Neural tube defects (NTDs), primarily spina bifida and anencephaly, arise from a complex interplay of multiple gene interactions and environmental exposures. After 30 years of clinical and basic research, the field remains unable to accurately predict the risk for an individual couple of having a child affected by NTD, how folic acid (FA) works to prevent NTDs, whether or what dose of FA is likely provide effective prevention for them or whether there is another nutrient/supplement or intervention that would provide greater benefit The recent confluence of information from genetic mouse models, capabilities of molecular biological and biochemical detection in embryonic systems and advances in genomics and computational genetics now provides sufficient power to successfully address this complex genetic disorder. Project 1 will test the following hypotheses: 1. that combinations of rare variant single nucleotide polymorphisms (SNPs) will display associations useful for the definition of individual NTD risk in humans, and 2. that recognition of interactions between these genetic patterns with environmental conditions, including FA intake and factors common to inflammation or oxidative/nitrosative stress, can further increase their predictive value. This project will use deep resequencing of NTD patient DNA, targeted to human counterparts of some 1,000 genes implicated in NTD pathogenesis by clinical and animal model studies, to identify rare variant alleles that are overrepresented in NTD patients. These will be used to design custom SNP assays for screening larger patient numbers for analyses of single gene and pair-wise associations with NTD. Computational modeling will assess the potential impact of NTD associated SNPs on key developmental and metabolic pathways. The functional significance of SNP associations in humans will be functionally tested first for impact on Wnt/PCP, FA metabolism and oxidative/nitrosative stress using in vitro and mouse systems assays that will also be used to validate and inform computational modeling. Because the overt NTD phenotypes are readily recognized in humans and experimental animals, NTDs may well be the first complex genetic disorder for which gene-gene and gene-environment interactions can be understood in depth. Progress made for this disorder can provide useful analytical tools for identifying molecular network interactions relevant to later-onset complex genetic disorders, like schizophrenia and autism.
This Program will provide the most comprehensive translational information to date toward the understanding of human NTD risk and prevention. It could also serve as a model strategy for investigating the involvement of FA metabolism and oxidative stress in other diseases, including complex genetic disorders such as autism and schizophrenia, thought to be subject to gene-environment interactions.
|Lei, Yunping; Fathe, Kristin; McCartney, Danielle et al. (2015) Rare LRP6 variants identified in spina bifida patients. Hum Mutat 36:342-9|
|Tsurubuchi, Takao; Allender, Elise V; Siddiqui, M Rizwan et al. (2014) A critical role of noggin in developing folate-nonresponsive NTD in Fkbp8 -/- embryos. Childs Nerv Syst 30:1343-53|
|Hansler, Alex; Chen, Qiuying; Gray, Jason D et al. (2014) Untargeted metabolite profiling of murine embryos to reveal metabolic perturbations associated with neural tube closure defects. Birth Defects Res A Clin Mol Teratol 100:623-32|
|Diani-Moore, Silvia; Ma, Yuliang; Gross, Steven S et al. (2014) Increases in levels of epoxyeicosatrienoic and dihydroxyeicosatrienoic acids (EETs and DHETs) in liver and heart in vivo by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and in hepatic EET:DHET ratios by cotreatment with TCDD and the soluble epoxide hydrolas Drug Metab Dispos 42:294-300|
|Lei, Yunping; Zhu, Huiping; Yang, Wei et al. (2014) Identification of novel CELSR1 mutations in spina bifida. PLoS One 9:e92207|
|Fathe, Kristin; Palacios, Ana; Finnell, Richard H (2014) Brief report novel mechanism for valproate-induced teratogenicity. Birth Defects Res A Clin Mol Teratol 100:592-7|
|Ismailoglu, Ismail; Chen, Qiuying; Popowski, Melissa et al. (2014) Huntingtin protein is essential for mitochondrial metabolism, bioenergetics and structure in murine embryonic stem cells. Dev Biol 391:230-40|
|Abbott, Geoffrey W; Tai, Kwok-Keung; Neverisky, Daniel L et al. (2014) KCNQ1, KCNE2, and Na+-coupled solute transporters form reciprocally regulating complexes that affect neuronal excitability. Sci Signal 7:ra22|
|Wallingford, John B; Niswander, Lee A; Shaw, Gary M et al. (2013) The continuing challenge of understanding, preventing, and treating neural tube defects. Science 339:1222002|
|Denny, Kerina J; Jeanes, Angela; Fathe, Kristin et al. (2013) Neural tube defects, folate, and immune modulation. Birth Defects Res A Clin Mol Teratol 97:602-9|
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