Combined oxidative phosphorylation deficiency 42

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Classifications

Harrison's Part

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Inheritance

1

Autosomal recessive inheritance HP:0000007

Both reported GATC families carry the same variant, c.233T>G (p.Met78Arg), in the homozygous state. The two families are reportedly unrelated but live in adjacent villages, which points to a shared founder haplotype rather than recurrent mutation, although no haplotype analysis was published. Co-segregation was confirmed in available affected and healthy siblings and parents across all five GatCAB families.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:30283131 SUPPORT Human Clinical

"In families 4 and 5, which are reportedly not related but reside in adjacent villages, we identified a homozygous missense variant in GATC: c.233T>G; p.Met78Arg."

Establishes homozygosity for a single recurrent allele in the two reported families.

PMID:30283131 SUPPORT Human Clinical

"Segregation analysis confirmed co-segregation among available affected and healthy siblings and parents in all families."

Confirms recessive segregation.

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Discussions and Knowledge Gaps

2

Could raising glutamine availability compensate for reduced GatCAB activity in a patient, as it appears to in patient fibroblasts?

KNOWLEDGE GAP OPEN coxpd42_glutamine_supplementation_untested

Attached to

pathophysiology#Impaired Transamidation of Glu-mt-tRNA(Gln)

This is the most obvious therapeutic idea the biology suggests, and it is entirely untested. The observation behind it is robust: patient fibroblasts charge mt-tRNA(Gln) at near-normal levels in glutamine-rich medium and fail only when glutamine is withdrawn, and complex I subassemblies become more prominent under withdrawal. Glutamine is the amide donor for the reaction, so substrate concentration plausibly compensates for reduced enzyme. Three things stand between that and a treatment, and this entry curates no treatment for exactly these reasons. First, the experiments show that supraphysiological culture glutamine masks the defect - not that physiologically achievable plasma glutamine would. Second, the cells in which the rescue is seen are fibroblasts, the tissue least affected in the disease; the heart is the tissue that must be rescued, and no cardiac model exists. Third, and most limiting, the chloramphenicol block-and-release experiment showed that translation keeps pace only briefly before charging falls behind sustained demand, which suggests the constraint is enzymatic throughput rather than substrate supply once demand is high. A cardiomyocyte never stops translating.

Proposed experiments

Glutamine dose-response across the physiological range

exp_coxpd42_glutamine_dose_response

Titrate glutamine across the physiological plasma range rather than comparing replete against absent, in patient fibroblasts and in cardiomyocytes differentiated from patient-derived induced pluripotent stem cells, with mt-tRNA(Gln) charging and mitochondrial translation as readouts. The question is whether any achievable concentration restores function, not whether an artificially high one does.

A cardiac model of GatC deficiency

exp_coxpd42_cardiomyocyte_model

Every mechanistic result in this disorder comes from fibroblasts, which are the least affected tissue and can look normal. Generate GATC p.Met78Arg cardiomyocytes, by editing or from patient cells, and determine whether the tissue gradient seen in post-mortem tissue is reproduced in vitro and whether the glutamine conditionality holds in a cell with high and continuous translational demand.

Does COXPD42 have a phenotypic range, or is everything known about it a property of one founder allele?

KNOWLEDGE GAP OPEN coxpd42_single_allele_single_report

Attached to

pathophysiology#Biallelic GATC Missense Variant

Everything in this entry describes five patients from two families in adjacent villages, all homozygous for the same GATC allele, reported in one paper. That is not a phenotype; it is one genotype observed several times. The distinction matters because the paper's own severity model predicts a range. It proposes that clinical severity tracks residual GatCAB activity, and that residual activity tracks the conservation of the mutated residue - which is how it explains the prenatal onset of the GATB and QRSL1 families against the infantile onset of the GATC ones. If that model is right, a GATC allele at a more conserved residue should produce a more severe, possibly prenatally lethal, disease, and a milder allele should produce something that survives infancy and has never been recognised as COXPD42. Neither has been reported. Nothing in the current literature can distinguish "COXPD42 is uniformly lethal in infancy" from "the one known GATC allele is lethal in infancy".

Proposed experiments

Functional assay for an allelic series of GATC variants

coxpd42_allelic_series_functional_assay

Build a quantitative assay of GatCAB activity - mt-tRNA(Gln) charging in a GATC-null background complemented with variant constructs - and use it to calibrate residual activity against the p.Met78Arg benchmark for GATC variants of unknown significance found in diagnostic sequencing. This would test the residual-activity model and make future GATC variants interpretable.

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Pathophysiology

7

Biallelic GATC Missense Variant

The initiating lesion is the homozygous GATC missense allele c.233T>G (p.Met78Arg), the only GATC variant reported in this disorder. That it is a missense rather than a null allele is not incidental. Complete loss of a tRNA-charging function is thought to be embryonically lethal, so a viable patient must retain some residual activity; every patient in the defining series carried at least one missense allele. The authors go further and propose that severity tracks the degree of conservation of the affected residue - the prenatal-onset GATB and QRSL1 families had variants at highly conserved residues, while the infantile-onset GATC families had a variant at a moderately conserved one. On that reading the later onset of COXPD42 relative to its GatCAB siblings is a consequence of a milder residual activity, not of the subunit affected.

GATC hgnc:25068

Genetic context variant_origin: GERMLINE zygosity: HOMOZYGOUS functional_impact_category: PARTIAL_LOSS_OF_FUNCTION

Homozygous germline missense. Curated as PARTIAL_LOSS_OF_FUNCTION rather than LOSS_OF_FUNCTION because residual activity is not an inference from the phenotype alone: GatC protein is reduced to about 20 percent of control rather than abolished, and the reasoning that complete loss would be embryonically lethal is stated explicitly in the source.

Downstream

GatCAB Trimer Destabilization

Show evidence (3 references)

PMID:30283131 SUPPORT Human Clinical

"In families 4 and 5, which are reportedly not related but reside in adjacent villages, we identified a homozygous missense variant in GATC: c.233T>G; p.Met78Arg."

Identifies the causal allele.

PMID:30283131 SUPPORT Human Clinical

"Due to their essential role in protein synthesis, residual enzyme activity characterizes disorders of tRNA synthetases, and complete loss-of-function is thought to be embryonically lethal"

The reasoning behind curating this as a partial rather than complete loss of function.

PMID:30283131 SUPPORT Human Clinical

"we observed a possible relation between clinical severity and the degree of amino acid conservation"

The proposed genotype-severity relationship, in the authors' own hedged terms.

GatCAB Trimer Destabilization

In the bacterial complex GatA carries the amidase function and GatB the kinase function, while GatC serves as a stabilizing linker between them. The patient data show that this architectural role is what fails. In GATC patient fibroblasts GatC protein falls to about 20 percent of control, and GatA and GatB fall by a comparable amount - even though neither of their genes is mutated. The likely explanation is that the individual subunits are unstable when not incorporated into the trimer. Crucially this is post-transcriptional: mRNA levels of QRSL1, GATB and GATC were unchanged in patient fibroblasts, so the loss of GatA and GatB is protein instability rather than a transcriptional response. A GATC lesion therefore behaves as a lesion of the whole amidotransferase, which is why a subunit with no catalytic activity of its own produces the same disease as the catalytic subunits.

Experimental models

GATC patient primary dermal fibroblasts PRIMARY CELL CULTURE The system in which GatC depletion to 20 percent of control, the parallel loss of GatA and GatB, and the unchanged transcript levels were measured.

Downstream

Impaired Transamidation of Glu-mt-tRNA(Gln)

Show evidence (3 references)

PMID:30283131 SUPPORT In Vitro

"In subject P4B with mutations in GATC, the steady state level of GatC in fibroblasts was decreased to 20% of controls (Fig. 3e), and the GatA and GatB protein levels were equally substantially decreased (Fig. 3e), probably due to the instability of the individual subunits when they are not..."

The central observation: a GATC variant depletes all three subunits, with the authors' own hedged explanation.

PMID:30283131 SUPPORT In Vitro

"we analyzed their mRNA levels in exponentially growing fibroblasts from patients P3A and P4B and found no significant changes in the transcriptional rate of the three genes compared to controls"

Excludes a transcriptional explanation and localises the effect to protein stability.

PMID:30283131 SUPPORT Other

"In the bacterial GatCAB complex, GatA and GatB possess the catalytic amidase and kinase functions, respectively, while GatC serves as a stabilizing linker between them."

Establishes GatC's structural rather than catalytic role, which is what makes trimer destabilization the mechanism.

Impaired Transamidation of Glu-mt-tRNA(Gln)

Mitochondria have no glutaminyl-tRNA synthetase. Glutaminyl mt-tRNA is therefore charged indirectly in two steps: EARS2 mischarges it with glutamate, and GatCAB transamidates the Glu-mt-tRNA(Gln) to Gln-mt-tRNA(Gln) using free glutamine as amide donor. The same paper closed the obvious escape route - cytoplasmic QARS had been reported in some databases as dual-localised, but QARS-GFP did not co-localise with TOM20, cellular fractionation showed no mitochondrial enrichment, and the trace that did fractionate with mitochondria was proteinase-K sensitive. Mitochondria depend exclusively on GatCAB. The defect is conditional on substrate supply, which is the single most important practical fact about this disorder. In standard glutamine-rich culture medium patient fibroblasts charge mt-tRNA(Gln) similarly to controls; only after three days without glutamine does charging fall. A normal-looking fibroblast assay run under standard conditions is therefore not evidence against the diagnosis.

glutaminyl-tRNA(Gln) formation by transamidation GO:0050567 ↓ DECREASED

Experimental models

GATC patient primary dermal fibroblasts PRIMARY CELL CULTURE Reproduces the charging defect, but conditionally: mt-tRNA(Gln) charging is similar to control in glutamine-replete medium and falls only after three days of glutamine withdrawal.

