Molecular scanning analysis of hepatocyte nuclear factor 1 alpha (TCF1) gene in typical familial type 2 diabetes in African Americans

Type 2 diabetes mellitus (TSDM) is strongly inherited, but the major genes for this disease have been elusive. In contrast, early-onset, autosomal-dom inant diabetes results from at least 5 loci, of which hepatocyte nuclear fa ctor 1 alpha (HNF1 alpha or TCF1) is the most common cause. Mutations in HN F1 alpha also cause later-onset diabetes in some Caucasian populations, but the role of these mutations has not been tested in African American popula tions. We used a variety of screening methods, including both single-strand conformation polymorphism (SSCP) analysis and dideoxy fingerprint analysis , to search for mutations in 51 African American subjects with onset of dia betes before age 50 years. Potential mutations were confirmed by direct seq uencing. We identified 21 different variants, of which 11 were unique to Af rican Americans. Four mutations either altered the amino acid sequence (Gly 52Ala and Gly574Ser) or were close to a splice site (intron 1 and intron 10 ). A 5-nucleotide insertion in intron 1 was present in both diabetic member s of a small family, but Gly52Ala, Gly574Ser, and the intron 10 mutation di d not segregate with diabetes. Gly574Ser was present in 2 large families an d 5% of controls, all of which appeared to share the same common HNF1 alpha haplotype. Surprisingly, radioactive SSCP analysis under 2 room-temperatur e conditions performed as well as methods using fluorescent labeling that w ere expected to be more sensitive. We conclude that in African American ind ividuals under age 50, variation in the HNF1 alpha gene is common but unlik ely to he a significant cause of T2DM. Copyright (C) 2000 by W.B, Saunders Company.