Molecular Sequencing Of MODY1-6 Genes In Uyghur Families With Maturity-onset Diabetes Of The Young

Objective:To screen for mutations and polymorphisms in six known MODY genes (HNF-4a, GCK, HNF-1α, IPF-1, HNF-1βand NEUROD1) in three Uyghur families with clinically diagnosed with probably MODY. Methods:Three Uyghur MODY family members from Xinjiang Uyghur Autonomous Region were involved in this research with their informed consents. The member's general informations, the blood glucose level and blood lipid level were collected. Proband and some family members from first and second families were analyzed for mutation in exon and exon-intron boundaries of six known MODY gene. Proband of third family were analyzed for mutation in exon and exon-intron boundaries of MODY3. PCR method was followed by direct DNA sequencing. All sequences were analyzed and compared with the reference sequence from NCBI with the Lasergene software (DNASTAR). Results:The statistical differences in age, body weight, waist circle, hip circle, BMI, SBP, DBP and LDL-C between euglycemia and diabetes groups were obvious(P<0.05). Seventeen sequence variations were identified and none of them were classified as pathogenic mutation. Results showed that sequence variants of HNF-1αgene were relatively more common. We identified two DNA variants in non-coding region including IVS2-5C>T, IVS4-52G>C in MODY1 gene. In screening of MODY3 gene, three synonymous mutations were observed in coding region including Exonl Leu17Leu, Exon7 Leu459Leu, Gln497Gln, two missense mutations including Exonl Ile27Leu, Exon7 Ans487Ser and five DNA variations in non-coding region including IVSlnt-42G>A, IVS2nt-23C>T, IVS5nt-42G>T, IVS7nt+7G>A, IVS9nt-24G>T. In screening of MODY4 gene, two DNA variations were identified in intron region including IVS2nt-70C>G and IVS2nt-68G>T. DNA variation IVS8nt-22C>T were observed in MODY5 gene. Non-coding variant c.164G>A was found in screening MODY6 gene. No pathogenic mutations or polymorphisms were found in MODY2 gene. HNF-1αexon7 Gln497Gln and NEUROD1 exonl c.164G>A were novel variation. Others were all previously described common polymorphisms. Conclusion:Mutations in MODY 1-6 genes might not be the cause of MODY in these three Uyghur families. MODY genes mutations present ethinical heterogeneity, there might unidentified genes (MODYX) which wait for find in the Uyghur MODY patients. More Uyghur diabetes pedigree and genetic analysis were needed to improve the role of MODY genes in Uyghur diabetes families.The clinical representations of metabolism syndrome presented in these families indicated that in the base of genetic susceptibility, life style, eviromental factors, diet habits might enhace the susceptibility of diabetes. These variations might enhance the risk of the susceptibility of DM in these MODY families. Results providing important prophase research basis for the study of MODY genes susceptibility in Uyghur MODY pedigree and the study of assiociations between MODY genes and T2DM.