Downstream

Deficient Mitochondrial Protein Synthesis

Show evidence (3 references)

PMID:30283131 SUPPORT Other

"mt-tRNAGln is indirectly charged by a transamidation reaction involving the GatCAB aminoacyl-tRNA amidotransferase complex."

States the indirect charging pathway this node represents.

PMID:30283131 SUPPORT In Vitro

"Therefore, mitochondria are exclusively dependent on the GatCAB complex for appropriate charging of mt-tRNAGln with glutamine."

Establishes that no alternative charging route exists, which is why a GatCAB defect cannot be compensated.

PMID:30283131 SUPPORT In Vitro

"After 3 days in culture medium without glutamine, fibroblasts from P1A, P3A, and P4B show decreased glutamine charging of mt-tRNAGln compared to control fibroblasts."

Demonstrates the charging defect and its dependence on glutamine withdrawal. P4B is one of the GATC patients, so this is direct evidence for this disorder rather than for a sibling GatCAB defect.

Deficient Mitochondrial Protein Synthesis

Pulse labelling with radiolabelled methionine in the presence of emetine, to silence cytoplasmic translation, showed a strong and generalized defect in mtDNA-encoded protein synthesis in the GATC patient's fibroblasts. Because glutamine codons occur throughout the thirteen mtDNA-encoded proteins, the defect is general rather than selective for one complex - this is the reason the disease is a combined rather than an isolated respiratory chain deficiency. A subtlety worth preserving: the reduction in newly synthesized protein was not accompanied by reduced steady-state levels of assembled OXPHOS subunits in fibroblasts. Chloramphenicol chase experiments showed the explanation is increased stability of the existing subunits, which together with residual GatCAB activity masks the defect in that cell type. A chloramphenicol block and release experiment made the kinetics visible: translation resumes at a near-normal rate for a few hours on accumulated charged tRNA, then falls behind as charging fails to keep up with demand.

mitochondrial translation GO:0032543 ↓ DECREASED

Experimental models

GATC patient primary dermal fibroblasts PRIMARY CELL CULTURE Radiolabelled-methionine pulse labelling under emetine block showed a strong generalized mtDNA-encoded translation defect in these cells, and a chloramphenicol block-and-release experiment resolved its kinetics.

mouse GatA (Qrsl1) RNA interference cell model CELL LINE Knockdown produces a strong mitochondrial translation defect without affecting the stability of newly synthesized proteins, and mass spectrometry found no glutamate substituted at glutamine positions - so the failure mode is loss of translation, not mistranslation.

Downstream

Combined Respiratory Chain Enzyme Deficiency

Show evidence (3 references)

PMID:30283131 SUPPORT In Vitro

"revealed a strong and generalized mtDNA-encoded protein synthesis defect after a 90-min pulse in P4B (GATC) and in P3A (QRSL1) patients' fibroblasts"

Direct measurement of the translation defect in the GATC patient's cells.

PMID:30283131 SUPPORT In Vitro

"However, during continued translation, the rate of charging mt-tRNAGln with glutamine cannot keep up with the demand, and translation efficiency decreases"

Establishes that the defect is one of charging throughput under sustained demand rather than an absolute block.

PMID:30283131 SUPPORT In Vitro

"It is remarkable that this impairment of mitochondrial DNA-encoded protein synthesis correlates with no apparent changes in the steady state levels of representative OXPHOS proteins reflecting the assembled mitochondrial complexes"

Curated as PARTIAL: the translation defect is real but is not reflected in steady-state subunit levels in fibroblasts, which is a caution against using that readout to exclude the diagnosis.

Combined Respiratory Chain Enzyme Deficiency

All patients showed a combined deficiency with decreased activities of complexes I and IV and low or borderline-low complex III, varying between tissues. The pattern is exactly what a general mitochondrial translation defect predicts: complexes I, III, IV and V contain mtDNA-encoded subunits and are affected, while complex II, which is entirely nuclear-encoded, is not. Incompletely assembled complex I subcomplexes are demonstrable, and are more prominent when glutamine is withdrawn. Conformance note: this node conforms to the module's central bioenergetic node, but only in part. The module pairs decreased oxidative phosphorylation with increased reactive oxygen species. Decreased oxidative phosphorylation is directly evidenced in these patients; the reactive oxygen species arm is evidenced only in a mouse-cell GatA knockdown, not in GATC patients, and is curated on that model rather than asserted here. The module's upstream node - age-related mitochondrial damage and mtDNA mutation - does not apply to a primary nuclear-gene translation defect, which is why conformance is declared at this node alone.

oxidative phosphorylation GO:0006119 ↓ DECREASED

Downstream

Tissue-Selective Bioenergetic Failure of the Myocardium

Show evidence (2 references)

PMID:30283131 SUPPORT Human Clinical

"Analysis of the mitochondrial respiratory chain enzymes in all patients showed a combined deficiency with decreased activities of complexes I and IV, and low or borderline-low activity of complex III, that varied between the different tissues tested"

The defining biochemical finding and its tissue variability.

PMID:30283131 SUPPORT In Vitro

"observed subassemblies of complex I were present in heart and muscle (Fig. 4b), and were more prominent in fibroblasts when grown in medium without glutamine"

Links assembly failure to the glutamine-conditional nature of the defect.

Tissue-Selective Bioenergetic Failure of the Myocardium

The translation defect is not expressed equally across tissues. It is most pronounced in heart, less so in skeletal muscle, and nearly absent in fibroblasts - a gradient that tracks oxidative demand and explains why a cardiomyopathy rather than a multisystem encephalopathy is the presenting disease. Post-mortem cardiac tissue from a GATC patient shows the morphological signature of the compensation attempted: massive mitochondrial proliferation displacing the contractile elements on electron microscopy, and a corresponding increase in mitochondrial mass by SDHB immunostaining.

cardiac muscle cell CL:0000746

Downstream

Lethal Infantile Cardiomyopathy with Lactic Acidosis

Show evidence (4 references)

PMID:30283131 SUPPORT Human Clinical

"these findings are consistent with a defect in mitochondrial translation with marked tissue specific differences most pronounced in heart, less in skeletal muscle, and near absent in fibroblasts, but exaggerated upon glutamine reduction"

States the tissue gradient and its dependence on glutamine availability.

PMID:30283131 SUPPORT Human Clinical

"k Electron microscopy of the heart showed extensive mitochondrial proliferation displacing the contractile elements in patients"

Documents mitochondrial proliferation displacing contractile elements in cardiac tissue; the figure panel cited covers patient P4A, a GATC patient.

PMID:30283131 SUPPORT Human Clinical

"l SDHB immunostaining in patient P4A (GatC) showed massive increase in mitochondria in the heart"

Quantitative-histological confirmation of increased mitochondrial mass, named to a GATC patient specifically.

+ 1 more reference

Lethal Infantile Cardiomyopathy with Lactic Acidosis

The clinical endpoint. All five GATC patients presented between two and 5.5 months with cardiomyopathy and lactic acidosis, and none survived beyond 6.5 months. Anaemia accompanied the presentation in every GATC patient in whom it was assessed, which is notable because anaemia is a rare feature of mitochondrial disease; bone marrow examination showed no ringed sideroblasts. Liver dysfunction and mildly elevated creatine kinase were present in four of the five. The onset timing separates COXPD42 from its GatCAB siblings: the GATB and QRSL1 families in the same report had prenatal onset with hydrops or growth restriction and died within days, whereas the GATC families presented in infancy.

Show evidence (2 references)

PMID:30283131 SUPPORT Human Clinical

"The onset of symptoms was either prenatal (families 1 and 3) or infantile at 2–5 months (families 2, 4, and 5), and no child survived beyond 6.5 months."

Dates onset and death. Families 4 and 5 are the GATC families, so the infantile arm of this statement is the COXPD42 course.

PMID:30283131 SUPPORT Human Clinical

"Anemia, which is a rare symptom in mitochondrial disorders11–13, was frequently present, ranging in severity from mild to severe prenatal anemia requiring intrauterine transfusions. The bone marrow biopsy did not show ringed sideroblasts in any of the subjects."

Documents anaemia as an unusual accompanying feature and excludes sideroblastic anaemia.

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Pathograph

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Phenotypes

6

Blood 1

Anemia HP:0001903

Show evidence (1 reference)

PMID:30283131 SUPPORT Human Clinical

"Anemia, which is a rare symptom in mitochondrial disorders11–13, was frequently present, ranging in severity from mild to severe prenatal anemia requiring intrauterine transfusions."

Documents anaemia and notes its rarity in this disease class.

Cardiovascular 1

Cardiomyopathy HP:0001638

Show evidence (1 reference)

PMID:30283131 SUPPORT Human Clinical

"We studied five families (Fig. 1b–f) with infants predominantly exhibiting severe cardiomyopathy and fatal lactic acidosis, which raised suspicion of mitochondrial disease."

Establishes cardiomyopathy as the presenting feature across the series.

Digestive 1

Liver Dysfunction Decreased liver function HP:0001410

Show evidence (1 reference)

PMID:30283131 SUPPORT Human Clinical

"Additional features present in several subjects include liver dysfunction, mildly elevated creatine kinase levels, and hydropic features including pericardial effusion."

Documents liver dysfunction among the accompanying features.

Metabolism 2

Lactic Acidosis HP:0003128

Show evidence (1 reference)

PMID:30283131 SUPPORT Human Clinical

"We studied five families (Fig. 1b–f) with infants predominantly exhibiting severe cardiomyopathy and fatal lactic acidosis, which raised suspicion of mitochondrial disease."

