The goal of this revised application is to illuminate the hereditary factors predisposing to neural tube defects (NTDs) and the interactions of these genes with one another and with the environment, eventually leading to mechanisms for the prevention of these frequent birth defects. Failed closure of the neural tube, the embryonic structure from which the brain and spinal cord are formed, leads to NTDs. The NTD complex includes the two most common forms of NTDs, spina bifida and anecephaly, as well as other less frequent manifestations. The frequency of NTD births in the US is approximately 1/1000. Multiple lines of evidence in humans and studies in experimental organisms provide compelling evidence that the predisposition to the development of NTDs includes a hereditary component. The increased risk to siblings over the general population rate is estimated at 25-50. The applicants propose to identify genetic factors involved in NTD development. We will collect both simplex and multiplex pedigrees in which the affected member(s) have a NTD. Extensive family history data and blood for DNA extraction will be obtained from these pedigrees. In addition, these pedigrees will be exhaustively characterized clinically, including radiographic assessment of facial dysmorphology, and cytogenetic assessments. In addition, the applicants will collect and database information on key environmental risk factors such as folic acid supplementation, maternal weight, and paternal military exposures to allow assessment of gene/environment interactions. These studies are aided by the plethora of well characterized murine models for NTDs, the human homologies for which have been identified in many cases. In the first two years of the study, specific candidate genes will be examined with SSCP analysis in available families. In year three, genomic screening of multiplex families will be performed, with follow-up investigations in years 4-5. These multiplex pedigrees will allow investigation of regions of interest unrelated to known candidate genes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039818-05
Application #
6615573
Study Section
Mammalian Genetics Study Section (MGN)
Program Officer
Gwinn, Katrina
Project Start
1999-08-01
Project End
2004-06-30
Budget Start
2003-07-01
Budget End
2004-06-30
Support Year
5
Fiscal Year
2003
Total Cost
$584,203
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
044387793
City
Durham
State
NC
Country
United States
Zip Code
27705
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