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Mutations in ATP-Sensitive K⁺ Channel Genes Cause Transient Neonatal Diabetes and Permanent Diabetes in Childhood or Adulthood

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

Address correspondence and reprint requests to Professor Andrew T. Hattersley, Peninsula Medical School, Barrack Road, Exeter, EX2 5DW, U.K. E-mail: a.t.hattersley{at}exeter.ac.uk

Abbreviations: K_ATP channel, ATP-sensitive K⁺ channel; PNDM, permanent neonatal diabetes mellitus; TNDM, transient neonatal diabetes mellitus

Transient neonatal diabetes mellitus (TNDM) is diagnosed in the first 6 months of life, with remission in infancy or early childhood. For 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 with ATP-sensitive K⁺ channel (K_ATP channel) gene mutations have been reported. We determined the 6q24 status in 97 patients with TNDM. In patients in whom no abnormality was identified, the KCNJ11 gene and/or ABCC8 gene, which encode the Kir6.2 and SUR1 subunits of the pancreatic ß-cell K_ATP channel, were sequenced. K_ATP channel mutations were found in 25 of 97 (26%) TNDM probands (12 KCNJ11 and 13 ABCC8), while 69 of 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 who were diagnosed and remitted earlier (all P < 0.001). K_ATP channel mutations were identified in 26 additional family members, 17 of whom had diabetes. Of 42 diabetic patients, 91% diagnosed before 6 months remitted, but those diagnosed after 6 months had permanent diabetes (P < 0.0001). K_ATP channel mutations account for 89% of patients with non-6q24 TNDM and result in a discrete clinical subtype that includes biphasic diabetes that can be treated with sulfonylureas. Remitting neonatal diabetes was observed in two of three mutation carriers, and permanent diabetes occurred after 6 months of age in subjects without an initial diagnosis of neonatal diabetes.

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