Permanent Neonatal Diabetes Caused by Dominant, Recessive, or Compound Heterozygous SUR1 Mutations with Opposite Functional Effects

• Published in: American journal of human genetics 2007-08, Vol.81 (2), p.375-382
• Main Authors: Ellard, Sian, Flanagan, Sarah E., Girard, Christophe A., Patch, Ann-Marie, Harries, Lorna W., Parrish, Andrew, Edghill, Emma L., Mackay, Deborah J.G., Proks, Peter, Shimomura, Kenju, Haberland, Holger, Carson, Dennis J., Shield, Julian P.H., Hattersley, Andrew T., Ashcroft, Frances M.
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatase; ATP-Binding Cassette Transporters - genetics; Babies; Biological and medical sciences; Cohort Studies; Diabetes; Diabetes Mellitus - congenital; Diabetes Mellitus - genetics; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinology and metabolism; Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fundamental and applied biological sciences. Psychology; General aspects. Genetic counseling; Genes; Genes, Dominant; Genes, Recessive; Genetics of eukaryotes. Biological and molecular evolution; Heterozygote; Human health and pathology; Humans; Infant, Newborn; Insulin - metabolism; Insulin Secretion; Life Sciences; Medical genetics; Medical sciences; Molecular and cellular biology; Molecular Sequence Data; Mutation; Pedigree; Potassium Channels - genetics; Potassium Channels, Inwardly Rectifying - genetics; Receptors, Drug - genetics; Sulfonylurea Receptors
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/519174

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.