COX6A2-Related COX Deficiency

Mendelian MONDO:0033653 Pathograph 31 Show in embeddings browser Mitochondrial Disease Inborn Error of Metabolism

COX6A2-related cytochrome c oxidase deficiency (MC4DN18) is an autosomal recessive mitochondrial disorder associated with biallelic missense variants in the nuclear-encoded complex IV structural subunit COX6A2. The two founding patients had congenital myopathy with limb and facial weakness and hypotonia; one had cardiomyopathy and died in early infancy, while the other survived into adolescence. Patient muscle shows reduced complex IV activity and impaired assembly and supercomplex formation. COX6A2 is enriched in striated muscle but is also expressed in cortical interneurons. Later mouse neuronal and human stem-cell-derived cardiomyocyte experiments identify cell-specific energy, redox and functional abnormalities. The surviving patient had preserved overall intelligence with relatively lower processing speed; a broader human neurologic syndrome remains unestablished.

Ask OpenScientist

Ask a research question about COX6A2-Related COX Deficiency. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

🏷

Classifications

Harrison's Part

Mechanistic Nosology

ICIMD (Inherited Metabolic Disorders)

👪

Inheritance

Autosomal recessive HP:0000007

The two founding patients carried homozygous or compound-heterozygous missense variants; the compound allelic phase was confirmed by cloning PCR products.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:31155743 SUPPORT Human Clinical

"The variants detected were homozygous c.117C > A (p.Ser39Arg) and compound heterozygous c.117C > A (p.Ser39Arg) and c.127T > C (p.Cys43Arg)."

The reported alleles were homozygous p.Ser39Arg and compound heterozygous p.Ser39Arg/p.Cys43Arg.

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z SUPPORT Human Clinical

"The allelic phases of the compound heterozygous variants in P2 were confirmed by cloning their PCR products"

ClinGen records phase confirmation for the second patient.

⚙

Pathophysiology

Reduced COX6A2 Protein Stability

The p.Ser39Arg and p.Cys43Arg proteins are less stable in HeLa expression experiments. Mitochondrial targeting persists, distinguishing protein instability from an import defect.

Experimental models

HeLa COX6A2 missense-expression models CELL LINE

Downstream

Reduced COX6A2 Protein Abundance Accelerated loss of mutant protein can reduce its steady-state abundance.

Show evidence (2 references)

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z SUPPORT In Vitro

"HeLa studies with COX6A2-fused EGFPs with WT and Ser39Arg mutation show transport to mitochondria, but dramatically reduced expression of protein after blocking de novo protein synthesis compared to WT at 2,4,6 hours"

ClinGen summarizes the allele-expression experiments: mitochondrial targeting was retained but mutant protein decayed more rapidly after translation blockade.

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z SUPPORT In Vitro

"HeLa studies with COX6A2-fused EGFPs with WT and Cys43Arg mutation show transport to mitochondria, but dramatically reduced expression of protein after blocking de novo protein synthesis compared to WT at 2,4,6 hours"

ClinGen also summarizes accelerated decay of p.Cys43Arg protein after translation blockade.

Reduced COX6A2 Protein Abundance

Reduced COX6A2 protein is documented in patient samples. Complete gene deletion is the experimental perturbation in mouse and engineered cardiomyocyte models; it does not reproduce the precise patient missense genotypes.

COX6A2 hgnc:2279

Experimental models

COX6A2-null hiPSC-derived cardiomyocytes IPSC DERIVED MODEL

Downstream

Impaired Complex IV Assembly Insufficient functional structural subunit impairs normal complex IV biogenesis.

Reduced Cardiomyocyte Respiration Engineered loss of COX6A2 produces a respiratory deficit through incompletely separated intermediate steps.

Increased Mitochondrial Superoxide Loss of COX6A2 perturbs mitochondrial redox handling in the engineered cell model.

Reduced Mitochondrial Membrane Potential COX6A2-deficient cardiomyocytes have lower membrane-potential-sensitive fluorescence.

Altered Cardiomyocyte Calcium Transients The knockout changes calcium handling; the intervening energy and redox pathways are not isolated.

Cardiomyocyte Hypertrophy COX6A2 knockout leads to cellular enlargement over differentiation; the intervening signaling is unresolved.

Reduced Interneuron ATP-to-ADP Ratio PV-specific gene deletion lowers the intracellular energy ratio.

Interneuron Oxidative DNA Damage Global knockout increases the oxidative DNA damage readout in PV interneurons.

Reduced Perineuronal Nets Knockout reduces WFA-positive matrix surrounding PV cells.

Impaired Fast-Spiking Maturation Knockout impairs the development of sustained fast-spiking activity.

Reduced Interneuron Dendritic Arborization Knockout limits later dendritic growth and branching.

Reduced PV Interneuron Synaptic Contacts Gene deletion reduces the measured contact number through unresolved developmental and metabolic intermediates.

Show evidence (2 references)

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z SUPPORT Human Clinical

"Uniformly faint COX staining, Isolated complex IV deficiency by spectrophotometry, decreased COX6A2 western blot"

ClinGen summarizes decreased COX6A2 protein and isolated complex IV deficiency in the founding patient material.

PMID:38072986 SUPPORT In Vitro

"The results indicated that no significant COX6A2 protein expression was present in COX6A2−/−hiPSCs (Fig. 1D,"

Protein depletion was confirmed in the engineered knockout stem-cell model.

Impaired Complex IV Assembly

Complex IV assembly is impaired in patient muscle. This is a structural-subunit defect with an assembly consequence, not a mutation in a dedicated assembly factor.

mitochondrial respiratory chain complex IV assembly GO:0033617 ↓ DECREASED

Animal models

Global Cox6a2 knockout mouse Mouse partially recapitulates

Downstream

Reduced Cytochrome c Oxidase Activity Impaired assembly limits functional complex IV capacity.

Impaired Complex IV Supercomplex Formation Complex IV assembly abnormalities accompany impaired higher-order respiratory assemblies.

Show evidence (1 reference)

PMID:31155743 SUPPORT Human Clinical

"Assembly of complex IV and its supercomplex formation were impaired in the muscle."

Patient muscle analysis demonstrates impaired complex IV assembly and supercomplex formation.

Reduced Cytochrome c Oxidase Activity

Complex IV activity is selectively reduced in patient skeletal muscle. COX6A2 supports the multimeric oxidase and is not itself the electron-transfer catalytic center. Reduced enzyme activity does not establish universal bulk ATP depletion. Unlike the combined electron-transfer and ATP-synthesis collapse described in the complex IV module, this activity defect can coexist with preserved bulk tissue ATP.

COX6A2 hgnc:2279

mitochondrial electron transport, cytochrome c to oxygen GO:0006123 ↓ DECREASED

cytochrome-c oxidase activity GO:0004129 ↓ DECREASED

Animal models

Global Cox6a2 knockout mouse Mouse partially recapitulates

Downstream

Limb muscle weakness The biochemical defect accompanies the congenital limb myopathy; tissue-level intermediates were not directly established.

Facial muscle weakness The same clinical-biochemical association supports facial myopathy without specifying its intervening steps.

Hypotonia The founding cases associate complex IV deficiency with reduced tone.

Cardiomyopathy Complex IV dysfunction can involve the heart; the clinical subtype and full causal sequence are not established in the founding abstract.

Show evidence (2 references)

PMID:31155743 SUPPORT Human Clinical

"We found specific reductions in complex IV activities in the skeletal muscle of both individuals."

The isolated complex IV biochemical defect was measured in patient skeletal muscle.

PMID:11788423 SUPPORT Model Organism

"Total COX activity was decreased in hearts from mutant mice, which appears to be a consequence of altered assembly of the holoenzyme COX."

The global knockout mouse study directly reports reduced cardiac COX activity and attributes it to altered holoenzyme assembly.

Impaired Complex IV Supercomplex Formation

Complex IV-containing respiratory supercomplex formation is impaired in patient muscle. This biochemical assembly outcome is distinct from oxidase enzymatic activity.

Show evidence (1 reference)

PMID:31155743 SUPPORT Human Clinical

"Assembly of complex IV and its supercomplex formation were impaired in the muscle."

Patient muscle analysis demonstrates impaired complex IV assembly and supercomplex formation.

Reduced Cardiomyocyte Respiration

Engineered COX6A2-null cardiomyocytes have lower basal and maximal oxygen consumption and ATP-linked respiration. Extracellular acidification also decreases, rather than showing compensatory glycolytic enhancement in this model.

cardiac muscle cell CL:0000746

Experimental models

COX6A2-null hiPSC-derived cardiomyocytes IPSC DERIVED MODEL

Downstream

Reduced Cardiomyocyte ATP Content Reduced energy metabolism is associated with lower cellular ATP in this model.

Show evidence (2 references)

PMID:38072986 SUPPORT In Vitro

"the basal respiration, maximal respiration, and ATP production of the KO cardiomyocytes were significantly lower compared with that of WT cardiomyocytes (Fig. 5B)."

Seahorse measurements show lower respiratory capacity and ATP-linked respiration in engineered knockout cardiomyocytes.

PMID:38072986 SUPPORT In Vitro

"The extracellular acidification rate of KO cardiomyocytes was also significantly lower compared with that of WT cardiomyocytes, suggesting that the glycolytic capacity of KO cardiomyocytes was significantly reduced (Fig. 5C)."

The glycolytic-capacity proxy decreases in the engineered cardiac cells.

Reduced Cardiomyocyte ATP Content

ATP-content assays show a deficit in engineered knockout cardiomyocytes that responds partially to L-carnitine and trimetazidine. This is a cellular measurement, not evidence of universal ATP depletion in affected patients or mouse muscles.

cardiac muscle cell CL:0000746

Experimental models

COX6A2-null hiPSC-derived cardiomyocytes IPSC DERIVED MODEL

Downstream

Altered Cardiomyocyte Calcium Transients Metabolic drug rescue improves calcium-transient parameters, supporting an indirect energy-calcium link.

Show evidence (1 reference)

PMID:38072986 SUPPORT In Vitro

"The ATP content of KO cardiomyocytes following LC, TMZ, and LC + TMZ treatment was restored to varying degrees, of which LC + TMZ exhibited the greatest effect (Fig. 7A)."

The ATP-content assay documents the energy deficit and its partial restoration by metabolic compounds in knockout cardiomyocytes.

Increased Mitochondrial Superoxide

MitoSOX fluorescence is increased in engineered COX6A2-null cardiomyocytes. Global knockout mice also show elevated skeletal-muscle DHE signal; neither assay alone resolves all sources of oxidants.

Experimental models

COX6A2-null hiPSC-derived cardiomyocytes IPSC DERIVED MODEL

Show evidence (2 references)

PMID:38072986 SUPPORT In Vitro

"Compared with WT cardiomyocytes, mitochondrial ROS in KO cardiomyocytes was significantly increased (Fig. 4F and Additional file 1: Fig. S3D),"

MitoSOX detects increased mitochondrial superoxide in knockout cardiomyocytes.

PMID:23460811 SUPPORT Model Organism

"elevated ROS levels were detected both in diaphragm and in hindlimb muscles of Cox6a2 −/− mice as compared to WT mice with the largest difference being measured in the diaphragm."

DHE labeling is increased in skeletal muscle from global knockout mice.

Reduced Mitochondrial Membrane Potential

TMRE fluorescence is lower in engineered knockout cardiomyocytes. The accompanying mitochondrial ultrastructural and calcium changes do not establish the direction of every causal feedback step.

cardiac muscle cell CL:0000746

Experimental models

COX6A2-null hiPSC-derived cardiomyocytes IPSC DERIVED MODEL

Show evidence (1 reference)

PMID:38072986 SUPPORT In Vitro

"Immunofluorescence staining showed that the red fluorescence intensity of WT cardiomyocytes was significantly higher than that of KO cardiomyocytes (Fig. 4G). This suggests that the mitochondrial membrane potential of cardiomyocytes was significantly reduced following COX6A2 knockout and..."

TMRE fluorescence supports reduced mitochondrial membrane potential in the cell model.

Altered Cardiomyocyte Calcium Transients

Calcium transients have smaller peaks and longer time-to-peak in knockout cardiomyocytes. These measurements support impaired calcium dynamics without directly measuring mitochondrial calcium overload.

cardiac muscle cell CL:0000746

Experimental models

COX6A2-null hiPSC-derived cardiomyocytes IPSC DERIVED MODEL

Downstream

Reduced Cardiomyocyte Contractility Altered calcium dynamics accompany impaired mechanical contraction; their causal relationship remains indirect in the knockout comparison.

