MUTATIONS IN THE HEPATOCYTE NUCLEAR FACTOR-1-ALPHA GENE ARE A COMMON-CAUSE OF MATURITY-ONSET DIABETES OF THE YOUNG IN THE UK

Mutations in the hepatocyte nuclear factor-1 alpha (HNF-1 alpha) gene have recently been shown to cause maturity-onset diabetes of the young (MODY). We have examined 15 U.K. MODY families for mutations in the c oding region of the HNF-1 alpha gene. Eight different mutations, three frameshift (P291fsinsC, P379fsdelCT, and A443fsdelCA) and five missen se mutations (P129T, R131W; R159W, P519L, and T620I), were identified in eleven families (73%). The previously reported mutation P291fsinsC was found in four pedigrees. A screen of a further 32 probands with ea rly onset (<40 years of age) NIDDM showed the mutation in two addition al families. This common mutation was present on at least three differ ent haplotypes, suggesting that its high frequency is due to recurrent mutation rather than a founder effect. We have demonstrated that muta tions in the HNF-1 alpha gene are a common cause of MODY in U.K. famil ies and result in early onset NIDDM with a progressive clinical course . Mutation-based genetic counseling can now be considered for the majo rity of patients with MODY.