{"gene":"MRPL49","run_date":"2026-06-10T02:59:51","timeline":{"discoveries":[{"year":2025,"finding":"Bi-allelic loss-of-function variants in MRPL49 cause combined oxidative phosphorylation deficiency (COXPD). Complexome profiling of patient fibroblasts revealed reduced levels of both small and large mitochondrial ribosomal subunits (with a more pronounced reduction of the large subunit), without evidence of altered mitoribosomal assembly. This results in reduced levels of OXPHOS enzyme complexes I and IV, establishing MRPL49 as a structural component of the mitochondrial ribosomal large subunit required for normal OXPHOS complex biogenesis.","method":"Complexome profiling of patient-derived fibroblasts with bi-allelic MRPL49 variants; genome sequencing; measurement of OXPHOS enzyme complex levels","journal":"American journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complexome profiling and OXPHOS enzyme quantification in patient fibroblasts from nine unrelated families, single lab, two orthogonal methods (complexome profiling + OXPHOS complex measurement)","pmids":["40043708"],"is_preprint":false},{"year":1996,"finding":"The human NOF (MRPL49) gene was cloned and characterized at chromosome 11q13, adjacent to FAU in a head-to-head configuration. The largest open reading frame encodes a 166 amino acid proline-rich protein with no homology to known genes at the time, and the locus is evolutionarily conserved with >80% identity to mouse and rat orthologs that also map next to the FAU gene.","method":"cDNA cloning, genomic sequencing, chromosomal mapping, BLAST homology analysis","journal":"Genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct cDNA cloning and genomic characterization; single lab but multiple orthogonal methods (sequencing, mapping, cross-species comparison)","pmids":["8786148"],"is_preprint":false}],"current_model":"MRPL49 (NOF) is a component of the mitochondrial ribosomal large subunit whose loss, due to bi-allelic variants, reduces mitoribosomal subunit levels and impairs OXPHOS complex I and IV biogenesis, causing combined oxidative phosphorylation deficiency with multisystem phenotypes including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency."},"narrative":{"mechanistic_narrative":"MRPL49 (NOF) is a structural component of the mitochondrial ribosomal large subunit required for normal biogenesis of the oxidative phosphorylation machinery [PMID:40043708]. Bi-allelic loss-of-function variants reduce levels of both mitoribosomal subunits—most markedly the large subunit—without disrupting mitoribosomal assembly, and consequently lower the abundance of OXPHOS complexes I and IV, causing combined oxidative phosphorylation deficiency with multisystem disease [PMID:40043708]. The gene maps to chromosome 11q13 in a head-to-head configuration with FAU and encodes a small proline-rich protein that is evolutionarily conserved across mammals [PMID:8786148]. Beyond its identification as a mitoribosomal large-subunit component and its disease association [PMID:40043708], no further mechanistic detail has been characterized in the available corpus.","teleology":[{"year":1996,"claim":"Before any function was known, the genomic identity and conservation of MRPL49 had to be established; cloning placed it at 11q13 head-to-head with FAU and defined a conserved small proline-rich product, providing the molecular handle for later functional work.","evidence":"cDNA cloning, genomic sequencing, chromosomal mapping, and cross-species homology comparison","pmids":["8786148"],"confidence":"Medium","gaps":["No molecular function or subcellular localization was assigned at this stage","No link to the mitochondrial ribosome was established","Functional significance of the FAU-adjacent head-to-head arrangement unresolved"]},{"year":2025,"claim":"It was unknown whether MRPL49 had a physiological role in mitochondrial translation; patient-derived complexome profiling showed bi-allelic loss reduces mitoribosomal subunit levels and OXPHOS complexes I and IV, establishing it as a structural mitoribosomal large-subunit component required for OXPHOS biogenesis and the cause of combined oxidative phosphorylation deficiency.","evidence":"Complexome profiling and OXPHOS complex quantification in fibroblasts from patients with bi-allelic MRPL49 variants across nine unrelated families; genome sequencing","pmids":["40043708"],"confidence":"Medium","gaps":["Single-lab study without independent replication of the molecular phenotype","Mechanism by which large-subunit loss propagates to reduced small-subunit levels not resolved","No structural placement of MRPL49 within the assembled mitoribosome demonstrated"]},{"year":null,"claim":"How MRPL49 is incorporated into the mitoribosomal large subunit and the precise step at which its loss limits OXPHOS complex I and IV biogenesis remain undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct demonstration of binding partners within the mitoribosome","No reconstitution or rescue experiment defining the assembly step