Show evidence (1 reference)

PMID:38072986 SUPPORT In Vitro

"Compared with WT cardiomyocytes, the peak value of calcium transients in KO cardiomyocytes was significantly reduced and the time to peak time was significantly prolonged (Fig. 6C–F),"

Fluo-4 imaging measures smaller and slower calcium transients. It does not directly establish mitochondrial calcium overload.

Reduced Cardiomyocyte Contractility

Video-based analysis of knockout cardiomyocytes shows reduced contraction intensity and frequency, with prolonged contraction and relaxation. A calibrated myocardial force measurement was not performed.

cardiac muscle cell CL:0000746

Experimental models

COX6A2-null hiPSC-derived cardiomyocytes IPSC DERIVED MODEL

Downstream

Cardiomyopathy The engineered-cell mechanical phenotype offers a partial model of cardiac dysfunction; it does not establish a patient cardiomyopathy subtype.

Show evidence (1 reference)

PMID:38072986 SUPPORT In Vitro

"Compared with WT cardiomyocytes, the contraction intensity of KO cardiomyocytes was significantly decreased (Fig. 6H). Moreover, the time to peak (Fig. 6I) and relaxation duration (Fig. 6J) were significantly prolonged."

Video-derived contraction intensity decreases and contraction/relaxation kinetics slow; this is not a calibrated force measurement.

Cardiomyocyte Hypertrophy

Engineered knockout cardiomyocytes enlarge during differentiation and show increased remodeling-associated transcripts. Cell size and collagen transcripts do not establish tissue fibrosis or a clinical hypertrophic cardiomyopathy diagnosis.

cardiac muscle cell CL:0000746

Experimental models

COX6A2-null hiPSC-derived cardiomyocytes IPSC DERIVED MODEL

Show evidence (2 references)

PMID:38072986 SUPPORT In Vitro

"the surface area of the KO cardiomyocytes was significantly increased compared with the WT cardiomyocytes as determined by laser confocal microscopy (Fig. 3A)."

Phalloidin imaging demonstrates increased cardiomyocyte area after knockout.

PMID:38072986 SUPPORT In Vitro

"Using qPCR, we found that the expression of ANP, BNP, COL1A1, and COL4A1 mRNA in cardiomyocytes following COX6A2 knockdown was significantly increased compared with that of the WT cells (Fig. 3D–G),"

Remodeling-associated transcripts increase in knockout cardiomyocytes.

Reduced Interneuron ATP-to-ADP Ratio

PV-specific Cox6a2 deletion lowers the basal ATP-to-ADP ratio measured with PercevalHR in ex vivo brain slices. COX6A2 expression in normal human cortex supports relevance beyond muscle, but equivalent patient-neuron bioenergetics have not been measured.

Parvalbumin-positive cortical GABAergic interneuron CL:0011005

Animal models

PV-specific conditional Cox6a2 knockout mouse Mouse partially recapitulates

Show evidence (2 references)

PMID:32744742 SUPPORT Model Organism

"Such dramatic effects were likely due to an essential role of COX6A2 in energy balance of PV+ interneurons, underscored by a decrease in the ATP-to-ADP ratio in Cox6a2-/- PV+ interneurons."

The abstract reports the reduced ATP-to-ADP ratio in knockout PV interneurons; the full paper identifies the conditional knockout and PercevalHR slice-imaging experiment.

url:https://www.embopress.org/doi/full/10.15252/embj.2020105759 SUPPORT INDIRECT Other

"In the adult human brain, all cortical PV ... + ... interneurons from Brodmann areas 9 and 10 (BA9, BA10), which correspond to the dorsolateral and medial prefrontal cortex and the anterior prefrontal cortex, respectively, express COX6A2, and PV ... + ... interneurons represent 60% of the cells..."

Postmortem human cortex expresses COX6A2 beyond muscle; PV cells comprise about 60% of COX6A2-positive cortical cells in these donors.

Interneuron Oxidative DNA Damage

PV interneurons in global knockout mouse somatosensory and motor cortex have increased 8-OHdG immunoreactivity. This is a model-specific oxidative DNA damage readout, not a demonstrated patient biomarker.

Parvalbumin-positive cortical GABAergic interneuron CL:0011005

Animal models

Global Cox6a2 knockout mouse Mouse partially recapitulates

Show evidence (1 reference)

url:https://www.embopress.org/doi/full/10.15252/embj.2020105759 SUPPORT Model Organism

"8‐OHdG immunoreactivity was significantly higher in PV ... + ... interneurons in both cortices in ... Cox6a2 ... −/− ... mice ( ... n ... = 4 WT, 4 ... Cox6a2 ... − ... / ... − ... ; 2 months old)."

Increased 8-OHdG signal supports oxidative DNA damage in knockout cortical PV interneurons.

Reduced Perineuronal Nets

WFA-positive perineuronal matrix surrounding cortical PV interneurons is reduced in global knockout mice. The experiments associate this with oxidative stress but do not isolate the causal sequence.

Parvalbumin-positive cortical GABAergic interneuron CL:0011005

Animal models

Global Cox6a2 knockout mouse Mouse partially recapitulates

Show evidence (1 reference)

url:https://www.embopress.org/doi/full/10.15252/embj.2020105759 SUPPORT Model Organism

"WFA immunoreactivity around PV ... + ... cells was lower in both cortices in ... Cox6a2 ... −/− ... mice ( ... n ... = 4 WT, 4 ... Cox6a2 ... − ... / ... − ... ; 2 months old)."

Reduced WFA labeling supports diminished perineuronal nets in the mouse model.

Impaired Fast-Spiking Maturation

Older knockout PV interneurons fail to acquire normal maximal sustained firing frequency. Increased excitability at threshold coexists with impaired repetitive firing, so a uniform reduction in excitability would be inaccurate.

Parvalbumin-positive cortical GABAergic interneuron CL:0011005

Animal models

Global Cox6a2 knockout mouse Mouse partially recapitulates

Show evidence (2 references)

url:https://www.embopress.org/doi/full/10.15252/embj.2020105759 SUPPORT Model Organism

"Thus, maximal firing frequency reached during 2‐s depolarizing current pulses was lower in P34–45 ... Cox6a2 ... − ... / ... − ... compared with WT PV ... + ... interneurons."

Older knockout PV interneurons fail to acquire normal sustained high-frequency firing.

url:https://www.embopress.org/doi/full/10.15252/embj.2020105759 SUPPORT Model Organism

"Consequently, the threshold was significantly more negative for ... Cox6a2 ... − ... / ... − ... than for WT PV ... + ... interneurons during the later stage of maturation (Fig ... 6 ... C and D)."

Older knockout neurons have a lower firing threshold despite impaired sustained fast spiking.

Reduced Interneuron Dendritic Arborization

At P34-P45, global knockout PV interneurons have reduced dendritic length and branch depth, whereas the younger P22-P33 groups are similar. This developmental mouse finding has not been demonstrated in patients.

Parvalbumin-positive cortical GABAergic interneuron CL:0011005

Animal models

Global Cox6a2 knockout mouse Mouse partially recapitulates

Show evidence (1 reference)

url:https://www.embopress.org/doi/full/10.15252/embj.2020105759 SUPPORT Model Organism

"However, at P34‐P45, ... Cox6a2 ... −/− ... PV ... + ... interneurons showed lower dendritic length and full branch depth than WT PV ... + ... interneurons."

Dendritic length and branch depth are reduced at the later developmental stage.

Reduced PV Interneuron Synaptic Contacts

Global knockout mice have fewer PV-interneuron-derived synaptic contacts onto cortical principal neurons. This anatomical readout is distinct from measured repetitive firing and has not been demonstrated in patients.

Parvalbumin-positive cortical GABAergic interneuron CL:0011005

Animal models

Global Cox6a2 knockout mouse Mouse partially recapitulates

Show evidence (1 reference)

url:https://www.embopress.org/doi/full/10.15252/embj.2020105759 SUPPORT Model Organism

"Furthermore, ... Cox6a2 ... − ... / ... − ... reduced the number of PV ... + ... interneuron‐derived synaptic contacts onto cortical principal neurons (Fig ... 3 ... D),"

The mouse study measures fewer PV-derived contacts onto cortical principal neurons.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

Cardiovascular 1

Cardiomyopathy HP:0001638

Show evidence (1 reference)

PMID:31155743 SUPPORT Human Clinical

"One patient had cardiomyopathy."

Cardiomyopathy was reported in one founding patient; its clinical subtype is not specified by this abstract.

Head and Neck 1

Facial muscle weakness Weakness of facial musculature HP:0030319

Show evidence (1 reference)

PMID:31155743 SUPPORT Human Clinical

"Both patients presented muscle weakness and hypotonia in 4 limbs along with facial muscle weakness."

The founding patients had limb and facial weakness with hypotonia.

Limbs 1

Limb muscle weakness HP:0003690

Show evidence (1 reference)

PMID:31155743 SUPPORT Human Clinical

"Both patients presented muscle weakness and hypotonia in 4 limbs along with facial muscle weakness."

The founding patients had limb and facial weakness with hypotonia.

Metabolism 1

Elevated blood lactate Increased circulating lactate concentration HP:0002151

Show evidence (1 reference)

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z SUPPORT Human Clinical

"Male ... Age of Report: ... 17 Years ... HPO terms(s): ... EMG abnormality (HP:0003457) ... Hypotonia (HP:0001252) ... Increased circulating lactate concentration (HP:0002151) ... Muscle weakness (HP:0001324) ... Waddling gait (HP:0002515)"

ClinGen records the adolescent compound-heterozygous patient with abnormal EMG, elevated lactate and waddling gait.

Musculoskeletal 2

Hypotonia HP:0001252

Show evidence (1 reference)

PMID:31155743 SUPPORT Human Clinical

"Both patients presented muscle weakness and hypotonia in 4 limbs along with facial muscle weakness."

The founding patients had limb and facial weakness with hypotonia.

EMG abnormality HP:0003457

Show evidence (1 reference)

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z SUPPORT Human Clinical

ClinGen records the adolescent compound-heterozygous patient with abnormal EMG, elevated lactate and waddling gait.

Nervous System 1

Waddling gait HP:0002515

Show evidence (1 reference)

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z SUPPORT Human Clinical

ClinGen records the adolescent compound-heterozygous patient with abnormal EMG, elevated lactate and waddling gait.

Respiratory 1

Respiratory insufficiency HP:0002093

Show evidence (1 reference)

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z SUPPORT Human Clinical

"Male ... Age of Death: ... 7 Weeks ... HPO terms(s): ... Cardiomyopathy (HP:0001638) ... Hypotonia (HP:0001252) ... Muscle weakness (HP:0001324) ... Respiratory insufficiency (HP:0002093)"

ClinGen records respiratory insufficiency and death at seven weeks in the homozygous founding patient.

🧬

Genetic Associations

COX6A2

Gene: COX6A2 hgnc:2279

Autosomal recessive

Show evidence (2 references)

PMID:31155743 SUPPORT Human Clinical

"The variants detected were homozygous c.117C > A (p.Ser39Arg) and compound heterozygous c.117C > A (p.Ser39Arg) and c.127T > C (p.Cys43Arg)."

The reported alleles were homozygous p.Ser39Arg and compound heterozygous p.Ser39Arg/p.Cys43Arg.

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z SUPPORT In Vitro

ClinGen summarizes the allele-expression experiments: mitochondrial targeting was retained but mutant protein decayed more rapidly after translation blockade.

Variants (2)

c.117C>A (p.Ser39Arg)

Homozygous in the infantile proband and in trans with p.Cys43Arg in the surviving proband.

Show evidence (2 references)

PMID:31155743 SUPPORT Human Clinical

"The variants detected were homozygous c.117C > A (p.Ser39Arg) and compound heterozygous c.117C > A (p.Ser39Arg) and c.127T > C (p.Cys43Arg)."

The reported alleles were homozygous p.Ser39Arg and compound heterozygous p.Ser39Arg/p.Cys43Arg.

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z SUPPORT In Vitro

ClinGen summarizes the allele-expression experiments: mitochondrial targeting was retained but mutant protein decayed more rapidly after translation blockade.

c.127T>C (p.Cys43Arg)

Compound heterozygous with p.Ser39Arg in the surviving proband.

