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Heterozygous activating mutations in the KCNJ11 gene encoding the pore-forming Kir6.2 subunit of the pancreatic beta cell K(ATP) channel are the most common cause of permanent neonatal diabetes (PNDM). Patients with PNDM due to a heterozygous activating mutation in the ABCC8 gene encoding the SUR1 regulatory subunit of the K(ATP) channel have recently been reported. We studied a cohort of 59 patients with permanent diabetes who received a diagnosis before 6 mo of age and who did not have a KCNJ11 mutation. ABCC8 gene mutations were identified in 16 of 59 patients and included 8 patients with heterozygous de novo mutations. A recessive mode of inheritance was observed in eight patients with homozygous, mosaic, or compound heterozygous mutations. Functional studies of selected mutations showed a reduced response to ATP consistent with an activating mutation that results in reduced insulin secretion. A novel mutational mechanism was observed in which a heterozygous activating mutation resulted in PNDM only when a second, loss-of-function mutation was also present.

Original publication

DOI

10.1086/519174

Type

Journal article

Journal

Am J Hum Genet

Publication Date

08/2007

Volume

81

Pages

375 - 382

Keywords

ATP-Binding Cassette Transporters, Cohort Studies, Diabetes Mellitus, Genes, Dominant, Genes, Recessive, Heterozygote, Humans, Infant, Newborn, Insulin, Molecular Sequence Data, Mutation, Pedigree, Potassium Channels, Potassium Channels, Inwardly Rectifying, Receptors, Drug, Sulfonylurea Receptors