title: Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood.
abstract: 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 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 beta-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.
authors: Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK.
authors: Sarah E
authors: SE
authors: Flanagan
authors: Ann-Marie
authors: AM
authors: Patch
authors: Deborah J G
authors: DJ
authors: Mackay
authors: Emma L
authors: EL
authors: Edghill
authors: Anna L
authors: AL
authors: Gloyn
authors: David
authors: D
authors: Robinson
authors: Julian P H
authors: JP
authors: Shield
authors: Karen
authors: K
authors: Temple
authors: Sian
authors: S
authors: Ellard
authors: Andrew T
authors: AT
authors: Hattersley
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000255:Adenosine Triphosphate; D002675:Child, Preschool; D003920:Diabetes Mellitus / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D009154:Mutation; D010375:Pedigree; D015221:Potassium Channels / Q000235:genetics*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D011955:Receptors, Drug / Q000235:genetics*; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D000255:Adenosine Triphosphate; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human