Exon skipping can reinitiate transcription and translation to overcome gene targeting.
To determine whether different gene-disruption strategies affect the phenotype of resulting mutant mice, we characterized Rhbdf1 mouse mutant lines generated by three commonly used strategies - definitive-null, targeted knockout (KO)-first, and CRISPR/Cas9. We find that Rhbdf1 frequently outmaneuvers KO strategies, to different degrees among the strategies, by skipping exons and reinitiating translation to yield gain-of-function alleles