Document Type
Article
Publication Date
5-1-2025
Original Citation
Pratt S,
Zarate-Mendez M,
Koludarova L,
Jansson S,
Airavaara M,
Hlushchuk I,
Coleman D,
Heffner C,
Horvath R,
Battersby B,
Burgess RW.
Evaluating the feasibility of gene replacement strategies to treat MTRFR deficiency. Dis Model Mech. 2025;18(5).
Keywords
JMG, Animals, Humans, Induced Pluripotent Stem Cells, Mitochondria, Genetic Therapy, Feasibility Studies, Phenotype, Neurons, Mitochondrial Proteins, Transgenes, Mice, Mice, Transgenic, Dependovirus, Mutation
JAX Source
Dis Model Mech. 2025;18(5).
ISSN
1754-8411
PMID
40452409
DOI
https://doi.org/10.1242/dmm.052120
Grant
R.W.B. is supported by the National Institute of Neurological Disorders and Stroke (R37NS054154). The Scientific Services at The Jackson Laboratory are supported by National Cancer Institute (CA34196).
Abstract
Mitochondrial translation release factor in rescue (MTRFR) catalyzes a termination step in protein synthesis, facilitating release of the nascent chain from mitoribosomes. Pathogenic variants in MTRFR cause MTRFR deficiency and are loss-of-function variants. Here, we tested gene replacement as a possible therapeutic strategy. A truncating mutation (K155*) was generated in mice; however, homozygotes die embryonically whereas mice heterozygous for this K155* allele are normal. We also generated transgenic strains expressing either wild-type human MTRFR or a partially functional MTRFR. Despite dose-dependent phenotypes from overexpression in vitro, neither transgene caused adverse effects in vivo. In K155* homozygous mice, the wild-type MTRFR transgene completely rescued the phenotype with only one copy present, whereas the mutant transgene rescued less efficiently. Detailed evaluation of mice rescued with the wild-type MTRFR transgene revealed no abnormalities. In human induced pluripotent stem cell (hiPSC)-derived knockdown neurons, mitochondrial phenotypes were corrected by AAV9-mediated delivery of MTRFR. Thus, we find no toxicity from truncated gene products or overexpression of MTRFR in vivo, and expression of MTRFR corrects phenotypes in both mouse and hiPSC models.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.