Mutations in the hepatocyte nuclear factor-1 alpha gene in Chinese MODY Families: prevalence and functional analysis

Abstract

Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of diabetes characterized by an early age of onset (usually <25 years). We screened for mutations in the hepatocyte nuclear factor (HNF)-1α (MODY 3) gene in 50 unrelated Southern Chinese families, which fulfilled the minimum criteria for MODY: two generations of type 2 DM with at least one member diagnosed under the age of 25 years. The 10 exons, flanking introns and promoter region of the HNF-1α gene were amplified by polymerase chain reaction and sequenced directly. Functional properties of the mutant proteins were investigated using site-directed mutagenesis and luciferase reporter assay. Six of the 50 (12%) subjects were found to have mutations, including one novel nonsense mutation Q176X, one novel intronic mutation IVS7-6 G→A and 4 reported mutations (frameshift mutation P379fsdelCT, nonsense mutation R171X, missense mutation G20R and P112L). The expression levels of wild type and mutant proteins in HeLa cells were similar except for R171X and Q176X which were not detected with the C-terminal antibody. The mutations locating in the coding region were found to have decreased trans-activating activity. The intronic mutation cosegregated with diabetes in the family, created a potential splice acceptor site and might alter the splicing of the HNF-1α mRNA. In conclusion, mutations in the HNF-1α gene appear to be an important cause of MODY in Southern Chinese. The mutations may affect normal islet function by altering the expression of the target genes.