OBJECTIVE-The clinical expression of maturity-onset diabetes of the young (MODY)-3 is highly variable. This may be due to environmental and/or genetic factors, including molecular characteristics of the hepatocyte nuclear factor 1-␣ (HNF1A) gene mutation. RESEARCH DESIGN AND METHODS-We analyzed the mutations identified in 356 unrelated MODY3 patients, including 118 novel mutations, and searched for correlations between the genotype and age at diagnosis of diabetes. RESULTS-Missense mutations prevailed in the dimerizationand DNA-binding domains (74%), while truncating mutations were predominant in the transactivation domain (62%). The majority (83%) of the mutations were located in exons 1-6, thus affecting the three HNF1A isoforms. Age at diagnosis of diabetes was lower in patients with truncating mutations than in those with missense mutations (18 vs. 22 years, P ϭ 0.005). Missense mutations affecting the dimerization/DNA-binding domains were associated with a lower age at diagnosis than those affecting the transactivation domain (20 vs. 30 years, P ϭ 10 Ϫ4 ). Patients with missense mutations affecting the three isoforms were younger at diagnosis than those with missense mutations involving one or two isoforms (P ϭ 0.03). MODY3 is characterized by a severe insulin secretion defect, a retained sensitivity to sulfonylureas, a decreased renal threshold for glucose reabsorption, and, in rare families, the occurrence of liver adenomatosis (3-6). CONCLUSIONS-TheseThe clinical expression of MODY3 is highly variable from one family to another or even within the same family (7). HNF1A mutation carriers may be normoglycemic while their siblings may be hyperglycemic at a comparable age (8). Symptoms at diagnosis may be variable. Some patients have metabolic decompensation, while in others diabetes is diagnosed by systematic screening. The severity and the course of insulin secretion defect also vary since approximately one-third of the patients are treated with insulin after 15 years of diabetes duration, whereas others control their diabetes by diet or oral hypoglycemic agents (9).As in other monogenic diseases, this phenotype variability may be explained by environmental and/or additional genetic factors. Two studies have shown that age at diagnosis of diabetes in offspring carrying a HNF1A mutation was lower by 5-10 years when maternal diabetes was diagnosed before pregnancy, suggesting the role of exposure of the fetus to maternal hyperglycemia (10,11). Modifier genetic factors may also modulate the phenotype of the disease. Age at onset of diabetes is partly inheritable within MODY3 families, and putative genetic modifier loci have been mapped but not identified yet (12). In the same vein, it has been recently shown that germ line CYP1B1 Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0859.HNF1A, hepatocyte nuclear factor 1-␣; MODY, maturity-onset diabetes of the young.

Differential diagnosis between MODY3 and early-onset type 2 diabetes remains difficult. Whether the proposed model will improve the pick-up rate of MODY3 diagnosis needs to be confirmed in independent populations.