The in utero exposure to the pharmaceutical compound Depakene (Valproic Acid;VPA) increases the incidence of congenital malformations and neurodevelopmental defects in humans. The objective of this research proposal is to identify and characterize the genetic modifiers of VPA-induced neural tube defects (NTDs). The proposed research is conducted in mouse models, but the resultant data is expected to enable clinicians, under FDA approval, to develop personalized medicine strategies based on an the risk posed by homologous gene variants in human patient populations. This is increasingly important as VPA is now used not only in epilepsy therapy, but also to treat migraine headaches, and bipolar and schizoaffective disorders, increasing exposure to women of reproductive age. We hypothesize that the etiology of NTDs and neurodevelopmental deficits involves fetal genetic contributions, and that their protein products are modifying the ability of VPA to induce neural abnormalities. Specifically, we propose to test the hypothesis that variation within Acyl-CoA Synthetase Medium-Chain (ACSM) genes are more prevalent in mouse embryos with NTDs following exposure to teratogenic concentrations of VPA, than in similarly exposed embryos that appear normal. We propose to fine map the critical region on chromosome 7 in order to identify novel gene variants responsible for NTDs and neurodevelopmental deficits induced by VPA, using our established mouse models of VPA-teratogenesis. We propose to re-sequence all known genes mapped to the critical region in affected and unaffected mouse fetuses following in utero VPA exposure. A combination of Sanger sequencing and targeted resequencing by next-generation sequencing techniques, using targeted enrichment (NimbleGen Sequence Capture Arrays and Agilent Technologies SureSelect System) of samples will be used to thoroughly interrogate the VPA-sensitivity loci. The goal of target enrichment prior to next-generation sequencing is to expand upon our whole genome association studies to: 1) define SNPs and unique genomic variations;and 2) correlate these variants to VPA-induced neurodevelopmental disease. We will then develop novel ACSM mutant mouse lines using existing targeted embryonic stem cell clones and validate this gene family as regulating susceptibility to VPA-induced NTDs.

Public Health Relevance

Public Health Relevance

Determining susceptibility to VPA-induced neural tube and related developmental malformations is of significant clinical importance, as the health-related expenses related to in utero drug exposure exceeds $500 million dollars annually in the US, not to mention the intra-family anguish and suffering. As this is the most widely used anticonvulsant medication in the US, the ability to identify individuals who would be at high-risk for an adverse outcome if pregnant, represents a highly significant breakthrough which can only happen when there is validation of the gene(s) regulating susceptibility and identification of variants within the gene.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21HD072251-01
Application #
8284871
Study Section
Genetics of Health and Disease Study Section (GHD)
Program Officer
Oster-Granite, Mary Lou
Project Start
2012-08-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$231,000
Indirect Cost
$81,000
Name
University of Texas Austin
Department
Social Sciences
Type
Schools of Arts and Sciences
DUNS #
170230239
City
Austin
State
TX
Country
United States
Zip Code
78712
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
Wang, Xueqian; Cabrera, Robert M; Li, Yue et al. (2013) Functional regulation of P-glycoprotein at the blood-brain barrier in proton-coupled folate transporter (PCFT) mutant mice. FASEB J 27:1167-75
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