Journal of cardiac failure · 2018
Insertional Mutagenesis Confounds the Mechanism of the Morbid Phenotype of a PLNR9C Transgenic Mouse Line.
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Kraev Alexander
Аннотация
BACKGROUND: A mouse line with heterozygous transgenic expression of phospholamban carrying a substitution of cysteine for arginine 9 (TgPLNR9C) under the control of α-myosin heavy chain (αMHC) promoter features dilated cardiomyopathy, heart failure, and premature death.
METHODS AND RESULTS: Determination of transgene chromosomal localization by conventional methods shows that in this line the transgenic array of 13 PLNR9C expression cassettes, arranged in a head-to-tail tandem orientation, have integrated into the bidirectional promoter of the αMHC (Myh6) gene and the gene for the regulatory noncoding RNA Myheart (Mhrt), both of which are known to be involved in cardiac development and pathology. Expression of the noncoding RNA Mhrt in TgPLNR9C mice exhibits profound deregulation, despite the presence of the second, intact allele.
CONCLUSIONS: The TgPLNR9C mouse strain is, in the best case, a functionally ambiguous phenocopy of the human PLNR9C heterozygote, because a similar constellation of genetically programmed events can not occur in a patient. Publications featuring "cardiac-specific overexpression" are focused on the phenotype and typically forgo the definition of the transgene integration site or transgene temporal expression profile, so caution should be exercised in attributing clinical relevance to pathologic phenomena observed in αMHC-driven transgenes.
METHODS AND RESULTS: Determination of transgene chromosomal localization by conventional methods shows that in this line the transgenic array of 13 PLNR9C expression cassettes, arranged in a head-to-tail tandem orientation, have integrated into the bidirectional promoter of the αMHC (Myh6) gene and the gene for the regulatory noncoding RNA Myheart (Mhrt), both of which are known to be involved in cardiac development and pathology. Expression of the noncoding RNA Mhrt in TgPLNR9C mice exhibits profound deregulation, despite the presence of the second, intact allele.
CONCLUSIONS: The TgPLNR9C mouse strain is, in the best case, a functionally ambiguous phenocopy of the human PLNR9C heterozygote, because a similar constellation of genetically programmed events can not occur in a patient. Publications featuring "cardiac-specific overexpression" are focused on the phenotype and typically forgo the definition of the transgene integration site or transgene temporal expression profile, so caution should be exercised in attributing clinical relevance to pathologic phenomena observed in αMHC-driven transgenes.