Show evidence (1 reference)

PMID:31155743 SUPPORT Human Clinical

"The variants detected were homozygous c.117C > A (p.Ser39Arg) and compound heterozygous c.117C > A (p.Ser39Arg) and c.127T > C (p.Cys43Arg)."

The reported alleles were homozygous p.Ser39Arg and compound heterozygous p.Ser39Arg/p.Cys43Arg.

💊

Medical Actions

Supportive rehabilitation and multidisciplinary care

Action: Supportive care Ontology label: Supportive Care NCIT:C15747

Primary mitochondrial disease consensus recommends rehabilitation and individualized specialist care to maintain mobility and function. Application to COX6A2 disease is extrapolated from that broader guidance; disease-specific clinical efficacy data are lacking.

Target Phenotypes: Limb muscle weakness HP:0003690 Hypotonia HP:0001252

Show evidence (1 reference)

PMID:28749475 SUPPORT INDIRECT Human Clinical

"Evaluation and care by a rehabilitation medicine specialist and therapy are used to maintain safety, mobility, and an active lifestyle."

This general mitochondrial care recommendation supports symptom-directed rehabilitation, rather than a proven COX6A2-specific treatment.

L-carnitine and trimetazidine (preclinical)

Action: Pharmacotherapy NCIT:C15986

Agent: L-carnitine CHEBI:16347 Trimetazidine CHEBI:94789

Platform: Small molecule

L-carnitine at 200 micromolar and trimetazidine at 50 micromolar were tested individually and together in engineered knockout cardiomyocytes. The combination gave the largest ATP-content recovery and ROS reduction, and improved respiration and calcium transients. These cell-culture concentrations and results do not establish clinical dosing, safety or efficacy in COX6A2 disease.

Mechanism Target:

Reduced Cardiomyocyte ATP Content — The compounds partially restore measured cellular ATP content.

Show evidence (1 reference)

PMID:38072986 SUPPORT In Vitro

"The ATP content of KO cardiomyocytes following LC, TMZ, and LC + TMZ treatment was restored to varying degrees, of which LC + TMZ exhibited the greatest effect (Fig. 7A)."

The ATP-content assay documents the energy deficit and its partial restoration by metabolic compounds in knockout cardiomyocytes.

Reduced Cardiomyocyte Respiration — Combined treatment improves the respiratory phenotype in the knockout cells.

Show evidence (1 reference)

PMID:38072986 SUPPORT In Vitro

"The results indicated that combination treatment of the KO myocardial cells improved energy metabolism (Fig. 7C–E),"

Combined treatment improves Seahorse respiratory measurements.

Altered Cardiomyocyte Calcium Transients — The combined intervention partially restores calcium-transient parameters.

Show evidence (1 reference)

PMID:38072986 SUPPORT In Vitro

"Finally, we measured the calcium transients of cardiomyocytes following treatment, and after drug intervention, the level of calcium transport in cardiomyocytes was restored to a certain extent (Fig. 7F, G)."

Calcium-transient measurements improve after intervention.

Show evidence (3 references)

PMID:38072986 SUPPORT In Vitro

"The ATP content of KO cardiomyocytes following LC, TMZ, and LC + TMZ treatment was restored to varying degrees, of which LC + TMZ exhibited the greatest effect (Fig. 7A)."

The ATP-content assay documents the energy deficit and its partial restoration by metabolic compounds in knockout cardiomyocytes.

PMID:38072986 SUPPORT In Vitro

"We examined the concentration gradient of the therapeutic drugs and determined the optimal concentration of LC 200 µmol/L and TMZ 50 µmol/L."

These concentrations were chosen for cell-culture experiments.

PMID:38072986 SUPPORT In Vitro

"Similarly, ROS levels in cardiomyocytes were determined after treatment with the three regimens, and the LC + TMZ group exhibited the greatest reduction in ROS (Fig. 7B)."

The combined treatment most strongly reduced the ROS readout.

🔬

Diagnosis

Molecular genetic diagnosis

Exome sequencing identified the biallelic missense variants in the founding cases. Sanger confirmation and phase assessment support interpretation in the clinical-biochemical context.

Show evidence (2 references)

PMID:31155743 SUPPORT Human Clinical

"Whole exome sequencing was performed in 2 unrelated individuals who were diagnosed with congenital myopathy and presented COX deficiency in muscle pathology."

Exome sequencing was used in the two founding congenital myopathy cases.

PMID:31155743 SUPPORT Human Clinical

"The variants detected were homozygous c.117C > A (p.Ser39Arg) and compound heterozygous c.117C > A (p.Ser39Arg) and c.127T > C (p.Cys43Arg)."

The reported alleles were homozygous p.Ser39Arg and compound heterozygous p.Ser39Arg/p.Cys43Arg.

Muscle respiratory-chain studies

Muscle histochemistry, enzymology and native electrophoresis support isolated complex IV deficiency with impaired assembly and supercomplex formation.

Show evidence (3 references)

PMID:31155743 SUPPORT Human Clinical

"We found specific reductions in complex IV activities in the skeletal muscle of both individuals."

The isolated complex IV biochemical defect was measured in patient skeletal muscle.

PMID:31155743 SUPPORT Human Clinical

"Assembly of complex IV and its supercomplex formation were impaired in the muscle."

Patient muscle analysis demonstrates impaired complex IV assembly and supercomplex formation.

CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z SUPPORT Human Clinical

"Complex IV staining was uniformly weak on muscle histology and complex IV deficiency was seen on respiratory chain analyses in muscle and fibroblasts."

ClinGen summarizes the diagnostic tissue and biochemical findings.

Cardiac and respiratory assessment

General primary-mitochondrial-disease consensus supports baseline ECG/echocardiography and respiratory assessment, with follow-up individualized to findings. These are broader care recommendations rather than a COX6A2-specific surveillance trial.

Show evidence (2 references)

PMID:28749475 SUPPORT INDIRECT Human Clinical

"Standard 12-lead electrocardiogram (ECG) and echocardiogram (with measurement of left ventricular mass and systolic/diastolic function)"

The consensus recommends baseline cardiac evaluation for primary mitochondrial disease.

PMID:28749475 SUPPORT INDIRECT Human Clinical

"Baseline evaluation of respiratory status to assess for muscle weakness and other cardiopulmonary comorbidities."

General mitochondrial care guidance supports evaluating respiratory involvement in this myopathic condition.

Cognitive assessment when clinically indicated

WAIS-III follow-up of the surviving founding patient found full-scale IQ111 and processing speed89. The within-person discrepancy suggests possible vulnerability but does not establish intellectual disability or a specific psychiatric diagnosis.

Show evidence (2 references)

url:https://www.embopress.org/doi/full/10.15252/embj.2020105759 SUPPORT Human Clinical

"Interestingly, the full‐scale intelligence quotient (IQ) and performance IQ of the patient were found to be above average (Fig ... 8 ... C). However, the score obtained for the processing speed (PS) was lower than average (Fig ... 8 ... C),"

The surviving founding patient had preserved overall IQ and relatively lower processing speed; this does not diagnose intellectual disability.

url:https://www.embopress.org/doi/full/10.15252/embj.2020105759 SUPPORT Human Clinical

"the large difference between PS (89 points) and full‐scale IQ (111 points)"

The full text provides the measured scores; interpretation remains limited to one patient.

📊

Related Datasets

Effect of normal and COX6A2-deficient human pluripotent stem cells on gene expression during cardiomyocyte differentiation. geo:GSE247580

RNA sequencing of day-45 wild-type and engineered COX6A2-knockout hiPSC-derived cardiomyocytes; this is a cell model, not a patient cohort.

Homo sapiens BULK RNA SEQ BGISEQ500, single-end 50-base reads

Conditions: Wild-type hiPSC-derived cardiomyocytes COX6A2-knockout hiPSC-derived cardiomyocytes

PMID:38072986

Show evidence (2 references)

PMID:38072986 SUPPORT In Vitro

"The mRNA library was established with purified cardiomyocytes on day 45 of differentiation."

The full text identifies the RNA-seq sample stage.

GEO:GSE247580 SUPPORT In Vitro

"COX6A2 gene knockout did not affect the pluripotency and differentiation efficiency of hiPSCs."

The verified GEO record identifies the engineered knockout study.

RNA-seq of PV+ interneurons in WT and Cox6a2-/- mice arrayexpress:E-MTAB-7879

Bulk RNA sequencing of sorted cortical PV interneurons from P15 wild-type and global knockout mice, four wild-type and six knockout libraries. Reduced Pvalb, Gad1 and Gad2 transcripts accompany altered neuronal signaling; transcript abundance does not directly measure GABA synthesis.

Mus musculus BULK RNA SEQ n=10 Illumina NextSeq500, single-end 75-base reads

Conditions: Wild-type cortical PV interneurons Cox6a2-/- cortical PV interneurons

PMID:32744742

Show evidence (3 references)

url:https://www.embopress.org/doi/full/10.15252/embj.2020105759 SUPPORT Model Organism

"PV ... + ... interneurons were sorted from cortices of PV‐EGFP WT and ... Cox6a2 ... − ... / ... − ... mice at P15 and processed for bulk RNA sequencing ( ... n ... = 4 WT, 6 ... Cox6a2 ... − ... / ... − ... ; P15)."

The primary report specifies cell population, age and group sample sizes.

url:https://www.embopress.org/doi/full/10.15252/embj.2020105759 SUPPORT Other

"The RNA‐seq data generated in this study have been deposited in the ArrayExpress database at EMBL‐EBI under accession number ... E‐MTAB‐7879"

The primary report deposits this dataset in ArrayExpress.

url:https://www.embopress.org/doi/full/10.15252/embj.2020105759 SUPPORT Model Organism

"Both glutamate decarboxylase 1 ( ... Gad1 ... ) and 2 ( ... Gad2 ... ) genes also exhibited a reduced expression (Fig ... 4 ... B),"

The study reports reduced Gad1/Gad2 transcripts in sorted knockout PV interneurons.

🧫

Experimental Models

HeLa COX6A2 missense-expression models CELL_LINE

p.Ser39Arg and p.Cys43Arg retain mitochondrial localization but show accelerated loss after translation blockade, as summarized in ClinGen from the 2019 study.

Cell source

HeLa cells expressing wild-type or mutant COX6A2-EGFP

Publication

PMID:31155743

Pathograph links

Reduced COX6A2 Protein Stability partially recapitulates observes: cellular

Limitations: Fusion-protein expression and translation blockade do not reproduce endogenous patient expression or tissue function.

Show evidence (1 reference)

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z SUPPORT In Vitro

ClinGen summarizes the allele-expression experiments: mitochondrial targeting was retained but mutant protein decayed more rapidly after translation blockade.

COX6A2-null hiPSC-derived cardiomyocytes IPSC_DERIVED_MODEL

Engineered null cells retain pluripotency and cardiac differentiation, then develop cellular hypertrophy, mitochondrial abnormalities, reduced respiration and ATP, altered calcium dynamics and impaired contraction. Remodeling transcripts and cell size are not equivalent to tissue fibrosis. L-carnitine/trimetazidine rescue is preclinical.

Organism

Homo sapiens NCBITaxon:9606

Cell source

Commercial U2 hiPSC line with CRISPR/Cas9 homozygous COX6A2 knockout

Publication

PMID:38072986

Pathograph links

Reduced COX6A2 Protein Abundance partially recapitulates observes: cellular

Limitations: Engineered complete knockout differs from the two patient missense genotypes; cultured cells cannot establish a clinical cardiomyopathy subtype or treatment efficacy.

Reduced Cardiomyocyte Respiration partially recapitulates observes: cellular

Limitations: Engineered complete knockout differs from the two patient missense genotypes; cultured cells cannot establish a clinical cardiomyopathy subtype or treatment efficacy.

Reduced Cardiomyocyte ATP Content partially recapitulates observes: cellular

Limitations: Engineered complete knockout differs from the two patient missense genotypes; cultured cells cannot establish a clinical cardiomyopathy subtype or treatment efficacy.

Increased Mitochondrial Superoxide partially recapitulates observes: cellular

Limitations: Engineered complete knockout differs from the two patient missense genotypes; cultured cells cannot establish a clinical cardiomyopathy subtype or treatment efficacy.

