Analysis of HNF-related genes responsible for the development of type 2 diabetes in Japanese

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Mutations in genes encoding HNF transcription factors are associated with MODY, a monogenic form of early-onset diabetes mellitus. The ability of the orphan receptor SHP to modulate the transcriptional activity of HNF-4α (MODY1), suggested SHP as a candidate MODY gene. We screened 173 unrelated Japanese subjects with early-onset diabetes for mutations in this gene and found five different mutations in six subjects, all present in the heterozygous state. Interestingly, all of the subjects with the mutations were mildly or moderately obese at onset of diabetes, and analysis of the lineages of these individuals indicated that the SHP mutations were associated with obesity rather than with MODY. Functional studies of the mutant proteins show that the mutations result in the loss of SHP activity. These results suggest that genetic variation in the SHP gene contributes to increased body weight.To clarify the possible interplay between the SHP mutations and other diabetogenic factors, diabeti … More c probands with the SHP mutations were re-screened for mutations in the MODY genes, and one MODY3 mutation was identified in one subject. Although MODY3 is characterized primarily by β-cell dysfunction, obesity and insulin resistance were observed in this subject, suggesting that the SHP mutation modifies the phenotype. As type 2 diabetes in Japanese also is due primarily to β-cell dysfunction, SHP mutations might influence susceptibility in people at risk. Accordingly, the prevalence of SHP mutations in adult-onset type 2 diabetes in Japanese was evaluated. Direct sequencing of the gene in 274 diabetic and 305 non-diabetic subjects was performed. Mutations with reduced activity were found in nine (3.3 %) and one (0.3 %) subjects in the diabetic and control groups, respectively. The frequency difference between the two groups was statistically significant (p=0.0088), suggesting that SHP mutations associated with mild obesity increase susceptibility to type 2 diabetes in later life in Japanese. Less