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Widespread discrepancy in Nnt genotypes and genetic backgrounds complicates granzyme A and other knockout mouse studies
- Source :
- eLife, Vol 11 (2022)
- Publication Year :
- 2022
- Publisher :
- eLife Sciences Publications Ltd, 2022.
-
Abstract
- Granzyme A (GZMA) is a serine protease secreted by cytotoxic lymphocytes, withGzma-/-mouse studies having informed our understanding of GZMA’s physiological function. We show herein thatGzma-/-mice have a mixed C57BL/6J and C57BL/6N genetic background and retain the full-length nicotinamide nucleotide transhydrogenase (Nnt) gene, whereasNntis truncated in C57BL/6J mice. Chikungunya viral arthritis was substantially ameliorated inGzma-/-mice; however, the presence ofNntand the C57BL/6N background, rather than loss of GZMA expression, was responsible for this phenotype. A new CRISPR active site mutant C57BL/6JGzmaS211Amouse provided the first insights into GZMA’s bioactivity free of background issues, with circulating proteolytically active GZMA promoting immune-stimulating and pro-inflammatory signatures. Remarkably, k-mer mining of the Sequence Read Archive illustrated that ≈27% of Run Accessions and ≈38% of BioProjects listing C57BL/6J as the mouse strain hadNntsequencing reads inconsistent with a C57BL/6J genetic background.Nntand C57BL/6N background issues have clearly complicated our understanding of GZMA and may similarly have influenced studies across a broad range of fields.
Details
- Language :
- English
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- eLife
- Accession number :
- edsair.doi.dedup.....3fe51b3c7e7187684994efb2122b89ef