was observed in 2/3 mutation carriers and permanent diabetes occurred after 6 months of age in subjects without an initial diagnosis of neonatal diabetes.


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