A NATURAL DISRUPTION OF THE SECRETORY GROUP-II PHOSPHOLIPASE-A(2) GENE IN INBRED MOUSE STRAINS

The synovial fluid or group II secretory phospholipase A(2) (sPLA(2)) has been implicated as an important agent involved in a number of inflammatory processes. In an attempt to determine the role of sPLA(2) in inflammation, we set out to generate sPL(2)-deficient mice. During this investigation, we observed that in a number of inbred mouse strains, the sPLA(2) gene was already disrupted by a frameshift mutation in exon 3. This mutation, a T insertion at position 166 from the ATG of the cDNA, terminates out of frame in exon 4, resulting in the disruption of the calcium binding domain in exon 3 and loss of both activity domains coded by exons 4 and 5. The mouse strains C57BL/6, 129/Sv, and B10.RIII were found to be homozygous for the defective sPLA(2) gene, whereas outbred CD-1:SW mice had variable genotype at this locus. BALB/c, C3H/HE, DBA/1, DBA/2, NZB/B1N, and MRL lpr/lpr mice had a normal sPLA(2) genotype. The sPLA(2) mRNA was expressed at very high levels in the BALB/c mouse small intestine, whereas in the small intestine of the sPLA(2) mutant mouse strains, sPLA(2) mRNA was undetectable. In addition, PLA(2) activity in acid extracts of the small intestine were approximately 40 times higher in BALB/c than in the mutant mice. Transcription of the mutant sPLA(2) gene resulted in multiple transcripts due to exon skipping. None of the resulting mutant mRNAs encoded an active product. The identification of this mutation should not only help define the physiological role of sPLA(2) but also has important implications in mouse inflammatory models developed by targeted mutagenesis.