Molecular Scanning On MODY Genes In Chinese Early Onset Familial Type 2 Diabetes

Objective: To explore the disease-associated gene mutations in early onset familial type 2 diabetes containing subjects with MODY. Methods: This study collected 100 early onset type 2 diabetes pedigrees in Beijing, in which the probands were diagnosed with type 2 diabetes before 40 years old and, at least, another first relative was diagnosed with type 2 diabetes before 45 years old. All the exons and exon/intron splice sites of MODY 1, MODY 2, MODY 3, MODY 4 and MODY 5 gene were amplified with PCR method, and the PCR products were sequenced to screen the DNA variants. Results: In screening of MODY1 gene, we identified 2 DNA variants in noncoding region including IVS1C +44A>T, IVS2 -5C>T,3 mutations in coding region including M49V , T130I, S462S. In our study we observed three DNA vatiants in MODY2 gene: one in exon4(ccc--->ccg, heterozygous silent mutation, pro145pro), one in exon7(gcc-->gcg, heterozygous silent mutation, ala233ala), and one in intron 9(IVS+8 C>T). The prevalences of these variant alleles were 0.5 in exon4, 0.5% in exon 7 and 36% in intron 9. An association study was conducted to examine the relationship between the IVS9+8 C>T polymorphism and early onset familial type 2 diabetes, the frequence of allele T of early onset familial type 2 diabetes population was significantly lower, and the frequency of allele C significantly higher, than that of control subjects(P<0.05). In screening of MODY3 gene, we identified 5 DNA variants in noncoding region including IVS1-16G>A, IVS2-23C>T, IVS5+9C>G,IVS7+7A>G, IVS9-24 C>T,4 silient mutations in coding region including leu171eu, gly288gly, thr515thr, leu459leu,3 misense mutations in coding region pro379ala, ile271eu,ser487asn. The pro379ala mutation cosegregated with diabetes in a pedigree, which was not found in 100 non-diabetic control subjects by DNA sequencing. In screening of MODY4 gene, we identified 2 DNA variants in noncoding region including IVS2 -68G>T,IVS2 –70G>C. In screening of MODY5 gene, we identified 2 DNA variants in noncoding region including IVS8 +42G>A,IVS9 -22C>T,1 mutations in coding region including A513T. Conclusion: There is not enough evidence to demonstrate that the variation in or near MDOY genes is the major cause of early onset type 2 diabetic in Chinese population, the IVS9+8 C>T polymorphism at MODY2 gene intron 9 was associated with early onset familial type 2diabetes, a novel mutation of MODY3 gene cosegregating with diabetes was found. Its mechanism need to be proved by the study of protein function.