open access
Determinants of the development of diabetes (maturity-onset diabetes of the young-3) in carriers of HNF-1 < font face=symbol > a < /font > mutations. Evidence for parent-of-origin effect
open access
Abstract
MATERIAL AND METHODS. Extended families (n = 104) with type 2 diabetes inherited in a dominant pattern were recruited and screened for diabetes-causing mutations in HNF-1a.
RESULTS. HNF-1a 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 × 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 (h2 = 0.47, P = 0.003). When parent of origin was included in the analyses, the magnitude of genetic contribution increased markedly (h2 = 0.91).
CONCLUSIONS. Mutations in HNF-1a accounts for diabetes in a small proportion of families with a dominant pattern of inheritance. Age at onset of diabetes in MODY 3 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).
Abstract
MATERIAL AND METHODS. Extended families (n = 104) with type 2 diabetes inherited in a dominant pattern were recruited and screened for diabetes-causing mutations in HNF-1a.
RESULTS. HNF-1a 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 × 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 (h2 = 0.47, P = 0.003). When parent of origin was included in the analyses, the magnitude of genetic contribution increased markedly (h2 = 0.91).
CONCLUSIONS. Mutations in HNF-1a accounts for diabetes in a small proportion of families with a dominant pattern of inheritance. Age at onset of diabetes in MODY 3 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).
Keywords
MODY 3; HNF-1a mutation; parent-of-origin effect
About this articleTitle
Determinants of the development of diabetes (maturity-onset diabetes of the young-3) in carriers of HNF-1a mutations. Evidence for parent-of-origin effect
Journal
Issue
Vol 4, No 1 (2003): Practical Diabetology
Article type
Other materials agreed with the Editors
Pages
75-88
Published online
2003-02-13
Page views
782
Article views/downloads
1383
Bibliographic record
Diabetologia Praktyczna 2003;4(1):75-88.
Keywords
MODY 3
HNF-1a mutation
parent-of-origin effect
Authors
Tomasz Klupa
James H. Warram
Anthony Antonellis
Marcus Pezzolesi
Moonsuk Nam
Maciej T. Małecki
Alessandro Doria
Stephen S. Rich
Andrzej S. Krolewski