title: Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood.
abstract: OBJECTIVE
  Insulin gene (INS) mutations have recently been described as a cause of permanent neonatal diabetes (PND). We aimed to determine the prevalence, genetics, and clinical phenotype of INS mutations in large cohorts of patients with neonatal diabetes and permanent diabetes diagnosed in infancy, childhood, or adulthood.
  
  
  METHODS
  The INS gene was sequenced in 285 patients with diabetes diagnosed before 2 years of age, 296 probands with maturity-onset diabetes of the young (MODY), and 463 patients with young-onset type 2 diabetes (nonobese, diagnosed <45 years). None had a molecular genetic diagnosis of monogenic diabetes.
  
  
  RESULTS
  We identified heterozygous INS mutations in 33 of 141 probands diagnosed at <6 months, 2 of 86 between 6 and 12 months, and none of 58 between 12 and 24 months of age. Three known mutations (A24D, F48C, and R89C) account for 46% of cases. There were six novel mutations: H29D, L35P, G84R, C96S, S101C, and Y103C. INS mutation carriers were all insulin treated from diagnosis and were diagnosed later than ATP-sensitive K(+) channel mutation carriers (11 vs. 8 weeks, P < 0.01). In 279 patients with PND, the frequency of KCNJ11, ABCC8, and INS gene mutations was 31, 10, and 12%, respectively. A heterozygous R6C mutation cosegregated with diabetes in a MODY family and is probably pathogenic, but the L68M substitution identified in a patient with young-onset type 2 diabetes may be a rare nonfunctional variant.
  
  
  CONCLUSIONS
  We conclude that INS mutations are the second most common cause of PND and a rare cause of MODY. Insulin gene mutation screening is recommended for all diabetic patients diagnosed before 1 year of age.
authors.affiliation: Institute of Biomedical and Clinical Science, Peninsula Medical School, Barrack Road, Exeter EX2 5DW, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Edghill
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Flanagan
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Patch
authors.forename: Chris
authors.initials: C
authors.lastname: Boustred
authors.forename: Andrew
authors.initials: A
authors.lastname: Parrish
authors.forename: Beverley
authors.initials: B
authors.lastname: Shields
authors.forename: Maggie H
authors.initials: MH
authors.lastname: Shepherd
authors.forename: Khalid
authors.initials: K
authors.lastname: Hussain
authors.forename: Ritika R
authors.initials: RR
authors.lastname: Kapoor
authors.forename: Maciej
authors.initials: M
authors.lastname: Malecki
authors.forename: Michael J
authors.initials: MJ
authors.lastname: MacDonald
authors.forename: Julie
authors.initials: J
authors.lastname: Støy
authors.forename: Donald F
authors.initials: DF
authors.lastname: Steiner
authors.forename: Louis H
authors.initials: LH
authors.lastname: Philipson
authors.forename: Graeme I
authors.initials: GI
authors.lastname: Bell
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Sian
authors.initials: S
authors.lastname: Ellard
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D002648:Child; D004252:DNA Mutational Analysis; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007328:Insulin / Q000235:genetics*; D009154:Mutation
chemical_list: D007328:Insulin