Determinants of the development of diabetes (maturity-onset diabetes of the young-3) in carriers of HNF-1α mutations -: Evidence for parent-of-origin effect

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. Research Design 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-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<7x10(-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).