KCNJ11 activating mutations cause both transient and permanent neonatal diabetes mellitus in Cypriot patients.

Heterozygous mutations of the KCNJ11 gene encoding the Kir6.2 subunit of the ATP-sensitive potassium channel (K(ATP) channel) of the pancreatic β-cell cause diabetes in about 30-60% of all permanent neonatal diabetes mellitus cases diagnosed before 6 months of age. The K(ATP) channel plays an essential role in the regulation of the electrical status of the membrane through which the secretion of insulin is activated. Transient neonatal diabetes mellitus due to KCNJ11 mutations is less frequent than abnormalities affecting the imprinted region of chromosome 6q24. We studied the genetic basis of two Cypriot patients who developed diabetes before 6 months of age. They both carried mutations of the KCNJ11 gene. The R201H mutation was identified in a patient who developed hyperglycemia and ketoacidosis at the age of 40 d and was successfully transferred to sulphonylureas which activate the channel through an ATP independent route. The R50Q mutation was identified in a child diagnosed at day 45 after birth with remission of his diabetes at 9 months of age. The same defect was identified both in his asymptomatic mother and the recently diagnosed 'type 2' diabetic maternal grandmother. The remission-relapse mechanism in cases of transient neonatal diabetes is not known. Nevertheless, it is possible that the residue of the mutation within the Kir6.2 molecule is associated with the sensitivity to ATP reflecting to the severity of the diabetic phenotype.