NOVEL MUTATIONS AND A MUTATIONAL HOTSPOT IN THE MODY3 GENE

Maturity-onset diabetes of the young 3 (MODY3) is a type of NIDDM caus ed by mutations in the transcription factor hepatocyte nuclear factor- 1 alpha (HNF-1 alpha) located on chromosome 12q. We have identified fo ur novel HNF-1 alpha missense mutations in MODY3 families, In four add itional and unrelated families, we observed an identical insertion mut ation that had occurred in a polycytidine tract in exon 4. Among those families, one exhibited a de novo mutation at this location. We propo se that instability of this sequence represents a general mutational m echanism in MODY3. We observed no HNF-1 alpha mutations among 86 unrel ated late-onset diabetic patients with relative insulin deficiency. He nce mutations in this gene appear to be most strongly associated with early-onset diabetes.