Reduced Mitochondrial Membrane Potential partially recapitulates observes: cellular

Limitations: Engineered complete knockout differs from the two patient missense genotypes; cultured cells cannot establish a clinical cardiomyopathy subtype or treatment efficacy.

Altered Cardiomyocyte Calcium Transients partially recapitulates observes: cellular

Limitations: Engineered complete knockout differs from the two patient missense genotypes; cultured cells cannot establish a clinical cardiomyopathy subtype or treatment efficacy.

Reduced Cardiomyocyte Contractility partially recapitulates observes: cellular

Limitations: Engineered complete knockout differs from the two patient missense genotypes; cultured cells cannot establish a clinical cardiomyopathy subtype or treatment efficacy.

Cardiomyocyte Hypertrophy partially recapitulates observes: cellular

Limitations: Engineered complete knockout differs from the two patient missense genotypes; cultured cells cannot establish a clinical cardiomyopathy subtype or treatment efficacy.

Show evidence (7 references)

PMID:38072986 SUPPORT In Vitro

"The U2 human induced pluripotent stem cell line (hiPSCs-U2, purchased from Cellapy, China)"

The study starts from a commercial stem-cell line, not a patient-specific line.

PMID:38072986 SUPPORT In Vitro

"the basal respiration, maximal respiration, and ATP production of the KO cardiomyocytes were significantly lower compared with that of WT cardiomyocytes (Fig. 5B)."

Seahorse measurements show lower respiratory capacity and ATP-linked respiration in engineered knockout cardiomyocytes.

PMID:38072986 SUPPORT In Vitro

"The ATP content of KO cardiomyocytes following LC, TMZ, and LC + TMZ treatment was restored to varying degrees, of which LC + TMZ exhibited the greatest effect (Fig. 7A)."

The ATP-content assay documents the energy deficit and its partial restoration by metabolic compounds in knockout cardiomyocytes.

+ 4 more references

🐁

Animal Models

Global Cox6a2 knockout mouse

Global knockout mice reproduce complex IV biochemical impairment and mild workload-dependent diastolic dysfunction. Bulk heart and skeletal-muscle ATP remain preserved. Skeletal muscle shifts toward oxidative fibers with increased isolated fatigue resistance, while uphill exercise performance decreases. Cortical PV cells have oxidative damage, reduced nets and impaired dendritic and fast-spiking maturation, without loss of PV-cell density. Female behavioral cohorts show locomotor hyperactivity with preserved social preference and prepulse inhibition; these are not human psychiatric diagnoses.

Species

Mouse

Genotype

Cox6a2-/-

Publication

PMID:11788423

Pathograph links

Impaired Complex IV Assembly partially recapitulates observes: organism

Limitations: Global null mice show substantial compensation and do not uniformly reproduce human myopathy or the ATP deficit of cultured cardiomyocytes.

Reduced Cytochrome c Oxidase Activity partially recapitulates observes: organism

Limitations: Global null mice show substantial compensation and do not uniformly reproduce human myopathy or the ATP deficit of cultured cardiomyocytes.

Interneuron Oxidative DNA Damage partially recapitulates observes: organism

Limitations: Global null mice show substantial compensation and do not uniformly reproduce human myopathy or the ATP deficit of cultured cardiomyocytes.

Reduced Perineuronal Nets partially recapitulates observes: organism

Limitations: Global null mice show substantial compensation and do not uniformly reproduce human myopathy or the ATP deficit of cultured cardiomyocytes.

Impaired Fast-Spiking Maturation partially recapitulates observes: organism

Limitations: Global null mice show substantial compensation and do not uniformly reproduce human myopathy or the ATP deficit of cultured cardiomyocytes.

Reduced Interneuron Dendritic Arborization partially recapitulates observes: organism

Limitations: Global null mice show substantial compensation and do not uniformly reproduce human myopathy or the ATP deficit of cultured cardiomyocytes.

Reduced PV Interneuron Synaptic Contacts partially recapitulates observes: cellular

Limitations: Mouse synaptic anatomy does not establish a human psychiatric diagnosis.

Behavioral findings depend on protocol and cohort: the metabolic study reported reduced spontaneous activity, whereas the later female cohort showed increased locomotion in the open-field and social-interaction tests.

Show evidence (15 references)

PMID:11788423 SUPPORT Model Organism

"Total COX activity was decreased in hearts from mutant mice, which appears to be a consequence of altered assembly of the holoenzyme COX."

The global knockout mouse study directly reports reduced cardiac COX activity and attributes it to altered holoenzyme assembly.

PMID:11788423 SUPPORT Model Organism

"However, total myocardial ATP was not significantly different in wild-type and mutant mice."

Bulk myocardial ATP was preserved despite the mouse cardiac phenotype.

PMID:23460811 SUPPORT Model Organism

"Finally, despite the loss of COX6A2 expression, ATP levels within the skeletal muscles of Cox6a2 −/− and WT mice were similar (Fig. 7E),"

Skeletal-muscle ATP was preserved in global knockout mice, unlike the ATP-content deficit in cultured cardiomyocytes.

+ 12 more references

PV-specific conditional Cox6a2 knockout mouse

Conditional deletion in PV interneurons permits cell-specific energy measurements with AAV-PercevalHR and two-photon imaging of ex vivo slices. The measured outcome is an ATP-to-ADP ratio.

Species

Mouse

Genotype

PV-Cre; Cox6a2fl/fl

Pathograph links

Reduced Interneuron ATP-to-ADP Ratio partially recapitulates observes: cellular

Limitations: Ex vivo neuronal ATP-to-ADP ratio is not a measurement of total brain ATP or human cognitive performance.

Show evidence (1 reference)

PMID:32744742 SUPPORT Model Organism

"Such dramatic effects were likely due to an essential role of COX6A2 in energy balance of PV+ interneurons, underscored by a decrease in the ATP-to-ADP ratio in Cox6a2-/- PV+ interneurons."

The abstract reports the reduced ATP-to-ADP ratio in knockout PV interneurons; the full paper identifies the conditional knockout and PercevalHR slice-imaging experiment.

