Mapping a chromosomal locus for valproic acid-induced exencephaly in mice

Yunxia Wang Lundberg, Robert M. Cabrera, Kimberly A. Greer, Jian Zhao, Rohit Garg, Richard H. Finnell

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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 × 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.

Original languageEnglish (US)
Pages (from-to)361-369
Number of pages9
JournalMammalian Genome
Issue number5
StatePublished - May 2004

ASJC Scopus subject areas

  • Genetics


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