Documents lactic acidosis alongside the cardiomyopathy.

Elevated Creatine Kinase Elevated circulating creatine kinase concentration HP:0003236

Show evidence (1 reference)

PMID:30283131 SUPPORT Human Clinical

"Additional features present in several subjects include liver dysfunction, mildly elevated creatine kinase levels, and hydropic features including pericardial effusion."

Documents the mildly elevated creatine kinase.

Other 1

Infantile Onset with Death Before Seven Months

Onset: INFANTILE

No `term:` is bound. The candidate HPO terms for onset timing (HP:0003593 Infantile onset) and for early death (HP:0001522 Death in infancy) sit under Clinical modifier and Age of death respectively, outside the `PhenotypeTerm` dynamic enum, which is reachable only from the phenotypic-abnormality root. The structured `onset` descriptor carries the timing instead.

Show evidence (1 reference)

PMID:30283131 SUPPORT Human Clinical

"The onset of symptoms was either prenatal (families 1 and 3) or infantile at 2–5 months (families 2, 4, and 5), and no child survived beyond 6.5 months."

Dates onset and death, with families 4 and 5 being the GATC families.

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Genetic Associations

1

GATC

Gene: GATC hgnc:25068 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (3 references)

PMID:30283131 SUPPORT Other

"This latter conversion is performed by GatCAB, the glutamyl-tRNAGln amidotransferase protein complex, that consists of three subunits: GatA encoded by QRSL1, GatB encoded by GATB, and GatC encoded by GATC"

Establishes the subunit-to-gene mapping of the complex.

PMID:30283131 SUPPORT Human Clinical

"Here, we describe nine patients from five families with genetic defects in a GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a lethal metabolic cardiomyopathy syndrome."

Establishes that all three subunit genes produce the same clinical syndrome, which is the basis for testing them together.

PMID:30283131 SUPPORT Other

"it is first charged with glutamic acid (Glu) by mitochondrial glutamyl-tRNA synthetase (EARS2), after which the Glu-mt-tRNAGln is transamidated into Gln-mt-tRNAGln, using free glutamine as an amide donor"

Places EARS2 upstream of GatCAB in the same pathway.

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Biochemical Markers

2

Respiratory Chain Enzyme Activities

Show evidence (1 reference)

PMID:30283131 SUPPORT Human Clinical

"In contrast to the fibroblasts of the GatA and GatC patients, clear respiratory chain enzyme deficiencies were observed in the fibroblasts of the GatB patients."

The subunit-specific difference in fibroblast expressivity that makes fibroblast testing unreliable for GATC.

Blood Lactate

Show evidence (1 reference)

PMID:30283131 SUPPORT Human Clinical

"infants predominantly exhibiting severe cardiomyopathy and fatal lactic acidosis, which raised suspicion of mitochondrial disease"

Establishes lactic acidosis as the trigger for mitochondrial investigation.

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Diagnosis

2

Sequencing of the Three GatCAB Subunit Genes

Molecular diagnosis is the practical route, because the three GatCAB disorders are clinically indistinguishable and the biochemical workup in fibroblasts can be normal. All five families in the defining series were solved by whole-exome sequencing. A targeted panel should include QRSL1, GATB and GATC together, and EARS2 as the upstream step of the same pathway.

Show evidence (1 reference)

PMID:30283131 SUPPORT Human Clinical

"Whole exome sequencing (WES) analysis in these families uncovered rare pathogenic variants in the three genes encoding the GatCAB complex subunits, in-line with autosomal recessive inheritance"

Documents exome sequencing as the diagnostic route in every reported family.

Respiratory Chain Analysis in Heart or Skeletal Muscle

If a tissue enzyme assay is done, the tissue matters. Deficiencies were clear in the fibroblasts of GatB patients but not of GatA or GatC patients, so a normal fibroblast panel cannot exclude COXPD42; heart and skeletal muscle carry the deficit. Where only fibroblasts are available, glutamine withdrawal unmasks the defect.

Show evidence (1 reference)

PMID:30283131 SUPPORT Human Clinical

"In contrast to the fibroblasts of the GatA and GatC patients, clear respiratory chain enzyme deficiencies were observed in the fibroblasts of the GatB patients."

The basis for preferring heart or muscle over fibroblasts in this disorder.

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Progression

1

Lethal infantile course

Onset at two to 5.5 months with cardiomyopathy and lactic acidosis, death by 6.5 months in every reported patient. No treatment altered the course. The prognosis is not specific to GATC - mitochondrial cardiomyopathy in children carries a markedly worse survival than mitochondrial disease without cardiomyopathy, with ten-year survival of 18 percent against 67 percent in one 137-patient cohort, and defects in the sibling gene QRSL1 appear among the deaths within the first year in that cohort.

Show evidence (2 references)

PMID:30283131 SUPPORT Human Clinical

"The onset of symptoms was either prenatal (families 1 and 3) or infantile at 2–5 months (families 2, 4, and 5), and no child survived beyond 6.5 months."

The course in the reported patients.

PMID:30642647 SUPPORT Human Clinical

"Ten-year Kaplan-Meier estimates of overall survival were 18 and 67%, respectively."

Curated as PARTIAL: this cohort contains no GATC patients, so it supplies the general prognosis of paediatric mitochondrial cardiomyopathy as context rather than a COXPD42-specific survival estimate.

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Prevalence

1

Worldwide

Cases In Literature Ultra Rare

Five patients from two families, all homozygous for the same GATC allele and all reported in a single 2018 paper. No population estimate exists and none can be derived. The two families reside in adjacent villages, so even the published count may reflect a single local founder allele rather than the disorder's true distribution.

Show evidence (1 reference)

PMID:30283131 SUPPORT Human Clinical

"In families 4 and 5, which are reportedly not related but reside in adjacent villages, we identified a homozygous missense variant in GATC: c.233T>G; p.Met78Arg."

The two families that constitute the entire published series, and their geographic proximity.

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Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from Combined oxidative phosphorylation deficiency 42:

Other mitochondrial aminoacylation and translation defects

Overlapping Features COXPD42 is the last entry in a decade-long series of mitochondrial aminoacylation disorders that began with DARS2, and it sits inside a larger group of paediatric mitochondrial cardiomyopathies caused by defects in mtDNA-encoded protein translation. Members of that group are separated by genotype rather than by phenotype; the presence of cardiomyopathy with lactic acidosis in infancy narrows the search to the group but not within it.

Show evidence (2 references)

PMID:30283131 SUPPORT Other

"Our study completes a decade of investigations on mitochondrial aminoacylation disorders, starting with DARS2 and ending with the GatCAB complex."

Places COXPD42 within the aminoacylation-disorder group.

PMID:29440775 SUPPORT Human Clinical

"Defects in mtDNA-encoded protein translation lead to severe pediatric cardiomyopathy and brain disease with OXPHOS abnormalities."

Establishes the wider group of mtDNA-translation defects presenting as paediatric cardiomyopathy, within which COXPD42 must be distinguished genetically. Note this series' patients also had early-onset brain disease, which was not reported in the GATC patients.

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Experimental Models

2

GATC patient primary dermal fibroblasts PRIMARY_CELL_CULTURE

Primary skin fibroblasts from patient P4B, homozygous for GATC p.Met78Arg. They are the system in which nearly all the mechanism in this entry was established, and they are also the clearest illustration of why fibroblasts are a poor diagnostic tissue for this disorder: under standard culture conditions their respiratory chain enzymes and steady-state OXPHOS subunit levels are normal, and the defect appears only when glutamine is withdrawn or translational demand is sustained.

Pathograph links

GatCAB Trimer Destabilization measures fidelity: high The system in which GatC depletion to 20 percent of control, the parallel loss of GatA and GatB, and the unchanged transcript levels were measured.

Limitations: Fibroblast is not the affected tissue. Whether the same degree of subunit depletion occurs in cardiomyocytes has not been measured.

Readouts

GatC steady-state protein level

Direction: DECREASED

Interpretation: Reduction to about a fifth of control, with GatA and GatB falling in parallel, is the measurement establishing trimer destabilization.

Show evidence (1 reference)

PMID:30283131 SUPPORT In Vitro

"Western blot analysis of control and patient P4B fibroblasts showed a strong reduction in GatC protein, and also reduced levels of GatA and GatB protein, with porin as loading control."

The western blot measurement underlying this readout.

Show evidence (1 reference)

PMID:30283131 SUPPORT In Vitro

"In subject P4B with mutations in GATC, the steady state level of GatC in fibroblasts was decreased to 20% of controls"

Establishes the model as informative for the trimer-destabilization node.

Impaired Transamidation of Glu-mt-tRNA(Gln) partially recapitulates fidelity: moderate Reproduces the charging defect, but conditionally: mt-tRNA(Gln) charging is similar to control in glutamine-replete medium and falls only after three days of glutamine withdrawal.

Limitations: The conditionality is the limitation. A negative result in glutamine-replete medium says nothing about the genotype, so this model must be run under glutamine restriction to be informative.

Readouts

mt-tRNA(Gln) aminoacylation by northern blot

Direction: DECREASED

Interpretation: Reduced charging under glutamine withdrawal, against normal charging in replete medium.

Show evidence (1 reference)

PMID:30283131 SUPPORT In Vitro

"After 3 days in culture medium without glutamine, fibroblasts from P1A, P3A, and P4B show decreased glutamine charging of mt-tRNAGln compared to control fibroblasts."

The northern blot measurement underlying this readout.

Show evidence (1 reference)

PMID:30283131 SUPPORT In Vitro

"While aminoacylation of mt-tRNAGln appears to show only minor changes in comparison to controls when patient cells are grown under standard conditions with high concentrations of the GatCAB substrate glutamine in the culture medium"

Curated as PARTIAL because the model reproduces the defect only under glutamine restriction.

