A MISSENSE MUTATION IN THE HEPATOCYTE NUCLEAR FACTOR-4 ALPHA-GENE IN A UK PEDIGREE WITH MATURITY-ONSET DIABETES OF THE YOUNG

Maturity-onset diabetes of the young (MODY) is a monogenic subgroup of non-insulin dependent diabetes mellitus (NIDDM) characterised by an e arly age of onset (< 25 years) and an autosomal dominant mode of inher itance. MODY is genetically heterogeneous with three different genes i dentified to date; hepatocyte nuclear factor 4 alpha (HNF-4 alpha) [MO DY1], glucokinase [MODY2] and hepatocyte nuclear factor 1 alpha (HNF-1 alpha) [MODY3]. A nonsense mutation in the HNF-4 alpha gene has recen tly been shown to cause MODY in a single large North American pedigree (RW). We screened a large UK Caucasian MODY family which showed weak evidence of linkage to the MODY1 locus on chromosome 20q (led score fo r ADA 0.68 at theta = 0) for mutations in the coding region of the HNF -4 alpha gene by direct sequencing. A missense mutation resulting in t he substitution of glutamine for glutamic acid was identified in exon 7 (E276Q). The mutation was present in all of the diabetic members of the pedigree plus two unaffected subjects and was not detected in 75 n ormal control subjects or 95 UK Caucasian subjects with late-onset NID DM. This is the first missense mutation to be described in the HNF-4 a lpha gene.