{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMTRFR (also known as C12orf65) is a mitochondrial protein that belongs to the class I peptide release factors characterized by a conserved GGQ motif. It plays a critical role in mitochondrial translation by facilitating the rescue of stalled mitoribosomes, thereby ensuring proper release of abortive peptidyl‐tRNA species and efficient synthesis of key mitochondrial proteins. Loss‐of‐function mutations in this gene disrupt oxidative phosphorylation, as evidenced by severe decreases in complex I, IV, and V activities that lead to encephalomyopathy, optic atrophy, and other mitochondrial dysfunctions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n \nIn-depth structural studies have revealed that the GGQ-containing domain of MTRFR adopts a conformation similar to that of classical bacterial release factors, which suggests a conserved mechanism of action. Experiments involving siRNA knockdown of C12orf65 in cultured cells showed increased reactive oxygen species production, altered mitochondrial membrane potential, and cell apoptosis. In addition, genotype-phenotype analyses in patients demonstrate that truncating mutations disrupting the GGQ motif result in a severe clinical spectrum including early-onset optic atrophy, peripheral neuropathy, and spastic paraplegia, whereas mutations affecting downstream regions tend to correlate with a milder presentation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "4"}]}, {"type": "t", "text": "\n \nFurther clinical genetic studies have identified novel and recurrent compound heterozygous mutations in MTRFR, confirming its indispensable role in mitochondrial translation. The observed spectrum—ranging from combined oxidative phosphorylation deficiency with Leigh-like features to spastic paraplegia with optic atrophy—underscores that proper MTRFR function is vital for maintaining mitochondrial integrity and cellular homeostasis. These findings provide clear evidence that disruption of MTRFR/C12orf65 impairs the recycling of stalled ribosomes, thereby contributing to the development of neuromuscular and neurodegenerative disorders."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Hana Antonicka, Elsebet Ostergaard, Florin Sasarman, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "Mutations in the mitochondrial gene C12ORF65 lead to syndromic autosomal recessive intellectual disability and show genotype phenotype correlation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Med Genet (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ejmg.2013.09.010"}], "href": "https://doi.org/10.1016/j.ejmg.2013.09.010"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24080142"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24080142"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Gena Heidary, Laurel Calderwood, Gerald F Cox, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Optic atrophy and a Leigh-like syndrome due to mutations in the c12orf65 gene: report of a novel mutation and review of the literature."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neuroophthalmol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1097/WNO.0000000000000076"}], "href": "https://doi.org/10.1097/WNO.0000000000000076"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24284555"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24284555"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Ronen Spiegel, Hanna Mandel, Ann Saada, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Delineation of C12orf65-related phenotypes: a genotype-phenotype relationship."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur J Hum Genet (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ejhg.2013.284"}], "href": "https://doi.org/10.1038/ejhg.2013.284"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24424123"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24424123"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Shuang-Zhu Lin, Xian-Ting Sun, Hong-Wei Ma "}, {"type": "b", "children": [{"type": "t", "text": "[Clinical features and C12orf65 mutations of autosomal recessive spastic paraplegia-55: a case report]."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Zhongguo Dang Dai Er Ke Za Zhi (2019)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31753091"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31753091"}]}]}]}