Deficient Mitochondrial Protein Synthesis recapitulates fidelity: high Radiolabelled-methionine pulse labelling under emetine block showed a strong generalized mtDNA-encoded translation defect in these cells, and a chloramphenicol block-and-release experiment resolved its kinetics.

Limitations: The translation defect does not translate into reduced steady-state OXPHOS subunit levels in this cell type, because the existing subunits are stabilised - so the model reproduces the primary defect but not its usual downstream readout.

Readouts

De novo mtDNA-encoded protein synthesis

Direction: DECREASED

Interpretation: Reduced incorporation of labelled methionine into mitochondrially translated peptides.

Show evidence (1 reference)

PMID:30283131 SUPPORT In Vitro

"a Decrease in newly synthesized peptides in GATA and GATC patient fibroblasts compared to control as determined by pulse labeling."

The pulse-labelling measurement underlying this readout. Note the figure legend writes "GATA" where the gene is QRSL1 (GatA); the GATC arm is the one relevant here.

Show evidence (1 reference)

PMID:30283131 SUPPORT In Vitro

"revealed a strong and generalized mtDNA-encoded protein synthesis defect after a 90-min pulse in P4B (GATC) and in P3A (QRSL1) patients' fibroblasts"

Establishes the model as informative for the translation node.

mouse GatA (Qrsl1) RNA interference cell model CELL_LINE

Knockdown of mouse GatA in mouse cells, published four years before the human disorder was described. It is the source of two claims that the patient data do not supply: that GatCAB loss raises reactive oxygen species, and that mischarged Glu-mt-tRNA(Gln) is rejected by the translation apparatus rather than being incorporated as glutamate.

Pathograph links

Deficient Mitochondrial Protein Synthesis recapitulates fidelity: moderate Knockdown produces a strong mitochondrial translation defect without affecting the stability of newly synthesized proteins, and mass spectrometry found no glutamate substituted at glutamine positions - so the failure mode is loss of translation, not mistranslation.

Limitations: Different subunit (GatA, not GatC), different species, and an acute knockdown rather than a hypomorphic germline missense allele. It cannot speak to the residual-activity question that governs severity in patients.

Readouts

Reactive oxygen species level

Direction: INCREASED

Interpretation: The only evidence in this entry for an oxidative-stress component; it is from mouse cells with a different subunit knocked down, not from GATC patients.

Show evidence (1 reference)

PMID:24579914 SUPPORT In Vitro

"As a result, interfered cells present an impairment of the oxidative phosphorylation system and a significant increase in ROS (reactive oxygen species) levels."

The measurement underlying this readout.

Show evidence (1 reference)

PMID:24579914 SUPPORT In Vitro

"we demonstrate that mgatA (mouse GatA) interference in mouse cells produces a strong defect in mitochondrial translation without affecting the stability of the newly synthesized proteins"

Establishes the translation defect on knockdown of a GatCAB subunit.

{ }

Source YAML

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name: Combined oxidative phosphorylation deficiency 42
creation_date: "2026-08-27T00:00:00Z"
description: >-
  Combined oxidative phosphorylation deficiency 42 (COXPD42) is a lethal
  infantile mitochondrial cardiomyopathy caused by biallelic variants in GATC.
  GATC encodes GatC, the smallest subunit of the mitochondrial glutamyl-tRNA(Gln)
  amidotransferase GatCAB. Mitochondria have no glutaminyl-tRNA synthetase, so
  glutaminyl mt-tRNA cannot be charged directly: it is first mischarged with
  glutamate by EARS2 and then transamidated to Gln-mt-tRNA(Gln) by GatCAB, using
  free glutamine as the amide donor. GatCAB is the sole route, so its failure
  compromises the translation of all thirteen mtDNA-encoded proteins and produces
  a combined respiratory chain deficiency rather than a single-complex one.

  Two features distinguish COXPD42 from a generic mitochondrial translation
  defect. The biochemical phenotype is conditional on glutamine supply - patient
  fibroblasts charge mt-tRNA(Gln) almost normally in standard glutamine-rich
  medium and fail only when glutamine is withdrawn or when translational demand
  is sustained - which is both a diagnostic trap and the origin of an untested
  therapeutic idea. And the tissue distribution is steeply skewed: the heart is
  devastated, skeletal muscle less so, and cultured fibroblasts look almost
  normal. All five reported GATC patients came from two families in adjacent
  villages, carried the same homozygous p.Met78Arg allele, and died by 6.5
  months.
category: Mendelian
parents:
- hereditary disease
synonyms:
- COXPD42
- GATC-related mitochondrial cardiomyopathy
- GatC deficiency
disease_term:
  preferred_term: Combined oxidative phosphorylation deficiency 42
  term:
    id: MONDO:0030008
    label: combined oxidative phosphorylation deficiency 42
classifications:
  harrisons_chapter:
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:30283131
      reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Whole exome sequencing (WES) analysis in these families uncovered rare
        pathogenic variants in the three genes encoding the GatCAB complex
        subunits, in-line with autosomal recessive inheritance
      explanation: >-
        Establishes a single-gene Mendelian basis identified by exome sequencing
        with recessive segregation.
  - classification_value: CARDIOVASCULAR
    evidence:
    - reference: PMID:30283131
      reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We studied five families (Fig. 1b–f) with infants predominantly exhibiting
        severe cardiomyopathy and fatal lactic acidosis, which raised suspicion of
        mitochondrial disease.
      explanation: >-
        Cardiomyopathy is the presenting and lethal manifestation.
references:
- reference: PMID:30283131
  title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
- reference: PMID:24579914
  title: "Glutamyl-tRNAGln amidotransferase is essential for mammalian mitochondrial translation in vivo."
- reference: PMID:30642647
  title: "Cardiomyopathy in children with mitochondrial disease: Prognosis and genetic background."
- reference: PMID:29440775
  title: "Genetic defects in mtDNA-encoded protein translation cause pediatric, mitochondrial cardiomyopathy with early-onset brain disease."
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Both reported GATC families carry the same variant, c.233T>G (p.Met78Arg), in
    the homozygous state. The two families are reportedly unrelated but live in
    adjacent villages, which points to a shared founder haplotype rather than
    recurrent mutation, although no haplotype analysis was published.
    Co-segregation was confirmed in available affected and healthy siblings and
    parents across all five GatCAB families.
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In families 4 and 5, which are reportedly not related but reside in adjacent
      villages, we identified a homozygous missense variant in GATC: c.233T>G;
      p.Met78Arg.
    explanation: >-
      Establishes homozygosity for a single recurrent allele in the two reported
      families.
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Segregation analysis confirmed co-segregation among available affected and
      healthy siblings and parents in all families.
    explanation: >-
      Confirms recessive segregation.
pathophysiology:
- name: Biallelic GATC Missense Variant
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    The initiating lesion is the homozygous GATC missense allele c.233T>G
    (p.Met78Arg), the only GATC variant reported in this disorder. That it is a
    missense rather than a null allele is not incidental. Complete loss of a
    tRNA-charging function is thought to be embryonically lethal, so a viable
    patient must retain some residual activity; every patient in the defining
    series carried at least one missense allele. The authors go further and
    propose that severity tracks the degree of conservation of the affected
    residue - the prenatal-onset GATB and QRSL1 families had variants at highly
    conserved residues, while the infantile-onset GATC families had a variant at
    a moderately conserved one. On that reading the later onset of COXPD42
    relative to its GatCAB siblings is a consequence of a milder residual
    activity, not of the subunit affected.
  genes:
  - preferred_term: GATC
    term:
      id: hgnc:25068
      label: GATC
  genetic_context:
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    variant_origin: GERMLINE
    zygosity: HOMOZYGOUS
    description: >-
      Homozygous germline missense. Curated as PARTIAL_LOSS_OF_FUNCTION rather
      than LOSS_OF_FUNCTION because residual activity is not an inference from
      the phenotype alone: GatC protein is reduced to about 20 percent of control
      rather than abolished, and the reasoning that complete loss would be
      embryonically lethal is stated explicitly in the source.
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In families 4 and 5, which are reportedly not related but reside in adjacent
      villages, we identified a homozygous missense variant in GATC: c.233T>G;
      p.Met78Arg.
    explanation: >-
      Identifies the causal allele.
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Due to their essential role in protein synthesis, residual enzyme activity
      characterizes disorders of tRNA synthetases, and complete loss-of-function
      is thought to be embryonically lethal
    explanation: >-
      The reasoning behind curating this as a partial rather than complete loss
      of function.
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we observed a possible relation between clinical severity and the degree of
      amino acid conservation
    explanation: >-
      The proposed genotype-severity relationship, in the authors' own hedged
      terms.
  downstream:
  - target: GatCAB Trimer Destabilization
    causal_link_type: DIRECT
- name: GatCAB Trimer Destabilization
  biological_scale: MOLECULAR
  role: central_effector
  mechanism_confidence: ESTABLISHED
  description: >-
    In the bacterial complex GatA carries the amidase function and GatB the
    kinase function, while GatC serves as a stabilizing linker between them. The
    patient data show that this architectural role is what fails. In GATC patient
    fibroblasts GatC protein falls to about 20 percent of control, and GatA and
    GatB fall by a comparable amount - even though neither of their genes is
    mutated. The likely explanation is that the individual subunits are unstable
    when not incorporated into the trimer.

