title: Determinants of the development of diabetes (maturity-onset diabetes of the young-3) in carriers of HNF-1alpha mutations: evidence for parent-of-origin effect.
abstract: OBJECTIVE
  To determine the distribution of the age at onset of diabetes (maturity-onset diabetes of the young-3 [MODY3]) and to identify determinants of the onset of diabetes in carriers of HNF-1alpha mutations.
  
  
  METHODS
  Extended families (n = 104) with type 2 diabetes inherited in a dominant pattern were recruited and screened for diabetes-causing mutations in HNF-1alpha.
  
  
  RESULTS
  HNF-1alpha mutations cosegregated with diabetes in only 13 families, all with a mean age at onset <35 years. Insulin secretion was diminished or absent in mutation carriers (n = 101), and diabetes developed in 65% by age 25 years and in 100% by age 50 years. If the mutation was inherited from the mother, diabetes onset was very young in those exposed to diabetes in utero; 57 +/- 8% were affected by age 15 years as compared with 0.0% in those not exposed (P < 7 x 10(-6)). By age 25 years, the difference was reduced (85 +/- 6 and 55 +/- 12%, respectively; P = 0.02). If the mutation was inherited from the father, diabetes developed in 52 +/- 8% by age 25 years. Age at diagnosis was shown to be highly heritable (h(2) = 0.47, P = 0.003). When parent of origin was included in the analyses, the magnitude of genetic contribution increased markedly (h(2) = 0.91).
  
  
  CONCLUSIONS
  Mutations in HNF-1alpha accounts for diabetes in a small proportion of families with a dominant pattern of inheritance. Age at onset of diabetes in MODY3 families varied widely and was influenced by familial factors (including modifying genes) and parent of origin (whether a mutation carrier was exposed to diabetes in utero).
authors.affiliation: Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Klupa
authors.forename: James H
authors.initials: JH
authors.lastname: Warram
authors.forename: Anthony
authors.initials: A
authors.lastname: Antonellis
authors.forename: Marcus
authors.initials: M
authors.lastname: Pezzolesi
authors.forename: Moonsuk
authors.initials: M
authors.lastname: Nam
authors.forename: Maciej T
authors.initials: MT
authors.lastname: Malecki
authors.forename: Alessandro
authors.initials: A
authors.lastname: Doria
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.forename: Andrzej S
authors.initials: AS
authors.lastname: Krolewski
mesh_terms: D000328:Adult; D017668:Age of Onset; D000368:Aged; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000175:diagnosis / Q000235:genetics*; D019281:Dimerization; D005220:Fathers; D005260:Female; D006580:Genetic Carrier Screening; D018392:Genomic Imprinting; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D051539:Hepatocyte Nuclear Factor 1-beta; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009035:Mothers; D009154:Mutation; D009687:Nuclear Proteins; D011110:Polymorphism, Genetic; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; C496495:HNF1B protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1; D051539:Hepatocyte Nuclear Factor 1-beta