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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.<\/jats:p>","DOI":"10.1242\/dmm.052120","type":"journal-article","created":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T06:40:21Z","timestamp":1748846421000},"source":"Crossref","is-referenced-by-count":6,"title":["Evaluating the feasibility of gene replacement strategies to treat <i>MTRFR<\/i> deficiency"],"prefix":"10.1242","volume":"18","author":[{"given":"Samia L.","family":"Pratt","sequence":"first","affiliation":[{"name":"The Jackson Laboratory 1 , Bar Harbor, ME 04609 ,","place":["USA"]},{"name":"Graduate School of Biomedical Science, Tufts University 2 Neuroscience Ph.D. Program , , Boston, MA 02111 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Zarate-Mendez","sequence":"additional","affiliation":[{"name":"John Van Geest Centre for Brain Repair, University of Cambridge 3 Department of Clinical Neurosciences , , CB2 0PY Cambridge ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lidiia","family":"Koludarova","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, HiLIFE, University of Helsinki 4 , 00014 Helsinki ,","place":["Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonja","family":"Jansson","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, HiLIFE, University of Helsinki 4 , 00014 Helsinki ,","place":["Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikko","family":"Airavaara","sequence":"additional","affiliation":[{"name":"University of Helsinki 5 Drug Research Program, Faculty of Pharmacy , , 00014 Helsinki ,","place":["Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Irena","family":"Hlushchuk","sequence":"additional","affiliation":[{"name":"University of Helsinki 5 Drug Research Program, Faculty of Pharmacy , , 00014 Helsinki ,","place":["Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Coleman","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory 1 , Bar Harbor, ME 04609 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caleb","family":"Heffner","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory 1 , Bar Harbor, ME 04609 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rita","family":"Horvath","sequence":"additional","affiliation":[{"name":"John Van Geest Centre for Brain Repair, University of Cambridge 3 Department of Clinical Neurosciences , , CB2 0PY Cambridge ,","place":["UK"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan J.","family":"Battersby","sequence":"additional","affiliation":[{"name":"Institute of Biotechnology, HiLIFE, University of Helsinki 4 , 00014 Helsinki ,","place":["Finland"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9229-3407","authenticated-orcid":false,"given":"Robert W.","family":"Burgess","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory 1 , Bar Harbor, ME 04609 ,","place":["USA"]},{"name":"Graduate School of Biomedical Science, Tufts University 2 Neuroscience Ph.D. Program , , Boston, MA 02111 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2025,6,2]]},"reference":[{"key":"2025060202401069100_DMM052120C1","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1126\/science.aaa1193","article-title":"Ribosome. 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