title: Heterozygous ABCC8 mutations are a cause of MODY.
abstract: OBJECTIVE
  The ABCC8 gene encodes the sulfonylurea receptor 1 (SUR1) subunit of the pancreatic beta cell ATP-sensitive potassium (K(ATP)) channel. Inactivating mutations cause congenital hyperinsulinism (CHI) and activating mutations cause transient neonatal diabetes (TNDM) or permanent neonatal diabetes (PNDM) that can usually be treated with sulfonylureas. Sulfonylurea sensitivity is also a feature of HNF1A and HNF4A MODY, but patients referred for genetic testing with clinical features of these types of diabetes do not always have mutations in the HNF1A/4A genes. Our aim was to establish whether mutations in the ABCC8 gene cause MODY that is responsive to sulfonylurea therapy.
  
  
  METHODS
  We sequenced the ABCC8 gene in 85 patients with a BMI <30 kg/m², no family history of neonatal diabetes and who were deemed sensitive to sulfonylureas by the referring clinician or were sulfonylurea-treated. All had tested negative for mutations in the HNF1A and HNF4A genes.
  
  
  RESULTS
  ABCC8 mutations were found in seven of the 85 (8%) probands. Four patients were heterozygous for previously reported mutations and four novel mutations, E100K, G214R, Q485R and N1245D, were identified. Only four probands fulfilled MODY criteria, with two diagnosed after 25 years and one patient, who had no family history of diabetes, as a result of a proven de novo mutation.
  
  
  CONCLUSIONS
  ABCC8 mutations can cause MODY in patients whose clinical features are similar to those with HNF1A/4A MODY. Therefore, sequencing of ABCC8 in addition to the known MODY genes should be considered if such features are present, to facilitate optimal clinical management of these patients.
authors: Peninsula NIHR Clinical Research Facility, Peninsula Medical School, University of Exeter, Exeter, UK.
authors: P
authors: P
authors: Bowman
authors: S E
authors: SE
authors: Flanagan
authors: E L
authors: EL
authors: Edghill
authors: A
authors: A
authors: Damhuis
authors: M H
authors: MH
authors: Shepherd
authors: R
authors: R
authors: Paisey
authors: A T
authors: AT
authors: Hattersley
authors: S
authors: S
authors: Ellard
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics*; D000328:Adult; D019943:Amino Acid Substitution; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D056726:Genetic Association Studies; D006579:Heterozygote; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000235:genetics*; D021122:Protein Subunits / Q000737:chemistry / Q000235:genetics; D011955:Receptors, Drug / Q000737:chemistry / Q000235:genetics*; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D064233:Sulfonylurea Receptors; D006113:United Kingdom; D055815:Young Adult; D000099161:Kcnj11 Channel
chemical_list: D018528:ATP-Binding Cassette Transporters; D007004:Hypoglycemic Agents; D024661:Potassium Channels, Inwardly Rectifying; D021122:Protein Subunits; D011955:Receptors, Drug; D013453:Sulfonylurea Compounds; D064233:Sulfonylurea Receptors; D000099161:Kcnj11 Channel; C577507:ABCC8 protein, human