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Mutations in the Genes Encoding the Transcription Factors Hepatocyte Nuclear Factor 1 Alpha and 4 Alpha in Maturity-Onset Diabetes of the Young and Hyperinsulinemic Hypoglycemia
Article first published online: 2 APR 2013
© 2013 Wiley Periodicals, Inc.
Volume 34, Issue 5, pages 669–685, May 2013
How to Cite
Colclough, K., Bellanne-Chantelot, C., Saint-Martin, C., Flanagan, S. E. and Ellard, S. (2013), Mutations in the Genes Encoding the Transcription Factors Hepatocyte Nuclear Factor 1 Alpha and 4 Alpha in Maturity-Onset Diabetes of the Young and Hyperinsulinemic Hypoglycemia. Hum. Mutat., 34: 669–685. doi: 10.1002/humu.22279
Communicated by Jurgen Horst
- Issue published online: 11 APR 2013
- Article first published online: 2 APR 2013
- Accepted manuscript online: 24 JAN 2013 09:03AM EST
- Manuscript Accepted: 8 JAN 2013
- Manuscript Received: 14 AUG 2012
Maturity-onset diabetes of the young (MODY) is a monogenic disorder characterized by autosomal dominant inheritance of young-onset (typically <25 years), noninsulin-dependent diabetes due to defective insulin secretion. MODY is both clinically and genetically heterogeneous with mutations in at least 10 genes. Mutations in the HNF1A gene encoding hepatocyte nuclear factor-1 alpha are the most common cause of MODY in most adult populations studied. The number of different pathogenic HNF1A mutations totals 414 in 1,247 families. Mutations in the HNF4A gene encoding hepatocyte nuclear factor-4 alpha are a rarer cause of MODY with 103 different mutations reported in 173 families to date. Sensitivity to treatment with sulfonylurea tablets is a feature of both HNF1A and HNF4A mutations. The HNF4A MODY phenotype has been expanded by the reports of macrosomia in ∼50% of babies, and more rarely, neonatal hyperinsulinemic hypoglycemia. The identification of an HNF1A or HNF4A gene mutation has important implications for clinical management in diabetes and pregnancy, but MODY is significantly underdiagnosed. Current research is focused on identifying biomarkers and developing probability models to identify those patients most likely to have MODY, until next generation sequencing technology enables cost-effective gene analysis for all patients with young onset diabetes.