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Hepatocyte Nuclear Factor-1 Gene Mutations and Diabetes in Norway

Center for Medical Genetics and Molecular Medicine (L.B., A.M., P.R.N.), Haukeland University Hospital, and Department of Pediatrics (J.V.S., O.S., P.R.N.), University of Bergen, N-5021 Bergen; and Hormone Laboratory (P.T.), Aker University Hospital, N-0514 Oslo, Norway

Address all correspondence and requests for reprints to: Pål Rasmus Njølstad, M.D., Ph.D., Department of Pediatrics, University of Bergen, N-5021 Bergen, Norway. E-mail: pal.njolstad{at}uib.no.

Mutations in the hepatocyte nuclear factor (HNF)-1 gene cause maturity-onset diabetes of the young (MODY), type 3. To estimate the prevalence of MODY3 in Norwegian diabetic pedigrees, we screened a total of 130 families for HNF-1 mutations; 42 families with clinical MODY, 75 with suspected MODY, and 13 pedigrees with multiplex type 1 diabetes. Twenty-two families with clinical MODY, 15 families with suspected MODY, and one family with type 1 diabetes multiplex harbored HNF-1 mutations. Thus, in about half of Norwegian families with clinical MODY, mutations in the HNF-1 gene could be detected. Eight of the 18 different mutations identified were novel (G47E, T196fsdelCCAA, IVS3–1G>A, S256T, A276D, S445fsdelAG, M522V, and S531T). Haplotypes were determined for recurrent mutations, indicating a founder effect in Norway for the hot-spot mutation P291fsinsC and possibly also for P112L and R131W. To examine the molecular mechanisms underlying MODY3, we investigated the functional properties of 13 HNF-1 mutations. Two mutant HNF-1 proteins (R171X, R263C) were unable to bind DNA and at least five mutants (R131W, R171X, P379fsdelCT, S445fsdelAG, and Q466X) showed defective nuclear translocation. Transcriptional activation was reduced for most of the MODY3-associated mutants. Accordingly, the functional studies of HNF-1 mutants indicate that ß-cell dysfunction in MODY3 is caused by loss-of-function mechanisms like reduced DNA binding, impaired transcriptional activation, and defects in subcellular localization.

This work was supported by grants from the Norwegian Diabetes Foundation, the Helse og Rehabilitering Foundation, the Meltzer Foundation, the Norwegian Research Council, University of Bergen, and Haukeland University Hospital.

Abbreviations: HNF, Hepatocyte nuclear factor; IGT, impaired glucose tolerance; MODY, maturity-onset diabetes of the young; NLS, nuclear localization signal.

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