    Crucially this is post-transcriptional: mRNA levels of QRSL1, GATB and GATC
    were unchanged in patient fibroblasts, so the loss of GatA and GatB is
    protein instability rather than a transcriptional response. A GATC lesion
    therefore behaves as a lesion of the whole amidotransferase, which is why a
    subunit with no catalytic activity of its own produces the same disease as
    the catalytic subunits.
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In subject P4B with mutations in GATC, the steady state level of GatC in
      fibroblasts was decreased to 20% of controls (Fig. 3e), and the GatA and
      GatB protein levels were equally substantially decreased (Fig. 3e),
      probably due to the instability of the individual subunits when they are not
      incorporated in the GatCAB trimer.
    explanation: >-
      The central observation: a GATC variant depletes all three subunits, with
      the authors' own hedged explanation.
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      we analyzed their mRNA levels in exponentially growing fibroblasts from
      patients P3A and P4B and found no significant changes in the transcriptional
      rate of the three genes compared to controls
    explanation: >-
      Excludes a transcriptional explanation and localises the effect to protein
      stability.
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In the bacterial GatCAB complex, GatA and GatB possess the catalytic amidase
      and kinase functions, respectively, while GatC serves as a stabilizing
      linker between them.
    explanation: >-
      Establishes GatC's structural rather than catalytic role, which is what
      makes trimer destabilization the mechanism.
  downstream:
  - target: Impaired Transamidation of Glu-mt-tRNA(Gln)
    causal_link_type: DIRECT
- name: Impaired Transamidation of Glu-mt-tRNA(Gln)
  biological_scale: MOLECULAR
  role: effector
  mechanism_confidence: ESTABLISHED
  description: >-
    Mitochondria have no glutaminyl-tRNA synthetase. Glutaminyl mt-tRNA is
    therefore charged indirectly in two steps: EARS2 mischarges it with
    glutamate, and GatCAB transamidates the Glu-mt-tRNA(Gln) to Gln-mt-tRNA(Gln)
    using free glutamine as amide donor. The same paper closed the obvious
    escape route - cytoplasmic QARS had been reported in some databases as
    dual-localised, but QARS-GFP did not co-localise with TOM20, cellular
    fractionation showed no mitochondrial enrichment, and the trace that did
    fractionate with mitochondria was proteinase-K sensitive. Mitochondria depend
    exclusively on GatCAB.

    The defect is conditional on substrate supply, which is the single most
    important practical fact about this disorder. In standard glutamine-rich
    culture medium patient fibroblasts charge mt-tRNA(Gln) similarly to controls;
    only after three days without glutamine does charging fall. A normal-looking
    fibroblast assay run under standard conditions is therefore not evidence
    against the diagnosis.
  molecular_functions:
  - preferred_term: glutaminyl-tRNA(Gln) formation by transamidation
    modifier: DECREASED
    term:
      id: GO:0050567
      label: glutaminyl-tRNA synthase (glutamine-hydrolyzing) activity
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      mt-tRNAGln is indirectly charged by a transamidation reaction involving the
      GatCAB aminoacyl-tRNA amidotransferase complex.
    explanation: >-
      States the indirect charging pathway this node represents.
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Therefore, mitochondria are exclusively dependent on the GatCAB complex for
      appropriate charging of mt-tRNAGln with glutamine.
    explanation: >-
      Establishes that no alternative charging route exists, which is why a
      GatCAB defect cannot be compensated.
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      After 3 days in culture medium without glutamine, fibroblasts from P1A,
      P3A, and P4B show decreased glutamine charging of mt-tRNAGln compared to
      control fibroblasts.
    explanation: >-
      Demonstrates the charging defect and its dependence on glutamine
      withdrawal. P4B is one of the GATC patients, so this is direct evidence for
      this disorder rather than for a sibling GatCAB defect.
  downstream:
  - target: Deficient Mitochondrial Protein Synthesis
    causal_link_type: DIRECT
- name: Deficient Mitochondrial Protein Synthesis
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: ESTABLISHED
  description: >-
    Pulse labelling with radiolabelled methionine in the presence of emetine, to
    silence cytoplasmic translation, showed a strong and generalized defect in
    mtDNA-encoded protein synthesis in the GATC patient's fibroblasts. Because
    glutamine codons occur throughout the thirteen mtDNA-encoded proteins, the
    defect is general rather than selective for one complex - this is the reason
    the disease is a combined rather than an isolated respiratory chain
    deficiency.

    A subtlety worth preserving: the reduction in newly synthesized protein was
    not accompanied by reduced steady-state levels of assembled OXPHOS subunits
    in fibroblasts. Chloramphenicol chase experiments showed the explanation is
    increased stability of the existing subunits, which together with residual
    GatCAB activity masks the defect in that cell type. A chloramphenicol block
    and release experiment made the kinetics visible: translation resumes at a
    near-normal rate for a few hours on accumulated charged tRNA, then falls
    behind as charging fails to keep up with demand.
  biological_processes:
  - preferred_term: mitochondrial translation
    modifier: DECREASED
    term:
      id: GO:0032543
      label: mitochondrial translation
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      revealed a strong and generalized mtDNA-encoded protein synthesis defect
      after a 90-min pulse in P4B (GATC) and in P3A (QRSL1) patients' fibroblasts
    explanation: >-
      Direct measurement of the translation defect in the GATC patient's cells.
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      However, during continued translation, the rate of charging mt-tRNAGln with
      glutamine cannot keep up with the demand, and translation efficiency
      decreases
    explanation: >-
      Establishes that the defect is one of charging throughput under sustained
      demand rather than an absolute block.
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      It is remarkable that this impairment of mitochondrial DNA-encoded protein
      synthesis correlates with no apparent changes in the steady state levels of
      representative OXPHOS proteins reflecting the assembled mitochondrial
      complexes
    explanation: >-
      Curated as PARTIAL: the translation defect is real but is not reflected in
      steady-state subunit levels in fibroblasts, which is a caution against using
      that readout to exclude the diagnosis.
  downstream:
  - target: Combined Respiratory Chain Enzyme Deficiency
    causal_link_type: DIRECT
- name: Combined Respiratory Chain Enzyme Deficiency
  biological_scale: CELLULAR
  role: effector
  mechanism_confidence: ESTABLISHED
  conforms_to: "mitochondrial_dysfunction#Bioenergetic Decline and Oxidative Stress"
  description: >-
    All patients showed a combined deficiency with decreased activities of
    complexes I and IV and low or borderline-low complex III, varying between
    tissues. The pattern is exactly what a general mitochondrial translation
    defect predicts: complexes I, III, IV and V contain mtDNA-encoded subunits and
    are affected, while complex II, which is entirely nuclear-encoded, is not.
    Incompletely assembled complex I subcomplexes are demonstrable, and are more
    prominent when glutamine is withdrawn.

    Conformance note: this node conforms to the module's central bioenergetic
    node, but only in part. The module pairs decreased oxidative phosphorylation
    with increased reactive oxygen species. Decreased oxidative phosphorylation
    is directly evidenced in these patients; the reactive oxygen species arm is
    evidenced only in a mouse-cell GatA knockdown, not in GATC patients, and is
    curated on that model rather than asserted here. The module's upstream node -
    age-related mitochondrial damage and mtDNA mutation - does not apply to a
    primary nuclear-gene translation defect, which is why conformance is declared
    at this node alone.
  biological_processes:
  - preferred_term: oxidative phosphorylation
    modifier: DECREASED
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Analysis of the mitochondrial respiratory chain enzymes in all patients
      showed a combined deficiency with decreased activities of complexes I and
      IV, and low or borderline-low activity of complex III, that varied between
      the different tissues tested
    explanation: >-
      The defining biochemical finding and its tissue variability.
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      observed subassemblies of complex I were present in heart and muscle (Fig.
      4b), and were more prominent in fibroblasts when grown in medium without
      glutamine
    explanation: >-
      Links assembly failure to the glutamine-conditional nature of the defect.
  downstream:
  - target: Tissue-Selective Bioenergetic Failure of the Myocardium
    causal_link_type: DIRECT
- name: Tissue-Selective Bioenergetic Failure of the Myocardium
  biological_scale: TISSUE
  role: effector
  mechanism_confidence: ESTABLISHED
  description: >-
    The translation defect is not expressed equally across tissues. It is most
    pronounced in heart, less so in skeletal muscle, and nearly absent in
    fibroblasts - a gradient that tracks oxidative demand and explains why a
    cardiomyopathy rather than a multisystem encephalopathy is the presenting
    disease. Post-mortem cardiac tissue from a GATC patient shows the
    morphological signature of the compensation attempted: massive mitochondrial
    proliferation displacing the contractile elements on electron microscopy, and
    a corresponding increase in mitochondrial mass by SDHB immunostaining.
  cell_types:
  - preferred_term: cardiac muscle cell
    term:
      id: CL:0000746
      label: cardiac muscle cell
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      these findings are consistent with a defect in mitochondrial translation
      with marked tissue specific differences most pronounced in heart, less in
      skeletal muscle, and near absent in fibroblasts, but exaggerated upon
      glutamine reduction
    explanation: >-
      States the tissue gradient and its dependence on glutamine availability.
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      k Electron microscopy of the heart showed extensive mitochondrial
      proliferation displacing the contractile elements in patients
    explanation: >-
      Documents mitochondrial proliferation displacing contractile elements in
      cardiac tissue; the figure panel cited covers patient P4A, a GATC patient.
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      l SDHB immunostaining in patient P4A (GatC) showed massive increase in
      mitochondria in the heart
    explanation: >-
      Quantitative-histological confirmation of increased mitochondrial mass,
      named to a GATC patient specifically.
  - reference: PMID:29440775
    reference_title: "Genetic defects in mtDNA-encoded protein translation cause pediatric, mitochondrial cardiomyopathy with early-onset brain disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This suggests that the heart and brain are particularly sensitive to defects
      in mitochondrial protein synthesis during late embryonic or early postnatal
      development, probably due to the massive mitochondrial biogenesis occurring
      at that stage.
    explanation: >-
      Offers a developmental explanation for why a general translation defect
      presents as cardiac disease, in the source's own hedged terms. It comes from
      a different set of translation-defect genes, not from GATC patients.
  downstream:
  - target: Lethal Infantile Cardiomyopathy with Lactic Acidosis
    causal_link_type: DIRECT
- name: Lethal Infantile Cardiomyopathy with Lactic Acidosis
  biological_scale: ORGANISM
  role: consequence
  mechanism_confidence: ESTABLISHED
  description: >-
    The clinical endpoint. All five GATC patients presented between two and 5.5
    months with cardiomyopathy and lactic acidosis, and none survived beyond 6.5
    months. Anaemia accompanied the presentation in every GATC patient in whom it
    was assessed, which is notable because anaemia is a rare feature of
    mitochondrial disease; bone marrow examination showed no ringed sideroblasts.
    Liver dysfunction and mildly elevated creatine kinase were present in four of
    the five.

