Molecular genetics of diabetes mellitus in Chinese subjects: identification of mutations in glucokinase and hepatocyte nuclear factor-1alpha genes in patients with early-onset type 2 diabetes mellitus/MODY.

Abstract

To examine the prevalence of identified MODY-related genes in Chinese subjects with early onset Type 2 diabetes mellitus and a positive family history of diabetes and to look for possible associations between the gene mutations and the development of diabetes. Ninety-two unrelated Chinese subjects with diabetes diagnosed before the age of 40 years who had a positive family history of diabetes were screened for mutations in hepatocyte nuclear factors (HNF-1alpha and HNF-4alpha) and glucokinase genes by direct sequencing. The family members of patients with mutations and 100 healthy controls were also examined. Mutations in the HNF-1alpha and the glucokinase genes were found in 5% and 3% of the diabetic subjects, respectively but no mutations were found in the coding region of the HNF-4alpha gene. Three mutations found in the glucokinase gene were novel missense mutations (I110T, A119D and G385V). The mutations in the HNF-1alpha gene were also new and included four missense mutations (G20R, R203H, S432C, I618M) and one splice acceptor site mutation (IVS2nt-1G-->A). Patients with mutations in these genes were clinically heterogeneous with respect to phenotype and basal pancreatic beta cell function. Genetic factors such as mutations in the HNF-1alpha and glucokinase genes may be important in the development of diabetes in Chinese people, especially when the disease is of early onset.