GENETIC-VARIATION IN THE HEPATOCYTE NUCLEAR FACTOR-1-ALPHA GENE IN DANISH CAUCASIANS WITH LATE-ONSET NIDDM

Non-insulin-dependent diabetes mellitus (NIDDM) is a phenotypically an d genetically heterogeneous disorder. A recent random genome mapping s tudy has localized a locus termed NIDDM2 that maps to the region of ch romosome 12 that includes MODY3, one of the three genes responsible fo r maturity-onset diabetes of the young, a monogenic form of NIDDM char acterized by early age of onset and autosomal dominant inheritance. Th ese findings suggest that NIDDM2 and MODY3 may represent different all eles of the same gene. MODY3 has recently been shown to be the gene en coding the transcription factor hepatocyte nuclear factor-1 alpha (HNF -1 alpha) thereby allowing us to determine whether mutations in the HN F-1 alpha gene are present in subjects with late-onset NIDDM. We scree ned 84 white NIDDM patients of Danish ancestry and found four nucleoti de substitutions that changed the sequence of HNF-1 alpha, Ile27-->Leu , Ala98-->Val, Ser487-->Asn and Arg583-->Gln, five nucleotide substitu tions that were silent and did not change the amino acid, Leu17, Gly28 8, Leu459 and Thr515, and five substitutions in the intron regions. Th e frequencies of the codon 27, 98 and 487 amino acid variants were sim ilar in 245 unrelated NIDDM patients and 242 age-matched control subje cts. The Arg583-->Gln mutation was found in 2 of 245 NIDDM patients an d in none of the control subjects. Thus, genetic variation in the HNF- 1 alpha gene is not a common factor contributing to NIDDM susceptibili ty in white subjects of Danish ancestry.