| Claim | Evidence type and quantitative observation | Source PMID, year, and DOI | Interpretation or limitation |
|---|---|---|---|
| **MRM2 p.Gly189Arg is associated with infantile MELAS-like encephalomyopathy** | **Single human case:** homozygous **NM_013393:c.567G>A, p.Gly189Arg**; onset at **8 months** with developmental delay and generalized dyskinesia; febrile deterioration at age 4; death during febrile sepsis at **7 years**. Both parents were heterozygous. (pqac-00000010, pqac-00000011, pqac-00000033) | **PMID 28973171**; Garone et al.; **2017**; [DOI 10.1093/hmg/ddx314](https://doi.org/10.1093/hmg/ddx314) | Strong segregation and functional evidence, but the original clinical association rests on **one patient**; phenotype frequencies, penetrance, and survival distributions cannot be estimated. |
| **Muscle mtDNA copy number was reduced, but strict depletion was not established** | **Human tissue:** muscle contained **40% residual mtDNA copy number**. The authors noted that this was above their cited **30% residual-level threshold** for clinically manifest depletion. (pqac-00000010, pqac-00000019, pqac-00000034) | **PMID 28973171**; **2017**; [DOI 10.1093/hmg/ddx314](https://doi.org/10.1093/hmg/ddx314) | Supports reduced mtDNA abundance, possibly secondary to translation or OXPHOS dysfunction; it does **not conclusively demonstrate primary mtDNA-maintenance failure**. |
| **Affected muscle had combined respiratory-chain deficiency, especially complexes I and IV** | **Human muscle biochemistry:** complex I **6.7**, reference **13–24**; complex IV **48**, reference **120–220**, normalized to citrate synthase. Complexes II, III, and II+III were within or near the stated ranges. (pqac-00000003, pqac-00000009, pqac-00000033) | **PMID 28973171**; **2017**; [DOI 10.1093/hmg/ddx314](https://doi.org/10.1093/hmg/ddx314) | Objective evidence of tissue-specific combined OXPHOS dysfunction; one biopsy cannot establish population-level biochemical sensitivity or specificity. |
| **Patient fibroblasts did not reproduce the molecular phenotype under routine conditions** | **Patient-derived cells:** MRM2 abundance was normal; no detectable reduction of **Um1369 methylation** or mitochondrial translation was found. Galactose stress reduced mitochondrial mass and respiratory-chain activities. (pqac-00000025, pqac-00000036, pqac-00000039) | **PMID 28973171**; **2017**; [DOI 10.1093/hmg/ddx314](https://doi.org/10.1093/hmg/ddx314) | Demonstrates marked **tissue and metabolic-context dependence**; unstressed fibroblast methylation or translation is unsuitable as a stand-alone exclusion test. |
| **The patient-equivalent substitution impairs mitochondrial function in yeast** | **Yeast functional model:** corresponding **Mrm2 p.Gly259Arg** failed to fully restore oxygen consumption in an *mrm2*-null strain and failed substantially to restore U2791 2′-O-methylation. A later review reported approximately **30% less methylated 21S mt-rRNA** than with wild-type complementation. (pqac-00000017, pqac-00000019) | Garone et al.; **PMID 28973171**; **2017**; [DOI 10.1093/hmg/ddx314](https://doi.org/10.1093/hmg/ddx314). Magistrati et al.; **2023**; [DOI 10.3390/ijms24032178](https://doi.org/10.3390/ijms24032178) | Provides orthogonal pathogenicity evidence, but differences in residue numbering, ribosome biology, and temperature sensitivity limit direct extrapolation to humans. |
| **MRM2 is required for human mitoribosome assembly, translation, and respiration** | **Human-cell RNAi:** MRM2 depletion caused aberrant mitochondrial large-subunit assembly, diminished mitochondrial translation, and respiratory incompetence. (pqac-00000018) | Rorbach et al.; **2014**; [DOI 10.1091/mbc.e14-01-0014](https://doi.org/10.1091/mbc.e14-01-0014) | Establishes a cellular loss-of-function mechanism, but acute knockdown may not reproduce residual activity or tissue specificity of patient alleles. |
| **MRM2 has a methyltransferase-independent assembly-factor function** | **Human knockout, complementation, and cryo-EM:** catalytically inactive **K59A** and **D154A** variants did not restore U3039 methylation but restored MT-CO2 and mitochondrial translation. MRM2-null particles retained immature rRNA conformations and the MALSU1:L0R8F8:mtACP anti-association module. (pqac-00000020, pqac-00000028, pqac-00000029, pqac-00000037) | Rebelo-Guiomar et al.; **2022**; [DOI 10.1038/s41467-022-28503-5](https://doi.org/10.1038/s41467-022-28503-5) | Indicates that defective late mtLSU remodeling, rather than absent methylation alone, is probably the key upstream lesion. K59A and D154A are experimental probes, not reported patient variants. |
| **MRM2 loss causes neuronal lethality and muscular dysfunction in flies** | **Drosophila RNAi:** ubiquitous depletion caused developmental delay and predominantly late-pupal death; **pan-neuronal knockdown was lethal**; pan-muscular knockdown impaired startle-induced climbing, **P < 0.00001**. (pqac-00000023, pqac-00000029) | Rebelo-Guiomar et al.; **2022**; [DOI 10.1038/s41467-022-28503-5](https://doi.org/10.1038/s41467-022-28503-5) | Supports nervous-system and muscle vulnerability. RNAi is not an exact knock-in model of human p.Gly189Arg or other alleles. |
| **Later literature suggests phenotypic expansion to complex dystonia** | **Human report identified, but patient-level data were unavailable in the retrieved corpus:** Shafique et al., *MRM2 variants in families with complex dystonic syndromes*. Open Targets links **PMID 36002240** and two ClinVar records to MTDPS17 and MRM2. (pqac-00000000) | **PMID 36002240**; online **2022**, journal issue **2023**; [DOI 10.1136/jmg-2022-108521](https://doi.org/10.1136/jmg-2022-108521) | Supports broader phenotypic heterogeneity, but exact variants, patient count, frequencies, and outcomes should not be assigned without inspecting the primary full text. |
| **Recent sequencing yields contextualize diagnosis but are not MRM2-specific** | **Retrospective PMD cohort:** **297** individuals; overall molecular diagnostic yield **31.3%**, including **37%** for clinical exome sequencing and **15.8%** for mitochondrial-genome sequencing; 71 individuals had PMD. (pqac-00000041) | Ambrose et al.; **2024**; [DOI 10.1186/s13023-024-03437-x](https://doi.org/10.1186/s13023-024-03437-x) | Supports combined nuclear and mtDNA testing in suspected PMD, but provides **no MRM2-specific diagnostic yield, prevalence, or performance estimate**. |
| **The exact OMIM identifier requires independent verification** | A 2023 review labels MTDPS17 as **OMIM 606906**, but the retrieved evidence does not independently establish whether this number denotes the phenotype, the MRM2 gene entry, or a transcription error. (pqac-00000017, pqac-00000022) | Magistrati et al.; **2023**; [DOI 10.3390/ijms24032178](https://doi.org/10.3390/ijms24032178) | Do not populate an OMIM field from this secondary citation alone. **MONDO:0032815–MRM2** mapping is independently supported by Open Targets. (pqac-00000000) |


*Table: Disease-specific clinical and functional evidence is separated from broader mitochondrial-disease context, with quantitative findings and limitations. The matrix emphasizes the small human evidence base and avoids overinterpreting reduced mtDNA copy number or the ambiguous OMIM assignment.*