MODY1 is caused by mutations in the HNF4A gene (OMIM 600281), which encodes the hepatocyte nuclear factor 4-alpha gene on chromosome 20q12-q13.1.  It is also known as TCF14 (transcription factor 14). HNF4A is a transcription factor that is expressed in the liver, kidney, intestine and pancreatic islet cells.  It controls expression of genes involved in glucose, cholesterol and fatty acid metabolism, including glucose transporter 2, aldolase B, glyceraldehyde-3-phosphate dehydrogenase and pyruvate kinase.   It also regulates transcription of the transcription factor HNF1A (OMIM 142410), which is the gene that causes MODY3.

 

HNF4A may also play a role in NIDDM, particularly in individuals with a young age at onset. Approximately 12 missense and nonsense mutations, as well as a splicing defect, in HNF4A have been identified in families with MODY1.  All appear to reduce gene expression.  MODY1 accounts for about 5% of all MODY cases.