title: Mapping a chromosomal locus for valproic acid-induced exencephaly in mice.
abstract: Human neural tube defects (NTDs) are among the most common congenital defects. They have a highly heterogeneous etiology, and, in addition to those seen in association with genetic syndromes, there are also NTDs induced by pharmaceutical compounds in utero, such as the widely used anti-epileptic drug valproic acid (VPA). Although familial studies have suggested a genetic contribution to VPA-induced NTDs, this trait has not been adequately studied, nor have the responsible genetic factors been identified. We generated a series of mouse crosses and backcrosses using the highly inbred SWV/Fnn and C57BL/6J strains, in order to identify possible chromosomal loci contributing to VPA sensitivity. When exposed to a high dose of sodium VPA (600 mg/kg) via maternal intraperitoneal injection on gestational day E8.5, the fetuses manifested exencephaly in a strain-dependent manner. Our data show an autosomal recessive trait, plus a gender-related effect or an overall X-Chromosome (Chr) effect, as being primarily responsible for determining sensitivity to VPA-induced exencephaly. Genome scanning and further linkage analysis of 131 exencephalic backcross fetuses identified a major locus linked to D7Mit285 (p < 2 x 10(-6)), exceeding the threshold for significant linkage. These results suggest a major chromosomal locus associated with the sensitivity to VPA-induced exencephaly in mice.
authors.affiliation: Genetics Department, Boys Town National Research Hospital, Omaha, Nebraska 68131, USA. Lundbergy@boystown.org
authors.forename: Yunxia Wang
authors.initials: YW
authors.lastname: Lundberg
authors.forename: Robert M
authors.initials: RM
authors.lastname: Cabrera
authors.forename: Kimberly A
authors.initials: KA
authors.lastname: Greer
authors.forename: Jian
authors.initials: J
authors.lastname: Zhao
authors.forename: Rohit
authors.initials: R
authors.lastname: Garg
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000633:toxicity*; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D005260:Female; D020022:Genetic Predisposition to Disease; D016678:Genome; D007274:Injections, Intraperitoneal; D008297:Male; D018811:Maternal Exposure / Q000009:adverse effects*; D051379:Mice; D008810:Mice, Inbred C57BL; D009436:Neural Tube Defects / Q000139:chemically induced*; D011247:Pregnancy; D014635:Valproic Acid / Q000633:toxicity*
chemical_list: D000927:Anticonvulsants; D014635:Valproic Acid