Dba/1-abca1tm1jdm/j mice

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).

Interest / Relevance: Tangier disease has been linked to mutations in the human ATP-binding cassette transporter 1 (hABCA1), a member of the ABC superfamily. In Tangier Disease, loss of ABCA1 prevents cells from exporting cholesterol and phospholipid, thus resulting in the build-up of cholesterol in the peripheral tissues and a loss of circulating HDL. Consistent with HDL being an athero-protective particle, Tangier patients are more prone to develop atherosclerosis.

The mouse ABCA1−/− phenotype of this ABCA1-deficient transgenic mice model corroborates the human Tangier disease linkage to ABCA1. It parallels the dyslipidemic phenotype observed in human Tangier disease, including substantial reductions in both apolipoprotein B and apolipoprotein AI with confounding affects on atherosclerosis.

This mouse model will be very useful in the study of lipid metabolism, renal inflammation, and cardiovascular disease and may reveal previously unsuspected relationships between them.
Keywords: ABC1 , DBA
Nat Cell Biol. 2000 Jul 2(7):399-406; Am J Clin Nutr. 2009 Jan 89(1):177-84; Circ Res. 2010 Dec 10 107(12):e20-31.



Business Developper
Giovanna CHIMINI
Inserm Transfert
Research Tools
Species: Mouse
Strain: DBA/1LacJ
Applications: Atherosclerosis - Tangier disease - Lipid metabolism - renal inflammation - cardiovascular disease
Rare disease:
Last update: 15/12/2021

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