Diabetes, Vol 46, Issue 6 1081-1086, Copyright © 1997 by American Diabetes Association

ARTICLES

Novel mutations and a mutational hotspot in the MODY3 gene

MA Glucksmann, M Lehto, O Tayber, S Scotti, L Berkemeier, JC Pulido, Y Wu, WJ Nir, L Fang, P Markel, KD Munnelly, J Goranson, M Orho, BM Young, JL Whitacre, C McMenimen, M Wantman, T Tuomi, J Warram, CM Forsblom, M Carlsson, J Rosenzweig, G Kennedy, GM Duyk, JD Thomas and al. et
Millennium Pharmaceuticals, Inc., Cambridge, Massachusetts 02139, USA.

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