    The onset timing separates COXPD42 from its GatCAB siblings: the GATB and
    QRSL1 families in the same report had prenatal onset with hydrops or growth
    restriction and died within days, whereas the GATC families presented in
    infancy.
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The onset of symptoms was either prenatal (families 1 and 3) or infantile at
      2–5 months (families 2, 4, and 5), and no child survived beyond 6.5 months.
    explanation: >-
      Dates onset and death. Families 4 and 5 are the GATC families, so the
      infantile arm of this statement is the COXPD42 course.
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anemia, which is a rare symptom in mitochondrial disorders11–13, was
      frequently present, ranging in severity from mild to severe prenatal anemia
      requiring intrauterine transfusions. The bone marrow biopsy did not show
      ringed sideroblasts in any of the subjects.
    explanation: >-
      Documents anaemia as an unusual accompanying feature and excludes
      sideroblastic anaemia.
phenotypes:
- category: Cardiovascular
  name: Cardiomyopathy
  description: >-
    Present in all five reported GATC patients and the manifestation that kills
    them. Histology shows pericardial clearing on light microscopy and, on
    electron microscopy, mitochondrial proliferation displacing the contractile
    apparatus. No frequency band is assigned: with five patients from two
    families sharing one allele, a percentage would imply a precision the series
    cannot support.
  phenotype_term:
    preferred_term: Cardiomyopathy
    term:
      id: HP:0001638
      label: Cardiomyopathy
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We studied five families (Fig. 1b–f) with infants predominantly exhibiting
      severe cardiomyopathy and fatal lactic acidosis, which raised suspicion of
      mitochondrial disease.
    explanation: >-
      Establishes cardiomyopathy as the presenting feature across the series.
- category: Metabolic
  name: Lactic Acidosis
  description: >-
    Accompanies the cardiomyopathy in every reported patient and is the
    biochemical signature that raises suspicion of mitochondrial disease. It is
    the expected consequence of a combined respiratory chain deficiency forcing
    anaerobic glycolysis.
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: Lactic acidosis
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We studied five families (Fig. 1b–f) with infants predominantly exhibiting
      severe cardiomyopathy and fatal lactic acidosis, which raised suspicion of
      mitochondrial disease.
    explanation: >-
      Documents lactic acidosis alongside the cardiomyopathy.
- category: Hematologic
  name: Anemia
  description: >-
    Unusual enough in mitochondrial disease that the reporting authors flag it,
    and present in every GATC patient in whom it was recorded. Severity ranged
    from mild to severe prenatal anaemia requiring intrauterine transfusion,
    though the severe prenatal end of that range was seen in the prenatal-onset
    GATB and QRSL1 families rather than in the GATC ones. Bone marrow biopsy
    showed no ringed sideroblasts in any subject, which separates this from the
    sideroblastic anaemia of other mitochondrial translation defects such as
    YARS2-related MLASA.
  phenotype_term:
    preferred_term: Anemia
    term:
      id: HP:0001903
      label: Anemia
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Anemia, which is a rare symptom in mitochondrial disorders11–13, was
      frequently present, ranging in severity from mild to severe prenatal anemia
      requiring intrauterine transfusions.
    explanation: >-
      Documents anaemia and notes its rarity in this disease class.
- category: Hepatic
  name: Liver Dysfunction
  description: >-
    Present in four of the five GATC patients. Liver is intermediate in the
    tissue gradient - complex I subassemblies were absent from liver in the
    patient examined, while present in heart and, less so, in skeletal muscle.
  phenotype_term:
    preferred_term: Abnormal liver function
    term:
      id: HP:0001410
      label: Decreased liver function
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional features present in several subjects include liver dysfunction,
      mildly elevated creatine kinase levels, and hydropic features including
      pericardial effusion.
    explanation: >-
      Documents liver dysfunction among the accompanying features.
- category: Musculoskeletal
  name: Elevated Creatine Kinase
  description: >-
    Mildly elevated in four of the five GATC patients. The elevation is mild,
    which is consistent with the tissue gradient placing skeletal muscle below
    heart in severity rather than with a primary myopathy.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase concentration
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase concentration
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additional features present in several subjects include liver dysfunction,
      mildly elevated creatine kinase levels, and hydropic features including
      pericardial effusion.
    explanation: >-
      Documents the mildly elevated creatine kinase.
- category: Neonatal
  name: Infantile Onset with Death Before Seven Months
  description: >-
    Onset between two and 5.5 months and death by 6.5 months in all five reported
    patients. This is the feature that separates COXPD42 from the GATB and QRSL1
    disorders in the same series, whose families had prenatal onset with hydrops
    or intrauterine growth restriction and died within days. Hydrops,
    intrauterine growth restriction and prematurity were absent from the GATC
    families.

    One feature quoted elsewhere in this entry is deliberately not curated as a
    phenotype. The source lists hydropic features including pericardial effusion
    among findings present in several subjects without naming them, and
    pericardial effusion has no row in the per-patient table, so it cannot be
    attributed to the GATC patients specifically. Hydrops itself does have a row,
    and was absent in all five of them.
  phenotype_term:
    preferred_term: Infantile onset
    onset:
      onset_category: INFANTILE
  notes: >-
    No `term:` is bound. The candidate HPO terms for onset timing (HP:0003593
    Infantile onset) and for early death (HP:0001522 Death in infancy) sit under
    Clinical modifier and Age of death respectively, outside the `PhenotypeTerm`
    dynamic enum, which is reachable only from the phenotypic-abnormality root.
    The structured `onset` descriptor carries the timing instead.
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The onset of symptoms was either prenatal (families 1 and 3) or infantile at
      2–5 months (families 2, 4, and 5), and no child survived beyond 6.5 months.
    explanation: >-
      Dates onset and death, with families 4 and 5 being the GATC families.
progression:
- phase: Lethal infantile course
  notes: >-
    Onset at two to 5.5 months with cardiomyopathy and lactic acidosis, death by
    6.5 months in every reported patient. No treatment altered the course. The
    prognosis is not specific to GATC - mitochondrial cardiomyopathy in children
    carries a markedly worse survival than mitochondrial disease without
    cardiomyopathy, with ten-year survival of 18 percent against 67 percent in
    one 137-patient cohort, and defects in the sibling gene QRSL1 appear among the
    deaths within the first year in that cohort.
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The onset of symptoms was either prenatal (families 1 and 3) or infantile at
      2–5 months (families 2, 4, and 5), and no child survived beyond 6.5 months.
    explanation: >-
      The course in the reported patients.
  - reference: PMID:30642647
    reference_title: "Cardiomyopathy in children with mitochondrial disease: Prognosis and genetic background."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ten-year Kaplan-Meier estimates of overall survival were 18 and 67%,
      respectively.
    explanation: >-
      Curated as PARTIAL: this cohort contains no GATC patients, so it supplies
      the general prognosis of paediatric mitochondrial cardiomyopathy as context
      rather than a COXPD42-specific survival estimate.
biochemical:
- name: Respiratory Chain Enzyme Activities
  notes: >-
    Combined deficiency of complexes I and IV with low or borderline-low complex
    III, varying by tissue. The diagnostic trap is the tissue chosen: clear
    deficiencies were seen in the fibroblasts of the GatB patients but not in
    those of the GatA and GatC patients, so a normal fibroblast respiratory chain
    panel does not exclude COXPD42. Heart and skeletal muscle are the informative
    tissues.
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to the fibroblasts of the GatA and GatC patients, clear
      respiratory chain enzyme deficiencies were observed in the fibroblasts of
      the GatB patients.
    explanation: >-
      The subunit-specific difference in fibroblast expressivity that makes
      fibroblast testing unreliable for GATC.
- name: Blood Lactate
  notes: >-
    Lactic acidosis is present in every reported patient and is the finding that
    prompts investigation for mitochondrial disease.
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      infants predominantly exhibiting severe cardiomyopathy and fatal lactic
      acidosis, which raised suspicion of mitochondrial disease
    explanation: >-
      Establishes lactic acidosis as the trigger for mitochondrial investigation.
genetic:
- name: GATC
  gene_term:
    preferred_term: GATC
    term:
      id: hgnc:25068
      label: GATC
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  notes: >-
    GATC encodes GatC, the smallest of the three subunits of the mitochondrial
    glutamyl-tRNA(Gln) amidotransferase. Unlike GatA (QRSL1) and GatB (GATB), it
    has no catalytic activity of its own: in the bacterial complex it is the
    stabilizing linker holding the amidase and kinase subunits together. That
    architecture is why a GATC lesion is not a milder version of the others but
    an equivalent one - loss of GatC depletes GatA and GatB too.

