The mutant ABC1 allele was generated by homologous recombination, by using a targeting vector containing a neomycin resistance and herpes simplex virus thymidine kinase genes to disrupt exons 17 and 22 of the Abca1 gene. This portion of the gene encodes the entire N-terminal ATP-binding cassette. The construct was electroporated into DBA/1LacJ-derived 252 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6J blastocysts to generate chimeric animals.This disruption leads to a null mutation, as demonstrated by the lack of expression of ABC1 mRNA and protein.Analysis of heterozygous intercrosses showed that the mutant allele is transmitted at mendelian frequency, with high lethality in ABC1-null pups during the first few weeks after birth. Autopsies revealed deep perivisceral hemorrhages in null animals but not in wild-type pups. No gross morphological defect was detected. Mating of homozygous mutant females produced no litters, irrespective of male genotype, because of impaired placental development, which is consistent with the high level of ABC1 expression in this organ.Pups that survive beyond birth have no detectable ABCA1 gene transcript in the tissues.This mouse model is deposited at The Jackson Laboratory (Jax stock#003897).