No evidence of linkage or diabetes-associated mutations in the transcription factors BETA2/NEUROD1 and PAX4 in Type II diabetes in France

Aims/hypothesis. The identification of mutations in hepatocyte nuclear fact ors-1 alpha, -4 alpha, -1 beta and insulin promoter factor-1 in maturity on set diabetes of the young (MODY) has highlighted the role that transcriptio n factors may have in the development of diabetes. This result has focused molecular genetic studies of diabetes on other transcription factors expres sed in the pancreatic beta cell. The basic helix-loop-helix transcription f actor BETA2/NEUROD1 (gene symbol, NEUROD1) and the paired box homeodomain t ranscription factor PAX4 (PAX4) have an important role in islet and beta-ce ll development. We have examined the contribution of these transcription fa ctors to the development of MODY and late-onset Type II (non-insulin-depend ent) diabetes mellitus. Methods. Linkage studies have been done in MODY families reported to have n o mutations in the five known MODY genes and in affected sibling pairs from families with late-onset Type II diabetes. Mutation screening of the codin g regions of both genes was also realised by SSCP followed by sequencing in MODY patients and in probands with late-onset Type II diabetes. Results. There was no evidence of linkage with the markers for NEUROD1 and PAX4 either with MODY or late-onset Type II diabetes. Mutation screening sh owed single nucleotide polymorphisms, several of which resulted in amino ac id substitutions : NEUROD1, Ala45Thr; PAX4, Pro321His and Pro334Ala. These amino acid sequence variants were not associated with Type II diabetes. Conclusion/interpretation. Our results indicate that NEUROD1 and PAX4 are n ot a common cause of either MODY or late-onset Type II diabetes in the Fren ch Caucasian population.