Research in the Molecular Pathogenesis is focused on defining changes in the genes that underlie inherited susceptibilities to common diseases such as cancer and birth defects. Changes in folate metabolism are correlated with tumor formation and birth defects. Folate genes are also involved in the methylation of DNA and proper brain function. . We are searching for genetic variants in genes related to folate, methionine and homocysteine metabolism. Individuals affected with cancer or Spina Bifida (one form of neural tube defects) will be tested for these variants. Variants found at higher frequency in individuals with disease will help us identify genes associated with risk. In the past year we have tested more than 15 genes for variants that might perturb folate metabolism and therefore be associated with an increase risk of having a child with an neural tube defect. We found that variants in one of these genes, TC2, appear to affect the levels of vitamin B12 in the blood during pregnancy. This finding may be related to birth defects and also may help to explain why some elderly individuals become anemic and suffer neurological symptoms from vitamin B12 deficiency. We also found that mothers carrying a specific variant in a second gene, MTHFD1, have a 50% increased risk bearing a child with a neural tube defect. This previously un-described variant may be responsible for up to 25% of all neural tube defects. Approximately one in five individuals in the population carry one of these risk factors. We have re-created these genes in the laboratory and are currently using an experimental system to determine exactly how these variants alter the function of these proteins. A detailed knowledge of the function of these two genes will add to our understanding of neural tube defects and potentially help guide public health policy in the area of nutritional supplementation.
| Molloy, Anne M; Brody, Lawrence C; Mills, James L et al. (2009) The search for genetic polymorphisms in the homocysteine/folate pathway that contribute to the etiology of human neural tube defects. Birth Defects Res A Clin Mol Teratol 85:285-94 |
| Mills, James L; Molloy, Anne M; Parle-McDermott, Anne et al. (2008) Folate-related gene polymorphisms as risk factors for cleft lip and cleft palate. Birth Defects Res A Clin Mol Teratol 82:636-43 |
| Molloy, Anne M; Kirke, Peadar N; Brody, Lawrence C et al. (2008) Effects of folate and vitamin B12 deficiencies during pregnancy on fetal, infant, and child development. Food Nutr Bull 29:S101-11;discussion S112-5 |
| Parle-McDermott, Anne; Pangilinan, Faith; Mills, James L et al. (2007) The 19-bp deletion polymorphism in intron-1 of dihydrofolate reductase (DHFR) may decrease rather than increase risk for spina bifida in the Irish population. Am J Med Genet A 143A:1174-80 |
| Lawrance, Andrea K; Deng, Liyuan; Brody, Lawrence C et al. (2007) Genetic and nutritional deficiencies in folate metabolism influence tumorigenicity in Apcmin/+ mice. J Nutr Biochem 18:305-12 |
| Parle-McDermott, Anne; Mills, James L; Molloy, Anne M et al. (2006) The MTHFR 1298CC and 677TT genotypes have opposite associations with red cell folate levels. Mol Genet Metab 88:290-4 |
| Parle-McDermott, Anne; Kirke, Peadar N; Mills, James L et al. (2006) Confirmation of the R653Q polymorphism of the trifunctional C1-synthase enzyme as a maternal risk for neural tube defects in the Irish population. Eur J Hum Genet 14:768-72 |
| O'leary, Valerie B; Pangilinan, Faith; Cox, Christopher et al. (2006) Reduced folate carrier polymorphisms and neural tube defect risk. Mol Genet Metab 87:364-9 |
| Swanson, Deborah A; Pangilinan, Faith; Mills, James L et al. (2005) Evaluation of transcobalamin II polymorphisms as neural tube defect risk factors in an Irish population. Birth Defects Res A Clin Mol Teratol 73:239-44 |
| Mills, James L; Druschel, Charlotte M; Pangilinan, Faith et al. (2005) Folate-related genes and omphalocele. Am J Med Genet A 136:8-11 |
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