affected","Tissue-specific basis of the multisystem phenotype unexplained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[0]}],"complexes":["mitochondrial ribosome large subunit"],"partners":[],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13405","full_name":"Large ribosomal subunit protein mL49","aliases":["39S ribosomal protein L49, mitochondrial","L49mt","MRP-L49","Neighbor of FAU","NOF","Protein NOF1"],"length_aa":166,"mass_kda":19.2,"function":"","subcellular_location":"Mitochondrion","url":"https://www.uniprot.org/uniprotkb/Q13405/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/MRPL49","classification":"Common Essential","n_dependent_lines":1010,"n_total_lines":1208,"dependency_fraction":0.8360927152317881},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MRPL49","total_profiled":1310},"omim":[{"mim_id":"621195","title":"COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 60; COXPD60","url":"https://www.omim.org/entry/621195"},{"mim_id":"609060","title":"COMBINED OXIDATIVE PHOSPHORYLATION DEFICIENCY 1; COXPD1","url":"https://www.omim.org/entry/609060"},{"mim_id":"606866","title":"MITOCHONDRIAL RIBOSOMAL PROTEIN L49; MRPL49","url":"https://www.omim.org/entry/606866"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/MRPL49"},"hgnc":{"alias_symbol":["NOF","NOF1","L49mt","mL49"],"prev_symbol":["C11orf4"]},"alphafold":{"accession":"Q13405","domains":[{"cath_id":"3.30.780.10","chopping":"40-166","consensus_level":"medium","plddt":94.8146,"start":40,"end":166}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13405","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13405-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13405-F1-predicted_aligned_error_v6.png","plddt_mean":84.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MRPL49","jax_strain_url":"https://www.jax.org/strain/search?query=MRPL49"},"sequence":{"accession":"Q13405","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13405.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13405/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13405"}},"corpus_meta":[{"pmid":"24737272","id":"PMC_24737272","title":"N-of-1 (single-patient) trials for statin-related myalgia.","date":"2014","source":"Annals of internal medicine","url":"https://pubmed.ncbi.nlm.nih.gov/24737272","citation_count":96,"is_preprint":false},{"pmid":"12533607","id":"PMC_12533607","title":"Light stimulates a transducin-independent increase of cytoplasmic Ca2+ and suppression of current in cones from the zebrafish mutant nof.","date":"2003","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/12533607","citation_count":82,"is_preprint":false},{"pmid":"34607609","id":"PMC_34607609","title":"Molecular profiling of advanced malignancies guides first-line N-of-1 treatments in the I-PREDICT treatment-naïve study.","date":"2021","source":"Genome medicine","url":"https://pubmed.ncbi.nlm.nih.gov/34607609","citation_count":78,"is_preprint":false},{"pmid":"17251445","id":"PMC_17251445","title":"Identification of a zebrafish cone photoreceptor-specific promoter and genetic rescue of achromatopsia in the nof mutant.","date":"2007","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/17251445","citation_count":72,"is_preprint":false},{"pmid":"25989944","id":"PMC_25989944","title":"PCSK9 inhibitors and neurocognitive adverse events: exploring the FDA directive and a proposal for N-of-1 trials.","date":"2015","source":"Drug safety","url":"https://pubmed.ncbi.nlm.nih.gov/25989944","citation_count":56,"is_preprint":false},{"pmid":"36516128","id":"PMC_36516128","title":"Consensus Guidelines for the Design and In Vitro Preclinical Efficacy Testing N-of-1 Exon Skipping Antisense Oligonucleotides.","date":"2022","source":"Nucleic acid therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/36516128","citation_count":43,"is_preprint":false},{"pmid":"1988463","id":"PMC_1988463","title":"Purification and characterization of an 82-kD membrane protein as a neurite outgrowth factor binding protein: possible involvement of NOF binding protein in axonal outgrowth in developing retina.","date":"1991","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/1988463","citation_count":35,"is_preprint":false},{"pmid":"16052316","id":"PMC_16052316","title":"A pilot study of ondansetron plus metopimazine vs. ondansetron monotherapy in children receiving highly emetogenic chemotherapy: a Bayesian randomized serial N-of-1 trials design.","date":"2005","source":"Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16052316","citation_count":29,"is_preprint":false},{"pmid":"39496921","id":"PMC_39496921","title":"The state-of-the-art of N-of-1 therapies and the IRDiRC N-of-1 development roadmap.","date":"2024","source":"Nature reviews. 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Complexome profiling of patient fibroblasts revealed reduced levels of both small and large mitochondrial ribosomal subunits (with a more pronounced reduction of the large subunit), without evidence of altered mitoribosomal assembly. This results in reduced levels of OXPHOS enzyme complexes I and IV, establishing MRPL49 as a structural component of the mitochondrial ribosomal large subunit required for normal OXPHOS complex biogenesis.