{ }

Source YAML

click to show

name: COX6A2-Related COX Deficiency
category: Mendelian
creation_date: '2026-06-23T00:00:00Z'
synonyms:
- COX6A2 deficiency
- Mitochondrial complex IV deficiency, nuclear type 18
- MC4DN18
- COX6A2-related cytochrome c oxidase deficiency
- Muscle-specific cytochrome c oxidase deficiency
disease_term:
preferred_term: COX6A2-related COX deficiency (MC4DN18)
term:
id: MONDO:0033653
label: mitochondrial complex IV deficiency, nuclear type 18
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
notes: >-
Clinical evidence remains limited to two founding probands and cognitive follow-up of the surviving proband.
These reports do not establish reliable phenotype frequencies, penetrance, a genotype-severity rule or separate
clinical subtypes. Mouse and engineered human-cell findings are mechanistic models rather than additional
clinical cases. Reduced ATP availability is context-dependent: total ATP was maintained in global knockout
mouse heart and skeletal muscle, while ATP content fell in cultured knockout cardiomyocytes and the ATP-to-ADP
ratio fell in PV-specific knockout neurons. The pvalb transcriptomic cell class excludes some parvalbumin-expressing
interneurons; the broader GABAergic interneuron binding represents the experimentally selected PV-positive
population.
classifications:
harrisons_chapter:
- classification_value: NEUROLOGIC
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Both patients presented muscle weakness and hypotonia in 4 limbs along with facial muscle weakness.
explanation: The founding patients had limb and facial weakness with hypotonia.
- classification_value: GENETICS_ENVIRONMENT_DISEASE
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The variants detected were homozygous c.117C > A (p.Ser39Arg) and compound heterozygous c.117C > A
(p.Ser39Arg) and c.127T > C (p.Cys43Arg).
explanation: >-
The reported alleles were homozygous p.Ser39Arg and compound heterozygous p.Ser39Arg/p.Cys43Arg.
mechanistic_category:
- classification_value: mitochondrial disease
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We found specific reductions in complex IV activities in the skeletal muscle of both individuals.
explanation: The isolated complex IV biochemical defect was measured in patient skeletal muscle.
icimd_category:
- classification_value: complex_iv_subunits_and_assembly_factors
notes: >-
ICIMD (Ferreira et al. 2021, PMID:33340416), nuclear-encoded complex IV subunit and assembly factor defects;
COX6A2 is a structural subunit.
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
The two founding patients carried homozygous or compound-heterozygous missense variants; the compound allelic
phase was confirmed by cloning PCR products.
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The variants detected were homozygous c.117C > A (p.Ser39Arg) and compound heterozygous c.117C > A (p.Ser39Arg)
and c.127T > C (p.Cys43Arg).
explanation: >-
The reported alleles were homozygous p.Ser39Arg and compound heterozygous p.Ser39Arg/p.Cys43Arg.
- reference: >-
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z
reference_title: curation results for Gene-Disease Validity
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The allelic phases of the compound heterozygous variants in P2 were confirmed by cloning their PCR products
explanation: ClinGen records phase confirmation for the second patient.
diagnosis:
- name: Molecular genetic diagnosis
description: >-
Exome sequencing identified the biallelic missense variants in the founding cases. Sanger confirmation
and phase assessment support interpretation in the clinical-biochemical context.
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Whole exome sequencing was performed in 2 unrelated individuals who were diagnosed with congenital myopathy
and presented COX deficiency in muscle pathology.
explanation: Exome sequencing was used in the two founding congenital myopathy cases.
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The variants detected were homozygous c.117C > A (p.Ser39Arg) and compound heterozygous c.117C > A (p.Ser39Arg)
and c.127T > C (p.Cys43Arg).
explanation: >-
The reported alleles were homozygous p.Ser39Arg and compound heterozygous p.Ser39Arg/p.Cys43Arg.
- name: Muscle respiratory-chain studies
description: >-
Muscle histochemistry, enzymology and native electrophoresis support isolated complex IV deficiency with
impaired assembly and supercomplex formation.
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We found specific reductions in complex IV activities in the skeletal muscle of both individuals.
explanation: The isolated complex IV biochemical defect was measured in patient skeletal muscle.
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Assembly of complex IV and its supercomplex formation were impaired in the muscle.
explanation: Patient muscle analysis demonstrates impaired complex IV assembly and supercomplex formation.
- reference: CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z
reference_title: COX6A2 / mitochondrial disease (Moderate)
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Complex IV staining was uniformly weak on muscle histology and complex IV deficiency was seen on respiratory
chain analyses in muscle and fibroblasts.
explanation: ClinGen summarizes the diagnostic tissue and biochemical findings.
- name: Cardiac and respiratory assessment
description: >-
General primary-mitochondrial-disease consensus supports baseline ECG/echocardiography and respiratory
assessment, with follow-up individualized to findings. These are broader care recommendations rather than
a COX6A2-specific surveillance trial.
evidence:
- reference: PMID:28749475
reference_title: >-
Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial
Medicine Society.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Standard 12-lead electrocardiogram (ECG) and echocardiogram (with measurement of left ventricular mass
and systolic/diastolic function)
explanation: The consensus recommends baseline cardiac evaluation for primary mitochondrial disease.
directness: INDIRECT
- reference: PMID:28749475
reference_title: >-
Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial
Medicine Society.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Baseline evaluation of respiratory status to assess for muscle weakness and other cardiopulmonary comorbidities.
explanation: >-
General mitochondrial care guidance supports evaluating respiratory involvement in this myopathic condition.
directness: INDIRECT
- name: Cognitive assessment when clinically indicated
description: >-
WAIS-III follow-up of the surviving founding patient found full-scale IQ111 and processing speed89. The
within-person discrepancy suggests possible vulnerability but does not establish intellectual disability
or a specific psychiatric diagnosis.
evidence:
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Interestingly, the full‐scale intelligence quotient (IQ) and performance IQ of the patient were found
to be above average (Fig ... 8 ... C). However, the score obtained for the processing speed (PS) was
lower than average (Fig ... 8 ... C),
explanation: >-
The surviving founding patient had preserved overall IQ and relatively lower processing speed; this does
not diagnose intellectual disability.
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: the large difference between PS (89 points) and full‐scale IQ (111 points)
explanation: The full text provides the measured scores; interpretation remains limited to one patient.
experimental_models:
- name: HeLa COX6A2 missense-expression models
experimental_model_type: CELL_LINE
cell_source: HeLa cells expressing wild-type or mutant COX6A2-EGFP
description: >-
p.Ser39Arg and p.Cys43Arg retain mitochondrial localization but show accelerated loss after translation
blockade, as summarized in ClinGen from the 2019 study.
publication: PMID:31155743
evidence:
- reference: >-
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z
reference_title: curation results for Gene-Disease Validity
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
HeLa studies with COX6A2-fused EGFPs with WT and Ser39Arg mutation show transport to mitochondria, but
dramatically reduced expression of protein after blocking de novo protein synthesis compared to WT at
2,4,6 hours
explanation: >-
ClinGen summarizes the allele-expression experiments: mitochondrial targeting was retained but mutant
protein decayed more rapidly after translation blockade.
modeled_mechanisms:
- target: Reduced COX6A2 Protein Stability
relationship: PARTIALLY_RECAPITULATES
model_scale: CELLULAR
limitations: >-
Fusion-protein expression and translation blockade do not reproduce endogenous patient expression or
tissue function.
- name: COX6A2-null hiPSC-derived cardiomyocytes
experimental_model_type: IPSC_DERIVED_MODEL
organism:
preferred_term: Homo sapiens
term:
id: NCBITaxon:9606
label: Homo sapiens
cell_types:
- preferred_term: cardiac muscle cell
term:
id: CL:0000746
label: cardiac muscle cell
cell_source: Commercial U2 hiPSC line with CRISPR/Cas9 homozygous COX6A2 knockout
description: >-
Engineered null cells retain pluripotency and cardiac differentiation, then develop cellular hypertrophy,
mitochondrial abnormalities, reduced respiration and ATP, altered calcium dynamics and impaired contraction.
Remodeling transcripts and cell size are not equivalent to tissue fibrosis. L-carnitine/trimetazidine rescue
is preclinical.
publication: PMID:38072986
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: The U2 human induced pluripotent stem cell line (hiPSCs-U2, purchased from Cellapy, China)
explanation: The study starts from a commercial stem-cell line, not a patient-specific line.
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
the basal respiration, maximal respiration, and ATP production of the KO cardiomyocytes were significantly
lower compared with that of WT cardiomyocytes (Fig. 5B).
explanation: >-
Seahorse measurements show lower respiratory capacity and ATP-linked respiration in engineered knockout
cardiomyocytes.
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The ATP content of KO cardiomyocytes following LC, TMZ, and LC + TMZ treatment was restored to varying
degrees, of which LC + TMZ exhibited the greatest effect (Fig. 7A).
explanation: >-
The ATP-content assay documents the energy deficit and its partial restoration by metabolic compounds
in knockout cardiomyocytes.
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Compared with WT cardiomyocytes, mitochondrial ROS in KO cardiomyocytes was significantly increased (Fig.
4F and Additional file 1: Fig. S3D),
explanation: MitoSOX detects increased mitochondrial superoxide in knockout cardiomyocytes.
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Compared with WT cardiomyocytes, the peak value of calcium transients in KO cardiomyocytes was significantly
reduced and the time to peak time was significantly prolonged (Fig. 6C–F),
explanation: >-
Fluo-4 imaging measures smaller and slower calcium transients. It does not directly establish mitochondrial
calcium overload.
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Compared with WT cardiomyocytes, the contraction intensity of KO cardiomyocytes was significantly decreased
(Fig. 6H). Moreover, the time to peak (Fig. 6I) and relaxation duration (Fig. 6J) were significantly
prolonged.
explanation: >-
Video-derived contraction intensity decreases and contraction/relaxation kinetics slow; this is not a
calibrated force measurement.
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
the surface area of the KO cardiomyocytes was significantly increased compared with the WT cardiomyocytes
as determined by laser confocal microscopy (Fig. 3A).
explanation: Phalloidin imaging demonstrates increased cardiomyocyte area after knockout.
modeled_mechanisms:
- target: Reduced COX6A2 Protein Abundance
relationship: PARTIALLY_RECAPITULATES
model_scale: CELLULAR
limitations: >-
Engineered complete knockout differs from the two patient missense genotypes; cultured cells cannot establish
a clinical cardiomyopathy subtype or treatment efficacy.
- target: Reduced Cardiomyocyte Respiration
relationship: PARTIALLY_RECAPITULATES
model_scale: CELLULAR
limitations: >-
Engineered complete knockout differs from the two patient missense genotypes; cultured cells cannot establish
a clinical cardiomyopathy subtype or treatment efficacy.
- target: Reduced Cardiomyocyte ATP Content
relationship: PARTIALLY_RECAPITULATES
model_scale: CELLULAR
limitations: >-
Engineered complete knockout differs from the two patient missense genotypes; cultured cells cannot establish
a clinical cardiomyopathy subtype or treatment efficacy.
- target: Increased Mitochondrial Superoxide
relationship: PARTIALLY_RECAPITULATES
model_scale: CELLULAR
limitations: >-
Engineered complete knockout differs from the two patient missense genotypes; cultured cells cannot establish
a clinical cardiomyopathy subtype or treatment efficacy.
- target: Reduced Mitochondrial Membrane Potential
relationship: PARTIALLY_RECAPITULATES
model_scale: CELLULAR
limitations: >-
Engineered complete knockout differs from the two patient missense genotypes; cultured cells cannot establish
a clinical cardiomyopathy subtype or treatment efficacy.
- target: Altered Cardiomyocyte Calcium Transients
relationship: PARTIALLY_RECAPITULATES
model_scale: CELLULAR
limitations: >-
Engineered complete knockout differs from the two patient missense genotypes; cultured cells cannot establish
a clinical cardiomyopathy subtype or treatment efficacy.
- target: Reduced Cardiomyocyte Contractility
relationship: PARTIALLY_RECAPITULATES
model_scale: CELLULAR
limitations: >-
Engineered complete knockout differs from the two patient missense genotypes; cultured cells cannot establish
a clinical cardiomyopathy subtype or treatment efficacy.
- target: Cardiomyocyte Hypertrophy
relationship: PARTIALLY_RECAPITULATES
model_scale: CELLULAR
limitations: >-
Engineered complete knockout differs from the two patient missense genotypes; cultured cells cannot establish
a clinical cardiomyopathy subtype or treatment efficacy.
animal_models:
- name: Global Cox6a2 knockout mouse
species: Mouse
genotype: Cox6a2-/-
description: >-
Global knockout mice reproduce complex IV biochemical impairment and mild workload-dependent diastolic
dysfunction. Bulk heart and skeletal-muscle ATP remain preserved. Skeletal muscle shifts toward oxidative
fibers with increased isolated fatigue resistance, while uphill exercise performance decreases. Cortical
PV cells have oxidative damage, reduced nets and impaired dendritic and fast-spiking maturation, without
loss of PV-cell density. Female behavioral cohorts show locomotor hyperactivity with preserved social preference
and prepulse inhibition; these are not human psychiatric diagnoses.
publication: PMID:11788423
evidence:
- reference: PMID:11788423
reference_title: Cardiac dysfunction in mice lacking cytochrome-c oxidase subunit VIaH.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Total COX activity was decreased in hearts from mutant mice, which appears to be a consequence of altered
assembly of the holoenzyme COX.
explanation: >-
The global knockout mouse study directly reports reduced cardiac COX activity and attributes it to altered
holoenzyme assembly.
- reference: PMID:11788423
reference_title: Cardiac dysfunction in mice lacking cytochrome-c oxidase subunit VIaH.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: However, total myocardial ATP was not significantly different in wild-type and mutant mice.
