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Mutation Screening of the Neurogenin-3 Gene in Autosomal Dominant Diabetes¹

Section on Genetics and Epidemiology, Research Division, Joslin Diabetes Center (S.-H.K., J.H.W., A.S.K., A.D.), and Department of Medicine, Harvard Medical School (S.-H.K., A.S.K., A.D.), Boston, Massachusetts 02215

Address all correspondence and requests for reprints to: Alessandro Doria, M.D. Ph.D., Section on Genetics and Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02215. E-mail: alessandro.doria{at}joslin.harvard.edu

We investigated whether genetic variability in neurogenin-3, a basic helix-loop-helix transcription factor that is expressed in the developing pancreas, contributes to the etiology of maturity-onset diabetes of the young or other forms of autosomal dominant diabetes. Ninety-one probands of families with autosomal dominant diabetes were screened for neurogenin-3 mutations by dideoxy fingerprinting. Three sequence differences were identified: a polymorphism not affecting the amino acid sequence (L75L), a CA insertion/deletion in intron 1 (-44ins/del), and a C to T transition causing a serine to phenylalanine substitution (S199F). None of these sequence differences were more frequent in the family probands than in 179 nondiabetic controls. In contrast, allele 199F was weakly, but significantly, associated with common type 2 diabetes (199F frequencies = 0.436 in 132 cases with type 2 diabetes vs. 0.346 in the family probands and 0.346 in controls; P = 0.05). The relative risk of type 2 diabetes for 199F carriers was 1.7 (95% confidence interval, 1.04–2.7). We conclude that sequence differences in the neurogenin-3 gene do not play a major role in the development of autosomal dominant diabetes. Rather, they might contribute to common type 2 diabetes, although this finding must be replicated in other populations.