Association Study Of PAK3 & RAC1 Genes Polymorphisms With Mental Retardation In The Qinba Mountain Area Population

The Qinba Mountain Area is one of the regions with high affecting of mental retardation (MR) in China. The investigation showed that familial clustering was found in the Qinba Mountain Area with several families having multiple affected members in one or more generations. This indicates that genetic factors may contribute to MR disorders. Therefore, hunting pathogenic gene has an important practical significance to prevent and control the disease in the Qinba Mountain Area.For several decades, it has been known that MR is associated with abnormalities in dendrites and dendritic spines. Thus, it is likely that abnormalities in these structures will impair information processing at the cellular and network level. PAK3 protein, a critical effector that links Rho GTPases to cytoskeleton reorganization and nuclear signaling, may be necessary for dendritic development and for the rapid cytoskeletal reorganization in dendritic spines associated with synaptic plasticity. Therefore, there is a possible genetic association of MR with PAK3 gene polymorphisms. To test this hypothesis, a case-control association study was conducted to focus on the Qinba Mountain area children using PCR-SSCP methods with three common SNPs (rs17327259, rs17327273, rs11152658). Rs17327273 is in intron 5 of PAK3, whereas rs17327259 and rs11152658 are upstream and downstream of PAK3 respectively. All of the genotype distributions matched the equilibrium law of Hardy-Weinberg. The results of the case-control analysis suggested that there were no significant differences of either allele or genotype frequencies of the single nucleotide polymorphisms between cases and controls. The pairwise linkage disequilibrium analysis also revealed that the three SNPs were not in LD (D'<0.5) and therefore a haplotype analysis was not performed.The protein encoded by RAC1 gene is a GTPase which belongs to the RAS superfamily of small GTP-binding proteins. It appears to regulate a diverse array of cellular events, including the control of cell growth, cytoskeletal reorganization, and the activation of protein kinases. To investigate the possible genetic association of mental retardation with RAC1 gene polymorphisms, a case-control association study was performed to focus on the Qinba Mountain Area children using three common SNPs in the gene (rs1647224, rs836488, rs702482). PCR-SSCP methods were used to detect the relationships between RAC1 polymorphisms and mental retardation. Genotype distributions showed no deviation from Hardy-Weinberg equilibrium. Pairwise linkage disequilibrium analysis indicated that the three SNPs were in strong linkage disequilibrium. The case-control study revealed that there were no significant differences of either allele or genotype frequencies at any of the SNPs between cases and controls. However haplotype G-C-A analysis showed positive results. The frequency of haplotype G-C-A was higher in cases than in controls, suggesting that G-C-A was a risk haplotype for the mental retardation in the Qinba Mountain Area children.