    Only one pathogenic GATC allele is reported: homozygous c.233T>G
    (p.Met78Arg), in two families from adjacent villages. The entire clinical
    description of COXPD42 therefore rests on one variant in five patients, and
    the allelic and phenotypic range of the disorder is unknown.

    GATC sits within a coherent gene group. QRSL1 (GatA) and GATB (GatB) cause
    the two sibling COXPD entities in the same report; upstream, EARS2 performs
    the first, mischarging step of the same two-step pathway. A COXPD42-like
    presentation should prompt sequencing of all three GatCAB genes rather than
    GATC alone, since they are clinically indistinguishable at presentation.
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      This latter conversion is performed by GatCAB, the glutamyl-tRNAGln
      amidotransferase protein complex, that consists of three subunits: GatA
      encoded by QRSL1, GatB encoded by GATB, and GatC encoded by GATC
    explanation: >-
      Establishes the subunit-to-gene mapping of the complex.
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe nine patients from five families with genetic defects in a
      GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a
      lethal metabolic cardiomyopathy syndrome.
    explanation: >-
      Establishes that all three subunit genes produce the same clinical
      syndrome, which is the basis for testing them together.
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      it is first charged with glutamic acid (Glu) by mitochondrial glutamyl-tRNA
      synthetase (EARS2), after which the Glu-mt-tRNAGln is transamidated into
      Gln-mt-tRNAGln, using free glutamine as an amide donor
    explanation: >-
      Places EARS2 upstream of GatCAB in the same pathway.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Five patients from two families, all homozygous for the same GATC allele and
    all reported in a single 2018 paper. No population estimate exists and none
    can be derived. The two families reside in adjacent villages, so even the
    published count may reflect a single local founder allele rather than the
    disorder's true distribution.
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In families 4 and 5, which are reportedly not related but reside in adjacent
      villages, we identified a homozygous missense variant in GATC: c.233T>G;
      p.Met78Arg.
    explanation: >-
      The two families that constitute the entire published series, and their
      geographic proximity.
experimental_models:
- name: GATC patient primary dermal fibroblasts
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Primary skin fibroblasts from patient P4B, homozygous for GATC p.Met78Arg.
    They are the system in which nearly all the mechanism in this entry was
    established, and they are also the clearest illustration of why fibroblasts
    are a poor diagnostic tissue for this disorder: under standard culture
    conditions their respiratory chain enzymes and steady-state OXPHOS subunit
    levels are normal, and the defect appears only when glutamine is withdrawn or
    translational demand is sustained.
  modeled_mechanisms:
  - target: GatCAB Trimer Destabilization
    relationship: MEASURES
    fidelity: HIGH
    description: >-
      The system in which GatC depletion to 20 percent of control, the parallel
      loss of GatA and GatB, and the unchanged transcript levels were measured.
    limitations: >-
      Fibroblast is not the affected tissue. Whether the same degree of subunit
      depletion occurs in cardiomyocytes has not been measured.
    readouts:
    - name: GatC steady-state protein level
      target: GatCAB Trimer Destabilization
      direction: DECREASED
      interpretation: >-
        Reduction to about a fifth of control, with GatA and GatB falling in
        parallel, is the measurement establishing trimer destabilization.
      evidence:
      - reference: PMID:30283131
        reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Western blot analysis of control and patient P4B fibroblasts showed a
          strong reduction in GatC protein, and also reduced levels of GatA and
          GatB protein, with porin as loading control.
        explanation: >-
          The western blot measurement underlying this readout.
    evidence:
    - reference: PMID:30283131
      reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        In subject P4B with mutations in GATC, the steady state level of GatC in
        fibroblasts was decreased to 20% of controls
      explanation: >-
        Establishes the model as informative for the trimer-destabilization node.
  - target: Impaired Transamidation of Glu-mt-tRNA(Gln)
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the charging defect, but conditionally: mt-tRNA(Gln) charging is
      similar to control in glutamine-replete medium and falls only after three
      days of glutamine withdrawal.
    limitations: >-
      The conditionality is the limitation. A negative result in glutamine-replete
      medium says nothing about the genotype, so this model must be run under
      glutamine restriction to be informative.
    readouts:
    - name: mt-tRNA(Gln) aminoacylation by northern blot
      target: Impaired Transamidation of Glu-mt-tRNA(Gln)
      direction: DECREASED
      interpretation: >-
        Reduced charging under glutamine withdrawal, against normal charging in
        replete medium.
      evidence:
      - reference: PMID:30283131
        reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          After 3 days in culture medium without glutamine, fibroblasts from P1A,
          P3A, and P4B show decreased glutamine charging of mt-tRNAGln compared to
          control fibroblasts.
        explanation: >-
          The northern blot measurement underlying this readout.
    evidence:
    - reference: PMID:30283131
      reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        While aminoacylation of mt-tRNAGln appears to show only minor changes in
        comparison to controls when patient cells are grown under standard
        conditions with high concentrations of the GatCAB substrate glutamine in
        the culture medium
      explanation: >-
        Curated as PARTIAL because the model reproduces the defect only under
        glutamine restriction.
  - target: Deficient Mitochondrial Protein Synthesis
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Radiolabelled-methionine pulse labelling under emetine block showed a strong
      generalized mtDNA-encoded translation defect in these cells, and a
      chloramphenicol block-and-release experiment resolved its kinetics.
    limitations: >-
      The translation defect does not translate into reduced steady-state OXPHOS
      subunit levels in this cell type, because the existing subunits are
      stabilised - so the model reproduces the primary defect but not its usual
      downstream readout.
    readouts:
    - name: De novo mtDNA-encoded protein synthesis
      target: Deficient Mitochondrial Protein Synthesis
      direction: DECREASED
      interpretation: >-
        Reduced incorporation of labelled methionine into mitochondrially
        translated peptides.
      evidence:
      - reference: PMID:30283131
        reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          a Decrease in newly synthesized peptides in GATA and GATC patient
          fibroblasts compared to control as determined by pulse labeling.
        explanation: >-
          The pulse-labelling measurement underlying this readout. Note the figure
          legend writes "GATA" where the gene is QRSL1 (GatA); the GATC arm is the
          one relevant here.
    evidence:
    - reference: PMID:30283131
      reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        revealed a strong and generalized mtDNA-encoded protein synthesis defect
        after a 90-min pulse in P4B (GATC) and in P3A (QRSL1) patients' fibroblasts
      explanation: >-
        Establishes the model as informative for the translation node.
- name: mouse GatA (Qrsl1) RNA interference cell model
  experimental_model_type: CELL_LINE
  description: >-
    Knockdown of mouse GatA in mouse cells, published four years before the human
    disorder was described. It is the source of two claims that the patient data
    do not supply: that GatCAB loss raises reactive oxygen species, and that
    mischarged Glu-mt-tRNA(Gln) is rejected by the translation apparatus rather
    than being incorporated as glutamate.
  modeled_mechanisms:
  - target: Deficient Mitochondrial Protein Synthesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Knockdown produces a strong mitochondrial translation defect without
      affecting the stability of newly synthesized proteins, and mass spectrometry
      found no glutamate substituted at glutamine positions - so the failure mode
      is loss of translation, not mistranslation.
    limitations: >-
      Different subunit (GatA, not GatC), different species, and an acute
      knockdown rather than a hypomorphic germline missense allele. It cannot
      speak to the residual-activity question that governs severity in patients.
    readouts:
    - name: Reactive oxygen species level
      target: Deficient Mitochondrial Protein Synthesis
      direction: INCREASED
      interpretation: >-
        The only evidence in this entry for an oxidative-stress component; it is
        from mouse cells with a different subunit knocked down, not from GATC
        patients.
      evidence:
      - reference: PMID:24579914
        reference_title: "Glutamyl-tRNAGln amidotransferase is essential for mammalian mitochondrial translation in vivo."
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          As a result, interfered cells present an impairment of the oxidative
          phosphorylation system and a significant increase in ROS (reactive oxygen
          species) levels.
        explanation: >-
          The measurement underlying this readout.
    evidence:
    - reference: PMID:24579914
      reference_title: "Glutamyl-tRNAGln amidotransferase is essential for mammalian mitochondrial translation in vivo."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        we demonstrate that mgatA (mouse GatA) interference in mouse cells produces
        a strong defect in mitochondrial translation without affecting the
        stability of the newly synthesized proteins
      explanation: >-
        Establishes the translation defect on knockdown of a GatCAB subunit.
diagnosis:
- name: Sequencing of the Three GatCAB Subunit Genes
  description: >-
    Molecular diagnosis is the practical route, because the three GatCAB
    disorders are clinically indistinguishable and the biochemical workup in
    fibroblasts can be normal. All five families in the defining series were
    solved by whole-exome sequencing. A targeted panel should include QRSL1,
    GATB and GATC together, and EARS2 as the upstream step of the same pathway.
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole exome sequencing (WES) analysis in these families uncovered rare
      pathogenic variants in the three genes encoding the GatCAB complex subunits,
      in-line with autosomal recessive inheritance
    explanation: >-
      Documents exome sequencing as the diagnostic route in every reported family.
- name: Respiratory Chain Analysis in Heart or Skeletal Muscle
  description: >-
    If a tissue enzyme assay is done, the tissue matters. Deficiencies were clear
    in the fibroblasts of GatB patients but not of GatA or GatC patients, so a
    normal fibroblast panel cannot exclude COXPD42; heart and skeletal muscle
    carry the deficit. Where only fibroblasts are available, glutamine withdrawal
    unmasks the defect.
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast to the fibroblasts of the GatA and GatC patients, clear
      respiratory chain enzyme deficiencies were observed in the fibroblasts of
      the GatB patients.
    explanation: >-
      The basis for preferring heart or muscle over fibroblasts in this disorder.
differential_diagnoses:
- name: QRSL1-related and GATB-related combined oxidative phosphorylation deficiency
  description: >-
    The two sibling disorders, caused by defects in the other two subunits of the
    same complex and described in the same report. They present with the same
    lethal metabolic cardiomyopathy and are not separable clinically; the reported
    difference is timing, with the GATB and QRSL1 families having prenatal onset
    and neonatal death against infantile onset in the GATC families. That
    difference is attributed to residual activity and residue conservation rather
    than to which subunit is affected, so it should not be used as a rule for
    predicting the gene.
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we describe nine patients from five families with genetic defects in a
      GatCAB complex subunit, including QRSL1, GATB, and GATC, each showing a
      lethal metabolic cardiomyopathy syndrome.
    explanation: >-
      Establishes that all three subunit disorders share one clinical syndrome.
- name: Other mitochondrial aminoacylation and translation defects
  description: >-
    COXPD42 is the last entry in a decade-long series of mitochondrial
    aminoacylation disorders that began with DARS2, and it sits inside a larger
    group of paediatric mitochondrial cardiomyopathies caused by defects in
    mtDNA-encoded protein translation. Members of that group are separated by
    genotype rather than by phenotype; the presence of cardiomyopathy with lactic
    acidosis in infancy narrows the search to the group but not within it.
  evidence:
  - reference: PMID:30283131
    reference_title: "Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Our study completes a decade of investigations on mitochondrial
      aminoacylation disorders, starting with DARS2 and ending with the GatCAB
      complex.
    explanation: >-
      Places COXPD42 within the aminoacylation-disorder group.
  - reference: PMID:29440775
    reference_title: "Genetic defects in mtDNA-encoded protein translation cause pediatric, mitochondrial cardiomyopathy with early-onset brain disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Defects in mtDNA-encoded protein translation lead to severe pediatric
      cardiomyopathy and brain disease with OXPHOS abnormalities.
    explanation: >-
      Establishes the wider group of mtDNA-translation defects presenting as
      paediatric cardiomyopathy, within which COXPD42 must be distinguished
      genetically. Note this series' patients also had early-onset brain disease,
      which was not reported in the GATC patients.
discussions:
- discussion_id: coxpd42_glutamine_supplementation_untested
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Could raising glutamine availability compensate for reduced GatCAB activity in
    a patient, as it appears to in patient fibroblasts?
  attaches_to:
  - "pathophysiology#Impaired Transamidation of Glu-mt-tRNA(Gln)"
  rationale: >-
    This is the most obvious therapeutic idea the biology suggests, and it is
    entirely untested. The observation behind it is robust: patient fibroblasts
    charge mt-tRNA(Gln) at near-normal levels in glutamine-rich medium and fail
    only when glutamine is withdrawn, and complex I subassemblies become more
    prominent under withdrawal. Glutamine is the amide donor for the reaction, so
    substrate concentration plausibly compensates for reduced enzyme.