explanation: Bulk myocardial ATP was preserved despite the mouse cardiac phenotype.
- reference: PMID:23460811
reference_title: >-
Mice deficient in the respiratory chain gene Cox6a2 are protected against high-fat diet-induced obesity
and insulin resistance.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Finally, despite the loss of COX6A2 expression, ATP levels within the skeletal muscles of Cox6a2 −/−
and WT mice were similar (Fig. 7E),
explanation: >-
Skeletal-muscle ATP was preserved in global knockout mice, unlike the ATP-content deficit in cultured
cardiomyocytes.
- reference: PMID:23460811
reference_title: >-
Mice deficient in the respiratory chain gene Cox6a2 are protected against high-fat diet-induced obesity
and insulin resistance.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
The specific force production (force/cross-sectional area) of soleus and extensor digitorum longus (EDL)
muscles (Fig. 7A), as well as the grip strength (Fig. 7B) were similar between WT and Cox6a2 −/− mice.
explanation: Global knockout did not reduce isolated specific muscle force or grip strength.
- reference: PMID:23460811
reference_title: >-
Mice deficient in the respiratory chain gene Cox6a2 are protected against high-fat diet-induced obesity
and insulin resistance.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
However, in a fatiguing protocol, isolated soleus muscle of Cox6a2 −/− mice was more resistant to fatigue
and recovered much faster as compared to WT muscle (Fig. 7D),
explanation: >-
Isolated knockout soleus was more fatigue-resistant, rather than recapitulating weakness uniformly.
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
8‐OHdG immunoreactivity was significantly higher in PV ... + ... interneurons in both cortices in ...
Cox6a2 ... −/− ... mice ( ... n ... = 4 WT, 4 ... Cox6a2 ... − ... / ... − ... ; 2 months old).
explanation: Increased 8-OHdG signal supports oxidative DNA damage in knockout cortical PV interneurons.
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
WFA immunoreactivity around PV ... + ... cells was lower in both cortices in ... Cox6a2 ... −/− ... mice
( ... n ... = 4 WT, 4 ... Cox6a2 ... − ... / ... − ... ; 2 months old).
explanation: Reduced WFA labeling supports diminished perineuronal nets in the mouse model.
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Thus, maximal firing frequency reached during 2‐s depolarizing current pulses was lower in P34–45 ...
Cox6a2 ... − ... / ... − ... compared with WT PV ... + ... interneurons.
explanation: Older knockout PV interneurons fail to acquire normal sustained high-frequency firing.
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
However, at P34‐P45, ... Cox6a2 ... −/− ... PV ... + ... interneurons showed lower dendritic length and
full branch depth than WT PV ... + ... interneurons.
explanation: Dendritic length and branch depth are reduced at the later developmental stage.
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Furthermore, ... Cox6a2 ... − ... / ... − ... reduced the number of PV ... + ... interneuron‐derived
synaptic contacts onto cortical principal neurons (Fig ... 3 ... D),
explanation: The mouse study measures fewer PV-derived contacts onto cortical principal neurons.
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We found that ... Cox6a2 ... −/− ... had negligible effect on the density and distribution of PV ...
+ ... interneurons in the cortex at ~ P60 and ~ P180 (Fig ... EV3 ... A–D).
explanation: >-
PV-cell density and distribution are largely retained despite molecular and functional abnormalities.
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In the OFT and SIT, ... Cox6a2 ... − ... / ... − ... mice exhibited increased locomotor activity since
they traveled longer distances and they did so faster than WT mice (Fig ... 7 ... B and D).
explanation: The female knockout cohort shows increased locomotor activity.
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
In the SIT, both ... Cox6a2 ... − ... / ... − ... and WT mice preferred to spend more time interacting
with a stranger mouse than with an inanimate object (Fig ... 7 ... D).
explanation: Social preference is preserved in the tested mouse cohort.
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
We did not detect significant differences in the PPI of the acoustic startle response in ... Cox6a2 ...
− ... / ... − ... mice at prepulses of 72, 74, 78, and 86 dB (Fig ... 7 ... G).
explanation: Prepulse inhibition is preserved under the tested conditions.
- reference: PMID:23460811
reference_title: >-
Mice deficient in the respiratory chain gene Cox6a2 are protected against high-fat diet-induced obesity
and insulin resistance.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
During the night, there was a non-significant increase in oxygen consumption and heat generation in Cox6a2
−/− mice, despite a 25% decrease in spontaneous activity compared to WT mice (Fig. 4C).
explanation: >-
The metabolic study measured lower spontaneous activity, illustrating the context dependence of behavioral
findings.
modeled_mechanisms:
- target: Impaired Complex IV Assembly
relationship: PARTIALLY_RECAPITULATES
model_scale: ORGANISM
limitations: >-
Global null mice show substantial compensation and do not uniformly reproduce human myopathy or the ATP
deficit of cultured cardiomyocytes.
- target: Reduced Cytochrome c Oxidase Activity
relationship: PARTIALLY_RECAPITULATES
model_scale: ORGANISM
limitations: >-
Global null mice show substantial compensation and do not uniformly reproduce human myopathy or the ATP
deficit of cultured cardiomyocytes.
- target: Interneuron Oxidative DNA Damage
relationship: PARTIALLY_RECAPITULATES
model_scale: ORGANISM
limitations: >-
Global null mice show substantial compensation and do not uniformly reproduce human myopathy or the ATP
deficit of cultured cardiomyocytes.
- target: Reduced Perineuronal Nets
relationship: PARTIALLY_RECAPITULATES
model_scale: ORGANISM
limitations: >-
Global null mice show substantial compensation and do not uniformly reproduce human myopathy or the ATP
deficit of cultured cardiomyocytes.
- target: Impaired Fast-Spiking Maturation
relationship: PARTIALLY_RECAPITULATES
model_scale: ORGANISM
limitations: >-
Global null mice show substantial compensation and do not uniformly reproduce human myopathy or the ATP
deficit of cultured cardiomyocytes.
- target: Reduced Interneuron Dendritic Arborization
relationship: PARTIALLY_RECAPITULATES
model_scale: ORGANISM
limitations: >-
Global null mice show substantial compensation and do not uniformly reproduce human myopathy or the ATP
deficit of cultured cardiomyocytes.
- target: Reduced PV Interneuron Synaptic Contacts
relationship: PARTIALLY_RECAPITULATES
model_scale: CELLULAR
limitations: Mouse synaptic anatomy does not establish a human psychiatric diagnosis.
notes: >-
Behavioral findings depend on protocol and cohort: the metabolic study reported reduced spontaneous activity,
whereas the later female cohort showed increased locomotion in the open-field and social-interaction tests.
- name: PV-specific conditional Cox6a2 knockout mouse
species: Mouse
genotype: PV-Cre; Cox6a2fl/fl
description: >-
Conditional deletion in PV interneurons permits cell-specific energy measurements with AAV-PercevalHR and
two-photon imaging of ex vivo slices. The measured outcome is an ATP-to-ADP ratio.
evidence:
- reference: PMID:32744742
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports
their function.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Such dramatic effects were likely due to an essential role of COX6A2 in energy balance of PV+ interneurons,
underscored by a decrease in the ATP-to-ADP ratio in Cox6a2-/- PV+ interneurons.
explanation: >-
The abstract reports the reduced ATP-to-ADP ratio in knockout PV interneurons; the full paper identifies
the conditional knockout and PercevalHR slice-imaging experiment.
modeled_mechanisms:
- target: Reduced Interneuron ATP-to-ADP Ratio
relationship: PARTIALLY_RECAPITULATES
model_scale: CELLULAR
limitations: >-
Ex vivo neuronal ATP-to-ADP ratio is not a measurement of total brain ATP or human cognitive performance.
datasets:
- accession: geo:GSE247580
title: >-
Effect of normal and COX6A2-deficient human pluripotent stem cells on gene expression during cardiomyocyte
differentiation.
description: >-
RNA sequencing of day-45 wild-type and engineered COX6A2-knockout hiPSC-derived cardiomyocytes; this is
a cell model, not a patient cohort.
organism:
preferred_term: Homo sapiens
term:
id: NCBITaxon:9606
label: Homo sapiens
data_type: BULK_RNA_SEQ
conditions:
- Wild-type hiPSC-derived cardiomyocytes
- COX6A2-knockout hiPSC-derived cardiomyocytes
platform: BGISEQ500, single-end 50-base reads
publication: PMID:38072986
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: The mRNA library was established with purified cardiomyocytes on day 45 of differentiation.
explanation: The full text identifies the RNA-seq sample stage.
- reference: GEO:GSE247580
reference_title: >-
Effect of normal and COX6A2-deficient human pluripotent stem cells on gene expression during cardiomyocyte
differentiation.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: COX6A2 gene knockout did not affect the pluripotency and differentiation efficiency of hiPSCs.
explanation: The verified GEO record identifies the engineered knockout study.
- accession: arrayexpress:E-MTAB-7879
title: RNA-seq of PV+ interneurons in WT and Cox6a2-/- mice
description: >-
Bulk RNA sequencing of sorted cortical PV interneurons from P15 wild-type and global knockout mice, four
wild-type and six knockout libraries. Reduced Pvalb, Gad1 and Gad2 transcripts accompany altered neuronal
signaling; transcript abundance does not directly measure GABA synthesis.
organism:
preferred_term: Mus musculus
term:
id: NCBITaxon:10090
label: Mus musculus
data_type: BULK_RNA_SEQ
sample_count: 10
conditions:
- Wild-type cortical PV interneurons
- Cox6a2-/- cortical PV interneurons
platform: Illumina NextSeq500, single-end 75-base reads
publication: PMID:32744742
evidence:
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
PV ... + ... interneurons were sorted from cortices of PV‐EGFP WT and ... Cox6a2 ... − ... / ... − ...
mice at P15 and processed for bulk RNA sequencing ( ... n ... = 4 WT, 6 ... Cox6a2 ... − ... / ... −
... ; P15).
explanation: The primary report specifies cell population, age and group sample sizes.
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: OTHER
snippet: >-
The RNA‐seq data generated in this study have been deposited in the ArrayExpress database at EMBL‐EBI
under accession number ... E‐MTAB‐7879
explanation: The primary report deposits this dataset in ArrayExpress.
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Both glutamate decarboxylase 1 ( ... Gad1 ... ) and 2 ( ... Gad2 ... ) genes also exhibited a reduced
expression (Fig ... 4 ... B),
explanation: The study reports reduced Gad1/Gad2 transcripts in sorted knockout PV interneurons.
description: >-
COX6A2-related cytochrome c oxidase deficiency (MC4DN18) is an autosomal recessive mitochondrial disorder
associated with biallelic missense variants in the nuclear-encoded complex IV structural subunit COX6A2.
The two founding patients had congenital myopathy with limb and facial weakness and hypotonia; one had cardiomyopathy
and died in early infancy, while the other survived into adolescence. Patient muscle shows reduced complex
IV activity and impaired assembly and supercomplex formation. COX6A2 is enriched in striated muscle but is
also expressed in cortical interneurons. Later mouse neuronal and human stem-cell-derived cardiomyocyte experiments
identify cell-specific energy, redox and functional abnormalities. The surviving patient had preserved overall
intelligence with relatively lower processing speed; a broader human neurologic syndrome remains unestablished.
references:
- reference: PMID:31155743
title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
- reference: PMID:38072986
title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
- reference: PMID:23460811
title: >-
Mice deficient in the respiratory chain gene Cox6a2 are protected against high-fat diet-induced obesity
and insulin resistance.
- reference: PMID:11788423
title: Cardiac dysfunction in mice lacking cytochrome-c oxidase subunit VIaH.
- reference: PMID:28749475
title: >-
Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial
Medicine Society.
- reference: CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z
title: COX6A2 / mitochondrial disease (Moderate)
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
- reference: >-
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z
title: curation results for Gene-Disease Validity
- reference: PMID:32744742
title: >-
Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports
their function.
pathophysiology:
- name: Reduced COX6A2 Protein Stability
description: >-
The p.Ser39Arg and p.Cys43Arg proteins are less stable in HeLa expression experiments. Mitochondrial targeting
persists, distinguishing protein instability from an import defect.
biological_scale: MOLECULAR
evidence:
- reference: >-
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z
reference_title: curation results for Gene-Disease Validity
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
HeLa studies with COX6A2-fused EGFPs with WT and Ser39Arg mutation show transport to mitochondria, but
dramatically reduced expression of protein after blocking de novo protein synthesis compared to WT at
2,4,6 hours
explanation: >-
ClinGen summarizes the allele-expression experiments: mitochondrial targeting was retained but mutant
protein decayed more rapidly after translation blockade.
- reference: >-
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z
reference_title: curation results for Gene-Disease Validity
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
HeLa studies with COX6A2-fused EGFPs with WT and Cys43Arg mutation show transport to mitochondria, but
dramatically reduced expression of protein after blocking de novo protein synthesis compared to WT at
2,4,6 hours
explanation: ClinGen also summarizes accelerated decay of p.Cys43Arg protein after translation blockade.
downstream:
- target: Reduced COX6A2 Protein Abundance
description: Accelerated loss of mutant protein can reduce its steady-state abundance.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: >-
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z
reference_title: curation results for Gene-Disease Validity
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
HeLa studies with COX6A2-fused EGFPs with WT and Ser39Arg mutation show transport to mitochondria,
but dramatically reduced expression of protein after blocking de novo protein synthesis compared to
WT at 2,4,6 hours
explanation: >-
ClinGen summarizes the allele-expression experiments: mitochondrial targeting was retained but mutant
protein decayed more rapidly after translation blockade.
directness: INDIRECT
- name: Reduced COX6A2 Protein Abundance
description: >-
Reduced COX6A2 protein is documented in patient samples. Complete gene deletion is the experimental perturbation
in mouse and engineered cardiomyocyte models; it does not reproduce the precise patient missense genotypes.
biological_scale: MOLECULAR
evidence:
- reference: >-
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z
reference_title: curation results for Gene-Disease Validity
