IDENTIFICATION OF 9 NOVEL MUTATIONS IN THE HEPATOCYTE NUCLEAR FACTOR-1 ALPHA-GENE ASSOCIATED WITH MATURITY-ONSET DIABETES OF THE YOUNG (MODY3)

Maturity-onset diabetes of the young (MODY) is a genetically heterogen eous subtype of non-insulin-dependent diabetes mellitus (NIDDM) charac terised by early onset, autosomal dominant inheritance and a primary d efect in insulin secretion, Recent studies have shown that mutations i n the two functionally related transcription factors, hepatocyte nucle ar factor 4 alpha (HNF-4 alpha) and hepatocyte nuclear factor 1 alpha (HNF-1 alpha) are associated with the MODY1 and MODY3 forms of diabete s respectively, whereas mutations in the enzyme glucokinase are the ca use of the MODY2 form, We have examined 10 unrelated Caucasian familie s in which MODY/NIDDM co-segregated with markers for MODY3 for mutatio ns in the HNF-1 alpha gene (TCF1), Ten different mutations were observ ed in these families, all of which co-segregated with diabetes, There were no obvious relationships between the nature of the mutations obse rved (i,e, frameshift, nonsense, or missense) or their location in the gene with clinical features of diabetes (age at onset, severity) in t hese families, The mechanisms by which mutations in the HNF-1 alpha ge ne cause diabetes mellitus are unclear but might include abnormal panc reatic islet development during foetal life thereby limiting their lat er function, as well as impaired transcriptional regulation of genes t hat play a key role in normal pancreatic beta cell function.