Synonymous mutations in the human dopamine receptor D2 (DRD2) affect mRNA stability and synthesis of the receptor

摘要: Although changes in nucleotide sequence affecting the composition and structure of proteins are well known, functional resulting from substitutions cannot always be inferred simple analysis DNA sequence. Because a strong synonymous codon usage bias human DRD2 gene, suggesting selection on positions, was revealed by relative independence G+C content third positions isochoric frequencies, we chose to investigate effects six known naturally occurring (C132T, G423A, T765C, C939T, C957T, G1101A) DRD2. We report here that some mutations have suggest novel genetic mechanism. 957T, rather than being 'silent', altered predicted mRNA folding, led decrease stability translation, dramatically changed dopamine-induced up-regulation expression. 1101A did not show an effect itself but annulled above 957T compound clone 957T/1101A, demonstrating combinations can consequences drastically different those each isolated mutation. C957T found linkage disequilibrium European-American population with -141C Ins/Del TaqI 'A' variants, which been reported associated schizophrenia alcoholism, respectively. These results call into question assumptions made about variation molecular genetics gene-mapping studies diseases complex inheritance, indicate potential pathophysiological pharmacogenetic importance.