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Uniformly faint COX staining, Isolated complex IV deficiency by spectrophotometry, decreased COX6A2 western
blot
explanation: >-
ClinGen summarizes decreased COX6A2 protein and isolated complex IV deficiency in the founding patient
material.
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The results indicated that no significant COX6A2 protein expression was present in COX6A2−/−hiPSCs (Fig.
1D,
explanation: Protein depletion was confirmed in the engineered knockout stem-cell model.
genes:
- preferred_term: COX6A2
term:
id: hgnc:2279
label: COX6A2
downstream:
- target: Impaired Complex IV Assembly
description: Insufficient functional structural subunit impairs normal complex IV biogenesis.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Assembly of complex IV and its supercomplex formation were impaired in the muscle.
explanation: Patient muscle analysis demonstrates impaired complex IV assembly and supercomplex formation.
directness: INDIRECT
- target: Reduced Cardiomyocyte Respiration
description: >-
Engineered loss of COX6A2 produces a respiratory deficit through incompletely separated intermediate
steps.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
the basal respiration, maximal respiration, and ATP production of the KO cardiomyocytes were significantly
lower compared with that of WT cardiomyocytes (Fig. 5B).
explanation: >-
Seahorse measurements show lower respiratory capacity and ATP-linked respiration in engineered knockout
cardiomyocytes.
directness: INDIRECT
- target: Increased Mitochondrial Superoxide
description: Loss of COX6A2 perturbs mitochondrial redox handling in the engineered cell model.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Compared with WT cardiomyocytes, mitochondrial ROS in KO cardiomyocytes was significantly increased
(Fig. 4F and Additional file 1: Fig. S3D),
explanation: MitoSOX detects increased mitochondrial superoxide in knockout cardiomyocytes.
directness: INDIRECT
- target: Reduced Mitochondrial Membrane Potential
description: COX6A2-deficient cardiomyocytes have lower membrane-potential-sensitive fluorescence.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Immunofluorescence staining showed that the red fluorescence intensity of WT cardiomyocytes was significantly
higher than that of KO cardiomyocytes (Fig. 4G). This suggests that the mitochondrial membrane potential
of cardiomyocytes was significantly reduced following COX6A2 knockout and mitochondrial function is
impaired,
explanation: TMRE fluorescence supports reduced mitochondrial membrane potential in the cell model.
directness: INDIRECT
- target: Altered Cardiomyocyte Calcium Transients
description: >-
The knockout changes calcium handling; the intervening energy and redox pathways are not isolated.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Compared with WT cardiomyocytes, the peak value of calcium transients in KO cardiomyocytes was significantly
reduced and the time to peak time was significantly prolonged (Fig. 6C–F),
explanation: >-
Fluo-4 imaging measures smaller and slower calcium transients. It does not directly establish mitochondrial
calcium overload.
directness: INDIRECT
- target: Cardiomyocyte Hypertrophy
description: >-
COX6A2 knockout leads to cellular enlargement over differentiation; the intervening signaling is unresolved.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
the surface area of the KO cardiomyocytes was significantly increased compared with the WT cardiomyocytes
as determined by laser confocal microscopy (Fig. 3A).
explanation: Phalloidin imaging demonstrates increased cardiomyocyte area after knockout.
directness: INDIRECT
- target: Reduced Interneuron ATP-to-ADP Ratio
description: PV-specific gene deletion lowers the intracellular energy ratio.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:32744742
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports
their function.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Such dramatic effects were likely due to an essential role of COX6A2 in energy balance of PV+ interneurons,
underscored by a decrease in the ATP-to-ADP ratio in Cox6a2-/- PV+ interneurons.
explanation: >-
The abstract reports the reduced ATP-to-ADP ratio in knockout PV interneurons; the full paper identifies
the conditional knockout and PercevalHR slice-imaging experiment.
directness: INDIRECT
- target: Interneuron Oxidative DNA Damage
description: Global knockout increases the oxidative DNA damage readout in PV interneurons.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
8‐OHdG immunoreactivity was significantly higher in PV ... + ... interneurons in both cortices in ...
Cox6a2 ... −/− ... mice ( ... n ... = 4 WT, 4 ... Cox6a2 ... − ... / ... − ... ; 2 months old).
explanation: Increased 8-OHdG signal supports oxidative DNA damage in knockout cortical PV interneurons.
directness: INDIRECT
- target: Reduced Perineuronal Nets
description: Knockout reduces WFA-positive matrix surrounding PV cells.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
WFA immunoreactivity around PV ... + ... cells was lower in both cortices in ... Cox6a2 ... −/− ...
mice ( ... n ... = 4 WT, 4 ... Cox6a2 ... − ... / ... − ... ; 2 months old).
explanation: Reduced WFA labeling supports diminished perineuronal nets in the mouse model.
directness: INDIRECT
- target: Impaired Fast-Spiking Maturation
description: Knockout impairs the development of sustained fast-spiking activity.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Thus, maximal firing frequency reached during 2‐s depolarizing current pulses was lower in P34–45 ...
Cox6a2 ... − ... / ... − ... compared with WT PV ... + ... interneurons.
explanation: Older knockout PV interneurons fail to acquire normal sustained high-frequency firing.
directness: INDIRECT
- target: Reduced Interneuron Dendritic Arborization
description: Knockout limits later dendritic growth and branching.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
However, at P34‐P45, ... Cox6a2 ... −/− ... PV ... + ... interneurons showed lower dendritic length
and full branch depth than WT PV ... + ... interneurons.
explanation: Dendritic length and branch depth are reduced at the later developmental stage.
directness: INDIRECT
- target: Reduced PV Interneuron Synaptic Contacts
description: >-
Gene deletion reduces the measured contact number through unresolved developmental and metabolic intermediates.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Furthermore, ... Cox6a2 ... − ... / ... − ... reduced the number of PV ... + ... interneuron‐derived
synaptic contacts onto cortical principal neurons (Fig ... 3 ... D),
explanation: The mouse study measures fewer PV-derived contacts onto cortical principal neurons.
directness: INDIRECT
- name: Impaired Complex IV Assembly
description: >-
Complex IV assembly is impaired in patient muscle. This is a structural-subunit defect with an assembly
consequence, not a mutation in a dedicated assembly factor.
biological_scale: MOLECULAR
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Assembly of complex IV and its supercomplex formation were impaired in the muscle.
explanation: Patient muscle analysis demonstrates impaired complex IV assembly and supercomplex formation.
conforms_to: complex_iv_assembly_deficiency#Complex IV Biogenesis Failure
biological_processes:
- preferred_term: mitochondrial respiratory chain complex IV assembly
term:
id: GO:0033617
label: mitochondrial respiratory chain complex IV assembly
modifier: DECREASED
downstream:
- target: Reduced Cytochrome c Oxidase Activity
description: Impaired assembly limits functional complex IV capacity.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We found specific reductions in complex IV activities in the skeletal muscle of both individuals.
explanation: The isolated complex IV biochemical defect was measured in patient skeletal muscle.
directness: INDIRECT
- target: Impaired Complex IV Supercomplex Formation
description: Complex IV assembly abnormalities accompany impaired higher-order respiratory assemblies.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Assembly of complex IV and its supercomplex formation were impaired in the muscle.
explanation: Patient muscle analysis demonstrates impaired complex IV assembly and supercomplex formation.
directness: INDIRECT
- name: Reduced Cytochrome c Oxidase Activity
description: >-
Complex IV activity is selectively reduced in patient skeletal muscle. COX6A2 supports the multimeric oxidase
and is not itself the electron-transfer catalytic center. Reduced enzyme activity does not establish universal
bulk ATP depletion. Unlike the combined electron-transfer and ATP-synthesis collapse described in the complex
IV module, this activity defect can coexist with preserved bulk tissue ATP.
biological_scale: MOLECULAR
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
We found specific reductions in complex IV activities in the skeletal muscle of both individuals.
explanation: The isolated complex IV biochemical defect was measured in patient skeletal muscle.
- reference: PMID:11788423
reference_title: Cardiac dysfunction in mice lacking cytochrome-c oxidase subunit VIaH.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Total COX activity was decreased in hearts from mutant mice, which appears to be a consequence of altered
assembly of the holoenzyme COX.
explanation: >-
The global knockout mouse study directly reports reduced cardiac COX activity and attributes it to altered
holoenzyme assembly.
genes:
- preferred_term: COX6A2
term:
id: hgnc:2279
label: COX6A2
molecular_functions:
- preferred_term: cytochrome-c oxidase activity
term:
id: GO:0004129
label: cytochrome-c oxidase activity
modifier: DECREASED
biological_processes:
- preferred_term: mitochondrial electron transport, cytochrome c to oxygen
term:
id: GO:0006123
label: mitochondrial electron transport, cytochrome c to oxygen
modifier: DECREASED
downstream:
- target: Limb muscle weakness
description: >-
The biochemical defect accompanies the congenital limb myopathy; tissue-level intermediates were not
directly established.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Both patients presented muscle weakness and hypotonia in 4 limbs along with facial muscle weakness.
explanation: The founding patients had limb and facial weakness with hypotonia.
directness: INDIRECT
- target: Facial muscle weakness
description: >-
The same clinical-biochemical association supports facial myopathy without specifying its intervening
steps.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Both patients presented muscle weakness and hypotonia in 4 limbs along with facial muscle weakness.
explanation: The founding patients had limb and facial weakness with hypotonia.
directness: INDIRECT
- target: Hypotonia
description: The founding cases associate complex IV deficiency with reduced tone.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Both patients presented muscle weakness and hypotonia in 4 limbs along with facial muscle weakness.
explanation: The founding patients had limb and facial weakness with hypotonia.
directness: INDIRECT
- target: Cardiomyopathy
description: >-
Complex IV dysfunction can involve the heart; the clinical subtype and full causal sequence are not established
in the founding abstract.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: One patient had cardiomyopathy.
explanation: >-
Cardiomyopathy was reported in one founding patient; its clinical subtype is not specified by this
abstract.
directness: INDIRECT
- name: Impaired Complex IV Supercomplex Formation
description: >-
Complex IV-containing respiratory supercomplex formation is impaired in patient muscle. This biochemical
assembly outcome is distinct from oxidase enzymatic activity.
biological_scale: MOLECULAR
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: Assembly of complex IV and its supercomplex formation were impaired in the muscle.
explanation: Patient muscle analysis demonstrates impaired complex IV assembly and supercomplex formation.
- name: Reduced Cardiomyocyte Respiration
description: >-
Engineered COX6A2-null cardiomyocytes have lower basal and maximal oxygen consumption and ATP-linked respiration.
Extracellular acidification also decreases, rather than showing compensatory glycolytic enhancement in
this model.
biological_scale: CELLULAR
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
the basal respiration, maximal respiration, and ATP production of the KO cardiomyocytes were significantly
lower compared with that of WT cardiomyocytes (Fig. 5B).
explanation: >-
Seahorse measurements show lower respiratory capacity and ATP-linked respiration in engineered knockout
cardiomyocytes.
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The extracellular acidification rate of KO cardiomyocytes was also significantly lower compared with
that of WT cardiomyocytes, suggesting that the glycolytic capacity of KO cardiomyocytes was significantly
reduced (Fig. 5C).
explanation: The glycolytic-capacity proxy decreases in the engineered cardiac cells.
cell_types:
- preferred_term: cardiac muscle cell
term:
id: CL:0000746
label: cardiac muscle cell
downstream:
- target: Reduced Cardiomyocyte ATP Content
description: Reduced energy metabolism is associated with lower cellular ATP in this model.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The ATP content of KO cardiomyocytes following LC, TMZ, and LC + TMZ treatment was restored to varying
degrees, of which LC + TMZ exhibited the greatest effect (Fig. 7A).
explanation: >-
The ATP-content assay documents the energy deficit and its partial restoration by metabolic compounds
in knockout cardiomyocytes.
directness: INDIRECT
- name: Reduced Cardiomyocyte ATP Content
description: >-
ATP-content assays show a deficit in engineered knockout cardiomyocytes that responds partially to L-carnitine
and trimetazidine. This is a cellular measurement, not evidence of universal ATP depletion in affected
patients or mouse muscles.
biological_scale: CELLULAR
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The ATP content of KO cardiomyocytes following LC, TMZ, and LC + TMZ treatment was restored to varying
degrees, of which LC + TMZ exhibited the greatest effect (Fig. 7A).
explanation: >-
The ATP-content assay documents the energy deficit and its partial restoration by metabolic compounds
in knockout cardiomyocytes.
cell_types:
- preferred_term: cardiac muscle cell
term:
id: CL:0000746
label: cardiac muscle cell
downstream:
- target: Altered Cardiomyocyte Calcium Transients
description: >-
Metabolic drug rescue improves calcium-transient parameters, supporting an indirect energy-calcium link.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Finally, we measured the calcium transients of cardiomyocytes following treatment, and after drug intervention,
the level of calcium transport in cardiomyocytes was restored to a certain extent (Fig. 7F, G).
explanation: >-
Calcium handling partially improves after the metabolic intervention; individual intervening pathways
are not resolved.
directness: INDIRECT
- name: Increased Mitochondrial Superoxide
description: >-
MitoSOX fluorescence is increased in engineered COX6A2-null cardiomyocytes. Global knockout mice also show
elevated skeletal-muscle DHE signal; neither assay alone resolves all sources of oxidants.
biological_scale: CELLULAR
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Compared with WT cardiomyocytes, mitochondrial ROS in KO cardiomyocytes was significantly increased (Fig.
4F and Additional file 1: Fig. S3D),
