New DHFR Deletion Polymorphism - A Risk Factor for SB?

  • Johnson, William (PI)

Project Details


DESCRIPTION (provided by applicant): Spinal bifida (SB) is a common birth defect that is determined by multiple genetic and environmental factors. Up to 72% of SB is preventable by periconceptual maternal folate supplementation. The C677T polymorphism of the methylenetetrahydrofolate reductase gene and some other functional polymorphisms appear to be risk factors for SB in some populations but not others. However, despite extensive study, the genetic risk factors for SB are poorly understood. We hypothesize that genetic factors which diminish bioavailability of reduced foliate in the mother during pregnancy may contribute to SB in her fetus. We recently discovered a new 1 9bp deletion of dihydrofolate reductase (DHFR) that is a common polymorphism (allele frequency 0.44) and is a good candidate for such a genetic factor. We found that homozygosity for this deletion allele was significantly more frequent in SB mothers compared with controls, SB fathers, and SB patients, as predicted by the hypothesis.We propose to confirm and extend this finding in a replication series of SB families. We will use a new method devised by the PI to test for transmission/disequilibrium in SIB maternal trios (SB mother, maternal grandmother and maternal grandfather) to document the action of the DHFR deletion allele as a teratogenic locus, that is, one that acts in a mother to affect the development of her fetus. We will also document whether the deletion allele decreases DHFR transcription or affects DHFR activity by another mechanism.If this hypothesis is confirmed, it will shed light on how foliate supplements prevent SB and may lead to improved forms of foliate supplementation for pregnancy. About half of dietary foliates and all of folic acid supplements are unreduced and must be reduced by DHFR to be available for mother and fetus. Forms of foliate that are already reduced could be preferable as foliate supplements during pregnancy for prevention of SB.
Effective start/end date9/15/026/30/05


  • National Institute of Neurological Disorders and Stroke: $184,656.00
  • National Institute of Neurological Disorders and Stroke: $184,656.00


  • Genetics
  • Pediatrics, Perinatology, and Child Health


Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.