Insertional mutagenesis in PLNR9Ctransgenic mouse: a case report and a review of the literature on cardiac-specific transgenic expression

A mouse line with heterozygous transgenic expression of phospholamban carrying a substitution of cysteine for arginine 9 (PLN R9C ) under the control of α-myosin heavy chain (αMHC) promoter features dilated cardiomyopathy, heart failure and premature death. In this line the transgenic array of 13 PLN R9C expression cassettes, arranged in a head-to-tail tandem orientation, has integrated into the homologous genomic site, the bi-directional promoter of the αMHC (Myh6) gene and the gene for the regulatory non-coding RNA Myheart (Mhrt), both of which are involved in the execution of the α/β MHC switch during cardiac development and pathology. PLN R9C overexpression is evident at the age of 1 month but declines dramatically along with a less pronounced concomitant decline of the resident PLN expression, until the animals die. Expression of the non-coding RNA Mhrt in PLN R9C mice also exhibits a profound deregulation, despite the presence of the second, intact allele. Hence the mouse strain does not faithfully model a human PLN R9C heterozygote, wherein both the mutant and the wildtype PLN alleles have, in all likelihood, the same temporal expression profile. The intricate regulatory circuit of the α/β MHC switch, involving the non-coding RNA Mhrt, was described in detail only recently, and since publications about αMHC-driven transgenes rarely contain the definition of the transgene integration site or temporal expression profile, it is suggested that some of the pathological phenomena attributed to expression of αMHC-driven transgenes may have an alternative explanation.