    Three things stand between that and a treatment, and this entry curates no
    treatment for exactly these reasons. First, the experiments show that
    supraphysiological culture glutamine masks the defect - not that
    physiologically achievable plasma glutamine would. Second, the cells in which
    the rescue is seen are fibroblasts, the tissue least affected in the disease;
    the heart is the tissue that must be rescued, and no cardiac model exists.
    Third, and most limiting, the chloramphenicol block-and-release experiment
    showed that translation keeps pace only briefly before charging falls behind
    sustained demand, which suggests the constraint is enzymatic throughput rather
    than substrate supply once demand is high. A cardiomyocyte never stops
    translating.
  proposed_experiments:
  - experiment_id: exp_coxpd42_glutamine_dose_response
    name: Glutamine dose-response across the physiological range
    description: >-
      Titrate glutamine across the physiological plasma range rather than
      comparing replete against absent, in patient fibroblasts and in
      cardiomyocytes differentiated from patient-derived induced pluripotent stem
      cells, with mt-tRNA(Gln) charging and mitochondrial translation as readouts.
      The question is whether any achievable concentration restores function, not
      whether an artificially high one does.
  - experiment_id: exp_coxpd42_cardiomyocyte_model
    name: A cardiac model of GatC deficiency
    description: >-
      Every mechanistic result in this disorder comes from fibroblasts, which are
      the least affected tissue and can look normal. Generate GATC p.Met78Arg
      cardiomyocytes, by editing or from patient cells, and determine whether the
      tissue gradient seen in post-mortem tissue is reproduced in vitro and
      whether the glutamine conditionality holds in a cell with high and
      continuous translational demand.
- discussion_id: coxpd42_single_allele_single_report
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Does COXPD42 have a phenotypic range, or is everything known about it a
    property of one founder allele?
  attaches_to:
  - "pathophysiology#Biallelic GATC Missense Variant"
  rationale: >-
    Everything in this entry describes five patients from two families in
    adjacent villages, all homozygous for the same GATC allele, reported in one
    paper. That is not a phenotype; it is one genotype observed several times.

    The distinction matters because the paper's own severity model predicts a
    range. It proposes that clinical severity tracks residual GatCAB activity, and
    that residual activity tracks the conservation of the mutated residue - which
    is how it explains the prenatal onset of the GATB and QRSL1 families against
    the infantile onset of the GATC ones. If that model is right, a GATC allele at
    a more conserved residue should produce a more severe, possibly prenatally
    lethal, disease, and a milder allele should produce something that survives
    infancy and has never been recognised as COXPD42. Neither has been reported.
    Nothing in the current literature can distinguish "COXPD42 is uniformly lethal
    in infancy" from "the one known GATC allele is lethal in infancy".
  proposed_experiments:
  - experiment_id: coxpd42_allelic_series_functional_assay
    name: Functional assay for an allelic series of GATC variants
    description: >-
      Build a quantitative assay of GatCAB activity - mt-tRNA(Gln) charging in a
      GATC-null background complemented with variant constructs - and use it to
      calibrate residual activity against the p.Met78Arg benchmark for GATC
      variants of unknown significance found in diagnostic sequencing. This would
      test the residual-activity model and make future GATC variants
      interpretable.
notes: >-
  Scope. This entry covers COXPD42 (MONDO:0030008), the GATC-related disorder.
  The two sibling GatCAB disorders caused by QRSL1 and GATB are curated here only
  as differential diagnoses; they are separate MONDO entities and their evidence
  should not be imported into this entry's pathograph even though it comes from
  the same paper.

  Read the patient labels. The defining paper reports nine patients across three
  genes in shared tables and figures, and its summary counts - cardiomyopathy 9/9,
  anaemia 7/7 - are for all nine, not for the five GATC patients. Wherever this
  entry states a GATC-specific count it is derived by reading the per-patient
  columns for P4A, P4B, P4C, P5A and P5B, and the evidence snippets attached are
  the sentences that name families 4 and 5 or the patients within them. No
  `frequency:` band is assigned anywhere in this entry: with five patients sharing
  one allele, a percentage would imply a precision the series cannot support.

  Where the mechanism is and is not from patients. The trimer-destabilization,
  charging, translation and respiratory-chain nodes all rest on measurements in
  the GATC patient's own fibroblasts, which is unusually good for a five-patient
  disorder. Two claims do not: the increase in reactive oxygen species and the
  finding that mischarged Glu-mt-tRNA(Gln) is rejected rather than mistranslated
  both come from a mouse-cell GatA knockdown, and are curated on that model with
  its species and subunit differences stated rather than folded into the human
  pathograph.

  No treatments block, deliberately. There is no treatment for COXPD42 and none
  was reported. The glutamine-conditional biochemistry invites a supplementation
  hypothesis, and that hypothesis is recorded as an open discussion with its three
  specific obstacles rather than curated as a treatment. Curating glutamine as a
  therapy on the strength of a culture-medium experiment in the least-affected
  tissue would be exactly the kind of over-reach the discussion exists to prevent.

  Conformance. The entry declares conformance to
  `mitochondrial_dysfunction#Bioenergetic Decline and Oxidative Stress` at the
  combined respiratory chain node only. The module is built around age-related
  mitochondrial damage, so its upstream nodes do not apply to a primary
  nuclear-gene translation defect, and its reactive-oxygen-species arm is not
  evidenced in these patients. The precedent for conforming a nuclear-gene
  mitochondrial disease at this node is `Mitochondrial_DNA_Depletion_Syndrome_14B`
  (OPA1), whose own `Combined Respiratory Chain Deficiency` node declares the same
  conformance; this entry follows it. The module's text also names that node as
  the state disease-specific mitochondrial lesions converge on. The other
  conformers are a different case and are not precedent here: Pearson, Kearns-Sayre
  and MELAS are primary mitochondrial-DNA disorders, and Fontaine progeroid
  syndrome is not a primary mitochondrial disease at all.

📚

References & Deep Research

References

4

PMID:30283131

Pathogenic variants in glutamyl-tRNA(Gln) amidotransferase subunits cause a lethal mitochondrial cardiomyopathy disorder.

No top-level findings curated for this source.

PMID:24579914

Glutamyl-tRNAGln amidotransferase is essential for mammalian mitochondrial translation in vivo.

No top-level findings curated for this source.

PMID:30642647

Cardiomyopathy in children with mitochondrial disease: Prognosis and genetic background.

No top-level findings curated for this source.

PMID:29440775

Genetic defects in mtDNA-encoded protein translation cause pediatric, mitochondrial cardiomyopathy with early-onset brain disease.

No top-level findings curated for this source.

Combined oxidative phosphorylation deficiency 42

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