Linkage and Molecular Scanning Analyses of MODY3/Hepatocyte Nuclear Factor-1α Gene in Typical Familial Type 2 Diabetes: Evidence for Novel Mutations in Exons 8 and 101

Mutations of the hepatocyte nuclear factor-1 alpha (HNF1 alpha) gene are an important cause of autosomal dominant diabetes with onset before age 25 yr [maturity-onset diabetes of the young (MODY)], and some regions of the HNF1 alpha gene appear to be hot spots for mutations. To evaluate the role of HNF1 alpha in the more common familial type 2 diabetes, we studied 62 families of Northern European origin by linkage analysis and molecular screening. Linkage was rejected under dominant models consistent with either late-onset type 2 diabetes or early-onset dominant diabetes. We used single strand conformation polymorphism analysis to screen 53 diabetic members of 36 families who reported diabetes diagnosed before age 40 yr, 9 members of 2 Utah families with typical MODY, and 24 additional members of families with possible linkage. One MODY family showed the previously reported frameshift mutation (P291fsinsC) in exon 4. Among the individuals with more typical type 2 diabetes, we identified the previously reported common polymorphisms, a new intronic polymorphism, and 3 common amino acid variants. We also identified 2 novel missense mutations that segregated with type 2 diabetes in 1 family each: lysine for glutamic acid substitution at codon 619 in exon 10 (E619K), and an arginine for threonine substitution at codon 537 in exon 8 (R537T) in a second family. The exon 8 mutation showed relatively low penetrance, and the role in this family remains uncertain. No coding mutations were identified in the family members screened on the basis of linkage but without early-onset diabetes. Although HNF1 alpha mutations are not a common cause of familial type 2 diabetes, they may account for 5% of families in which at least 1 member has onset of type 2 diabetes before age 40 yr. Incomplete penetrance and a high sporadic frequency make linkage an inefficient screening tool.