Molecular Genetic Study Of Diabetes Family

The study includes three parts of diabetes families which are complete mtDNA genomes of maternally inherited type2diabetes in two Chinese families, Detection and Characterization of Three Mutations in Maturity-Onset Diabetes of the Young (MODY)Genes in Three Chinese Families and whole-genome chip scanned in a diabetes family.Previous work has revealed that mitochondrial DNA has a close affinity with type2diabetes mellitus (T2DM). Thus, sequencing complete mtDNA genomes from unrelated families with patients with maternally inherited T2DM, with similar penetrance, should shed light on the potential pathogenic role of mtDNA on T2DM. In this study, the complete mitochondrial DNA (mtDNA) genomes from two families from Southwest China showing maternally inherited T2DM were sequenced and analyzed. MtDNA sequence variants in the two families suggested that they belong to distinct haplogroups, groups A4and D4h1for families A and B, respectively. Although the private variation G13759A in the MT-ND5gene was detected in family B, which occurs at the first base pair of the codon and causes an amino acid change from alanine to threonine, further evolutionary and phylogenetic analyses conclude that this mutation has multiple origins and is likely to be a polymorphism, rather than a disease causing mutation. Our data failed to define any putatively pathogenic mutation shared between the two families with maternally inherited T2DM families from Southwest China. The differing mtDNA haplogroups of families A and B support the conclusion that similar penetrances of maternally inherited T2DM may arise in Chinese individuals with strikingly different maternal genetic backgrounds.Maturity-onset diabetes of the young (MODY) is characterized by onset of diabetes before25years, positive family history, high genetic predisposition, and an autosomal dominant inheritance. We aimed to investigate mutations and to characterize phenotypes in Chinese MODY families. Detailed clinical assessments and genetic screening for mutations in the HNF-4a, GCK, HNF-la, IPF-1, HNF1β, NEUROD1genes were carried out in three MODY families. One HNF4A mutation (p.T130I) and two HNF1A polymorphisms (p.I27L and p.S487N) were identified in three MODY families. Mutation p. T130I was associated with both early-onset and late-onset diabetes and caused HNF4A expression down, whereas HNF1A polymorphisms p.I27L and p.S487N were associated with diagnosis age of diabetes. We demonstrated mutation p. T130I in HNF4A was pathogenic and predicted polymorphisms p.I27L and p.S487N in HNF1A to be pathogenic. Our results showed that mutations in HNF4A and HNF1A genes might be common in Chinese MODY families.13members of a diabetes family were whole-genome scanned, then were detected by TagSNP multipoint parameters and nonparameters analysis and haplotype analysis. The LOD score of chromosome2023.5～30.8cM and chromosome1691.24～91.61cM reached2. It was supposed that these areas appeared linkage inheritance. These areas included energetic metabolism related genes(LCB1、PLCB4、LAMP5、PAK7SNAP25-AS1、SNAP25、MKKS、SLX4IP、JAG1).We did genetic sequencing of these genes but did not find significative mutation.