\",\n      \"method\": \"Complexome profiling of patient-derived fibroblasts with bi-allelic MRPL49 variants; genome sequencing; measurement of OXPHOS enzyme complex levels\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complexome profiling and OXPHOS enzyme quantification in patient fibroblasts from nine unrelated families, single lab, two orthogonal methods (complexome profiling + OXPHOS complex measurement)\",\n      \"pmids\": [\"40043708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"The human NOF (MRPL49) gene was cloned and characterized at chromosome 11q13, adjacent to FAU in a head-to-head configuration. The largest open reading frame encodes a 166 amino acid proline-rich protein with no homology to known genes at the time, and the locus is evolutionarily conserved with >80% identity to mouse and rat orthologs that also map next to the FAU gene.\",\n      \"method\": \"cDNA cloning, genomic sequencing, chromosomal mapping, BLAST homology analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct cDNA cloning and genomic characterization; single lab but multiple orthogonal methods (sequencing, mapping, cross-species comparison)\",\n      \"pmids\": [\"8786148\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MRPL49 (NOF) is a component of the mitochondrial ribosomal large subunit whose loss, due to bi-allelic variants, reduces mitoribosomal subunit levels and impairs OXPHOS complex I and IV biogenesis, causing combined oxidative phosphorylation deficiency with multisystem phenotypes including sensorineural hearing loss, leukodystrophy, and ovarian insufficiency.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MRPL49 (NOF) is a structural component of the mitochondrial ribosomal large subunit required for normal biogenesis of the oxidative phosphorylation machinery [#0]. Bi-allelic loss-of-function variants reduce levels of both mitoribosomal subunits—most markedly the large subunit—without disrupting mitoribosomal assembly, and consequently lower the abundance of OXPHOS complexes I and IV, causing combined oxidative phosphorylation deficiency with multisystem disease [#0]. The gene maps to chromosome 11q13 in a head-to-head configuration with FAU and encodes a small proline-rich protein that is evolutionarily conserved across mammals [#1]. Beyond its identification as a mitoribosomal large-subunit component and its disease association [#0], no further mechanistic detail has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Before any function was known, the genomic identity and conservation of MRPL49 had to be established; cloning placed it at 11q13 head-to-head with FAU and defined a conserved small proline-rich product, providing the molecular handle for later functional work.\",\n      \"evidence\": \"cDNA cloning, genomic sequencing, chromosomal mapping, and cross-species homology comparison\",\n      \"pmids\": [\"8786148\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No molecular function or subcellular localization was assigned at this stage\",\n        \"No link to the mitochondrial ribosome was established\",\n        \"Functional significance of the FAU-adjacent head-to-head arrangement unresolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"It was unknown whether MRPL49 had a physiological role in mitochondrial translation; patient-derived complexome profiling showed bi-allelic loss reduces mitoribosomal subunit levels and OXPHOS complexes I and IV, establishing it as a structural mitoribosomal large-subunit component required for OXPHOS biogenesis and the cause of combined oxidative phosphorylation deficiency.\",\n      \"evidence\": \"Complexome profiling and OXPHOS complex quantification in fibroblasts from patients with bi-allelic MRPL49 variants across nine unrelated families; genome sequencing\",\n      \"pmids\": [\"40043708\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single-lab study without independent replication of the molecular phenotype\",\n        \"Mechanism by which large-subunit loss propagates to reduced small-subunit levels not resolved\",\n        \"No structural placement of MRPL49 within the assembled mitoribosome demonstrated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MRPL49 is incorporated into the mitoribosomal large subunit and the precise step at which its loss limits OXPHOS complex I and IV biogenesis remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct demonstration of binding partners within the mitoribosome\",\n        \"No reconstitution or rescue experiment defining the assembly step affected\",\n        \"Tissue-specific basis of the multisystem phenotype unexplained\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"mitochondrial ribosome large subunit\"],\n    \"partners\": [],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":3,"faith_pct":100.0}}