The prevalence of folate-remedial MTHFR enzyme variants in humans Export

@article{citeulike:2885128, abstract = {10.1073/pnas.0802813105 Studies of rare, inborn metabolic diseases establish that the phenotypes of some mutations in vitamin-dependent enzymes can be suppressed by supplementation of the cognate vitamin, which restores function of the defective enzyme. To determine whether polymorphisms exist that more subtly affect enzymes yet are augmentable in the same way, we sequenced the coding region of a prototypical vitamin-dependent enzyme, methylenetetrahydrofolate reductase (MTHFR), from 564 individuals of diverse ethnicities. All nonsynonymous changes were evaluated in functional assays in to identify enzymatic defects and folate remediability of impaired alleles. We identified 14 nonsynonymous changes: 11 alleles with minor allele frequencies <1\% and 3 common alleles (A222V, E429A, and R594Q). Four of 11 low-frequency alleles affected enzyme function, as did A222V. Of the five impaired alleles, four could be restored to normal functionality by elevating intracellular folate levels. All five impaired alleles mapped to the N-terminal catalytic domain of the enzyme, whereas changes in the C-terminal regulatory domain had little effect on activity. Impaired activity correlated with the phosphorylation state of MTHFR, with more severe mutations resulting in lower abundance of the phosphorylated protein. Significantly, diploid yeast heterozygous for mutant alleles were impaired for growth, particularly with lower folate supplementation. These results suggested that multiple less-frequent alleles, in aggregate, might significantly contribute to metabolic dysfunction. Furthermore, vitamin remediation of mutant enzymes may be a common phenomenon in certain domains of proteins.}, author = {Marini, Nicholas J. and Gin, Jennifer and Ziegle, Janet and Keho, Kathryn H. and Ginzinger, David and Gilbert, Dennis A. and Rine, Jasper}, citeulike-article-id = {2885128}, citeulike-linkout-0 = {http://dx.doi.org/10.1073/pnas.0802813105}, citeulike-linkout-1 = {http://www.pnas.org/content/105/23/8055.abstract}, citeulike-linkout-2 = {http://www.pnas.org/content/105/23/8055.full.pdf}, citeulike-linkout-3 = {http://www.pnas.org/cgi/content/abstract/105/23/8055}, citeulike-linkout-4 = {http://view.ncbi.nlm.nih.gov/pubmed/18523009}, citeulike-linkout-5 = {http://www.hubmed.org/display.cgi?uids=18523009}, day = {10}, doi = {10.1073/pnas.0802813105}, journal = {Proceedings of the National Academy of Sciences}, keywords = {bioinformatics, epidemiology, genetics, genotype, human, iem, metabolic, mutation, pediatric, phenotype, prevalence, vitamin}, month = {June}, number = {23}, pages = {8055--8060}, posted-at = {2009-08-26 14:44:40}, priority = {2}, title = {The prevalence of folate-remedial MTHFR enzyme variants in humans}, url = {http://dx.doi.org/10.1073/pnas.0802813105}, volume = {105}, year = {2008} }

TY - JOUR ID - citeulike:2885128 L3 - citeulike-article-id:2885128 N2 - 10.1073/pnas.0802813105 Studies of rare, inborn metabolic diseases establish that the phenotypes of some mutations in vitamin-dependent enzymes can be suppressed by supplementation of the cognate vitamin, which restores function of the defective enzyme. To determine whether polymorphisms exist that more subtly affect enzymes yet are augmentable in the same way, we sequenced the coding region of a prototypical vitamin-dependent enzyme, methylenetetrahydrofolate reductase (MTHFR), from 564 individuals of diverse ethnicities. All nonsynonymous changes were evaluated in functional assays in to identify enzymatic defects and folate remediability of impaired alleles. We identified 14 nonsynonymous changes: 11 alleles with minor allele frequencies <1% and 3 common alleles (A222V, E429A, and R594Q). Four of 11 low-frequency alleles affected enzyme function, as did A222V. Of the five impaired alleles, four could be restored to normal functionality by elevating intracellular folate levels. All five impaired alleles mapped to the N-terminal catalytic domain of the enzyme, whereas changes in the C-terminal regulatory domain had little effect on activity. Impaired activity correlated with the phosphorylation state of MTHFR, with more severe mutations resulting in lower abundance of the phosphorylated protein. Significantly, diploid yeast heterozygous for mutant alleles were impaired for growth, particularly with lower folate supplementation. These results suggested that multiple less-frequent alleles, in aggregate, might significantly contribute to metabolic dysfunction. Furthermore, vitamin remediation of mutant enzymes may be a common phenomenon in certain domains of proteins. IS - 23 JF - Proceedings of the National Academy of Sciences EP - 8060 TI - The prevalence of folate-remedial MTHFR enzyme variants in humans VL - 105 SP - 8055 KW - bioinformatics KW - epidemiology KW - genetics KW - genotype KW - human KW - iem KW - metabolic KW - mutation KW - pediatric KW - phenotype KW - prevalence KW - vitamin AU - Marini, Nicholas AU - Gin, Jennifer AU - Ziegle, Janet AU - Keho, Kathryn AU - Ginzinger, David AU - Gilbert, Dennis AU - Rine, Jasper PY - 2008/06/10/ UR - http://dx.doi.org/10.1073/pnas.0802813105 ER -