Mapping a chromosomal locus for valproic acid-induced exencephaly in mice.
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.
Lundberg
Yunxia Wang
YW
Genetics Department, Boys Town National Research Hospital, Omaha, Nebraska 68131, USA. Lundbergy@boystown.org
Cabrera
Robert M
RM
Greer
Kimberly A
KA
Zhao
Jian
J
Garg
Rohit
R
Finnell
Richard H
RH
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*
D000927:Anticonvulsants; D014635:Valproic Acid