explanation: MitoSOX detects increased mitochondrial superoxide in knockout cardiomyocytes.
- reference: PMID:23460811
reference_title: >-
Mice deficient in the respiratory chain gene Cox6a2 are protected against high-fat diet-induced obesity
and insulin resistance.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
elevated ROS levels were detected both in diaphragm and in hindlimb muscles of Cox6a2 −/− mice as compared
to WT mice with the largest difference being measured in the diaphragm.
explanation: DHE labeling is increased in skeletal muscle from global knockout mice.
- name: Reduced Mitochondrial Membrane Potential
description: >-
TMRE fluorescence is lower in engineered knockout cardiomyocytes. The accompanying mitochondrial ultrastructural
and calcium changes do not establish the direction of every causal feedback step.
biological_scale: CELLULAR
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Immunofluorescence staining showed that the red fluorescence intensity of WT cardiomyocytes was significantly
higher than that of KO cardiomyocytes (Fig. 4G). This suggests that the mitochondrial membrane potential
of cardiomyocytes was significantly reduced following COX6A2 knockout and mitochondrial function is impaired,
explanation: TMRE fluorescence supports reduced mitochondrial membrane potential in the cell model.
cell_types:
- preferred_term: cardiac muscle cell
term:
id: CL:0000746
label: cardiac muscle cell
- name: Altered Cardiomyocyte Calcium Transients
description: >-
Calcium transients have smaller peaks and longer time-to-peak in knockout cardiomyocytes. These measurements
support impaired calcium dynamics without directly measuring mitochondrial calcium overload.
biological_scale: CELLULAR
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Compared with WT cardiomyocytes, the peak value of calcium transients in KO cardiomyocytes was significantly
reduced and the time to peak time was significantly prolonged (Fig. 6C–F),
explanation: >-
Fluo-4 imaging measures smaller and slower calcium transients. It does not directly establish mitochondrial
calcium overload.
cell_types:
- preferred_term: cardiac muscle cell
term:
id: CL:0000746
label: cardiac muscle cell
downstream:
- target: Reduced Cardiomyocyte Contractility
description: >-
Altered calcium dynamics accompany impaired mechanical contraction; their causal relationship remains
indirect in the knockout comparison.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Compared with WT cardiomyocytes, the contraction intensity of KO cardiomyocytes was significantly decreased
(Fig. 6H). Moreover, the time to peak (Fig. 6I) and relaxation duration (Fig. 6J) were significantly
prolonged.
explanation: >-
Video-derived contraction intensity decreases and contraction/relaxation kinetics slow; this is not
a calibrated force measurement.
directness: INDIRECT
- name: Reduced Cardiomyocyte Contractility
description: >-
Video-based analysis of knockout cardiomyocytes shows reduced contraction intensity and frequency, with
prolonged contraction and relaxation. A calibrated myocardial force measurement was not performed.
biological_scale: CELLULAR
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Compared with WT cardiomyocytes, the contraction intensity of KO cardiomyocytes was significantly decreased
(Fig. 6H). Moreover, the time to peak (Fig. 6I) and relaxation duration (Fig. 6J) were significantly
prolonged.
explanation: >-
Video-derived contraction intensity decreases and contraction/relaxation kinetics slow; this is not a
calibrated force measurement.
cell_types:
- preferred_term: cardiac muscle cell
term:
id: CL:0000746
label: cardiac muscle cell
downstream:
- target: Cardiomyopathy
description: >-
The engineered-cell mechanical phenotype offers a partial model of cardiac dysfunction; it does not establish
a patient cardiomyopathy subtype.
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Compared with WT cardiomyocytes, the contraction intensity of KO cardiomyocytes was significantly decreased
(Fig. 6H). Moreover, the time to peak (Fig. 6I) and relaxation duration (Fig. 6J) were significantly
prolonged.
explanation: >-
Video-derived contraction intensity decreases and contraction/relaxation kinetics slow; this is not
a calibrated force measurement.
directness: INDIRECT
- name: Cardiomyocyte Hypertrophy
description: >-
Engineered knockout cardiomyocytes enlarge during differentiation and show increased remodeling-associated
transcripts. Cell size and collagen transcripts do not establish tissue fibrosis or a clinical hypertrophic
cardiomyopathy diagnosis.
biological_scale: CELLULAR
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
the surface area of the KO cardiomyocytes was significantly increased compared with the WT cardiomyocytes
as determined by laser confocal microscopy (Fig. 3A).
explanation: Phalloidin imaging demonstrates increased cardiomyocyte area after knockout.
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Using qPCR, we found that the expression of ANP, BNP, COL1A1, and COL4A1 mRNA in cardiomyocytes following
COX6A2 knockdown was significantly increased compared with that of the WT cells (Fig. 3D–G),
explanation: Remodeling-associated transcripts increase in knockout cardiomyocytes.
cell_types:
- preferred_term: cardiac muscle cell
term:
id: CL:0000746
label: cardiac muscle cell
- name: Reduced Interneuron ATP-to-ADP Ratio
description: >-
PV-specific Cox6a2 deletion lowers the basal ATP-to-ADP ratio measured with PercevalHR in ex vivo brain
slices. COX6A2 expression in normal human cortex supports relevance beyond muscle, but equivalent patient-neuron
bioenergetics have not been measured.
biological_scale: CELLULAR
evidence:
- reference: PMID:32744742
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports
their function.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Such dramatic effects were likely due to an essential role of COX6A2 in energy balance of PV+ interneurons,
underscored by a decrease in the ATP-to-ADP ratio in Cox6a2-/- PV+ interneurons.
explanation: >-
The abstract reports the reduced ATP-to-ADP ratio in knockout PV interneurons; the full paper identifies
the conditional knockout and PercevalHR slice-imaging experiment.
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: OTHER
snippet: >-
In the adult human brain, all cortical PV ... + ... interneurons from Brodmann areas 9 and 10 (BA9, BA10),
which correspond to the dorsolateral and medial prefrontal cortex and the anterior prefrontal cortex,
respectively, express COX6A2, and PV ... + ... interneurons represent 60% of the cells expressing COX6A2
(Fig ... 2 ... E and F).
explanation: >-
Postmortem human cortex expresses COX6A2 beyond muscle; PV cells comprise about 60% of COX6A2-positive
cortical cells in these donors.
directness: INDIRECT
cell_types:
- preferred_term: Parvalbumin-positive cortical GABAergic interneuron
term:
id: CL:0011005
label: GABAergic interneuron
- name: Interneuron Oxidative DNA Damage
description: >-
PV interneurons in global knockout mouse somatosensory and motor cortex have increased 8-OHdG immunoreactivity.
This is a model-specific oxidative DNA damage readout, not a demonstrated patient biomarker.
biological_scale: CELLULAR
evidence:
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
8‐OHdG immunoreactivity was significantly higher in PV ... + ... interneurons in both cortices in ...
Cox6a2 ... −/− ... mice ( ... n ... = 4 WT, 4 ... Cox6a2 ... − ... / ... − ... ; 2 months old).
explanation: Increased 8-OHdG signal supports oxidative DNA damage in knockout cortical PV interneurons.
cell_types:
- preferred_term: Parvalbumin-positive cortical GABAergic interneuron
term:
id: CL:0011005
label: GABAergic interneuron
- name: Reduced Perineuronal Nets
description: >-
WFA-positive perineuronal matrix surrounding cortical PV interneurons is reduced in global knockout mice.
The experiments associate this with oxidative stress but do not isolate the causal sequence.
biological_scale: CELLULAR
evidence:
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
WFA immunoreactivity around PV ... + ... cells was lower in both cortices in ... Cox6a2 ... −/− ... mice
( ... n ... = 4 WT, 4 ... Cox6a2 ... − ... / ... − ... ; 2 months old).
explanation: Reduced WFA labeling supports diminished perineuronal nets in the mouse model.
cell_types:
- preferred_term: Parvalbumin-positive cortical GABAergic interneuron
term:
id: CL:0011005
label: GABAergic interneuron
- name: Impaired Fast-Spiking Maturation
description: >-
Older knockout PV interneurons fail to acquire normal maximal sustained firing frequency. Increased excitability
at threshold coexists with impaired repetitive firing, so a uniform reduction in excitability would be
inaccurate.
biological_scale: CELLULAR
evidence:
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Thus, maximal firing frequency reached during 2‐s depolarizing current pulses was lower in P34–45 ...
Cox6a2 ... − ... / ... − ... compared with WT PV ... + ... interneurons.
explanation: Older knockout PV interneurons fail to acquire normal sustained high-frequency firing.
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Consequently, the threshold was significantly more negative for ... Cox6a2 ... − ... / ... − ... than
for WT PV ... + ... interneurons during the later stage of maturation (Fig ... 6 ... C and D).
explanation: Older knockout neurons have a lower firing threshold despite impaired sustained fast spiking.
cell_types:
- preferred_term: Parvalbumin-positive cortical GABAergic interneuron
term:
id: CL:0011005
label: GABAergic interneuron
- name: Reduced Interneuron Dendritic Arborization
description: >-
At P34-P45, global knockout PV interneurons have reduced dendritic length and branch depth, whereas the
younger P22-P33 groups are similar. This developmental mouse finding has not been demonstrated in patients.
biological_scale: CELLULAR
evidence:
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
However, at P34‐P45, ... Cox6a2 ... −/− ... PV ... + ... interneurons showed lower dendritic length and
full branch depth than WT PV ... + ... interneurons.
explanation: Dendritic length and branch depth are reduced at the later developmental stage.
cell_types:
- preferred_term: Parvalbumin-positive cortical GABAergic interneuron
term:
id: CL:0011005
label: GABAergic interneuron
- name: Reduced PV Interneuron Synaptic Contacts
description: >-
Global knockout mice have fewer PV-interneuron-derived synaptic contacts onto cortical principal neurons.
This anatomical readout is distinct from measured repetitive firing and has not been demonstrated in patients.
biological_scale: CELLULAR
evidence:
- reference: url:https://www.embopress.org/doi/full/10.15252/embj.2020105759
reference_title: >-
Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports
their function | The EMBO Journal | Springer Nature Link
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: >-
Furthermore, ... Cox6a2 ... − ... / ... − ... reduced the number of PV ... + ... interneuron‐derived
synaptic contacts onto cortical principal neurons (Fig ... 3 ... D),
explanation: The mouse study measures fewer PV-derived contacts onto cortical principal neurons.
cell_types:
- preferred_term: Parvalbumin-positive cortical GABAergic interneuron
term:
id: CL:0011005
label: GABAergic interneuron
phenotypes:
- name: Limb muscle weakness
description: Both founding patients had congenital weakness involving the four limbs.
phenotype_term:
preferred_term: Limb muscle weakness
term:
id: HP:0003690
label: Limb muscle weakness
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Both patients presented muscle weakness and hypotonia in 4 limbs along with facial muscle weakness.
explanation: The founding patients had limb and facial weakness with hypotonia.
- name: Hypotonia
description: Reduced tone of the four limbs was reported in both founding patients.
phenotype_term:
preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Both patients presented muscle weakness and hypotonia in 4 limbs along with facial muscle weakness.
explanation: The founding patients had limb and facial weakness with hypotonia.
- name: Facial muscle weakness
description: Facial weakness accompanied the limb myopathy in both patients.
phenotype_term:
preferred_term: Facial muscle weakness
term:
id: HP:0030319
label: Weakness of facial musculature
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Both patients presented muscle weakness and hypotonia in 4 limbs along with facial muscle weakness.
explanation: The founding patients had limb and facial weakness with hypotonia.
- name: Cardiomyopathy
description: >-
Reported in the infantile homozygous p.Ser39Arg case. The clinical subtype should not be inferred from
hypertrophic or dilated pathway annotations in engineered cells.
phenotype_term:
preferred_term: Cardiomyopathy
term:
id: HP:0001638
label: Cardiomyopathy
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: One patient had cardiomyopathy.
explanation: >-
Cardiomyopathy was reported in one founding patient; its clinical subtype is not specified by this abstract.
- name: Respiratory insufficiency
description: ClinGen records respiratory insufficiency in the homozygous infant who died at seven weeks.
phenotype_term:
preferred_term: Respiratory insufficiency
term:
id: HP:0002093
label: Respiratory insufficiency
evidence:
- reference: >-
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z
reference_title: curation results for Gene-Disease Validity
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Male ... Age of Death: ... 7 Weeks ... HPO terms(s): ... Cardiomyopathy (HP:0001638) ... Hypotonia (HP:0001252)
... Muscle weakness (HP:0001324) ... Respiratory insufficiency (HP:0002093)
explanation: >-
ClinGen records respiratory insufficiency and death at seven weeks in the homozygous founding patient.
- name: Waddling gait
description: >-
ClinGen records a waddling gait in the compound-heterozygous patient reported at seventeen years.
phenotype_term:
preferred_term: Waddling gait
term:
id: HP:0002515
label: Waddling gait
evidence:
- reference: >-
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z
reference_title: curation results for Gene-Disease Validity
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Male ... Age of Report: ... 17 Years ... HPO terms(s): ... EMG abnormality (HP:0003457) ... Hypotonia
(HP:0001252) ... Increased circulating lactate concentration (HP:0002151) ... Muscle weakness (HP:0001324)
... Waddling gait (HP:0002515)
explanation: >-
ClinGen records the adolescent compound-heterozygous patient with abnormal EMG, elevated lactate and
waddling gait.
- name: Elevated blood lactate
description: >-
ClinGen records elevated circulating lactate in the adolescent patient; this does not by itself establish
acidosis.
phenotype_term:
preferred_term: Elevated blood lactate
term:
id: HP:0002151
label: Increased circulating lactate concentration
evidence:
- reference: >-
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z
reference_title: curation results for Gene-Disease Validity
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Male ... Age of Report: ... 17 Years ... HPO terms(s): ... EMG abnormality (HP:0003457) ... Hypotonia
(HP:0001252) ... Increased circulating lactate concentration (HP:0002151) ... Muscle weakness (HP:0001324)
... Waddling gait (HP:0002515)
explanation: >-
ClinGen records the adolescent compound-heterozygous patient with abnormal EMG, elevated lactate and
waddling gait.
- name: EMG abnormality
description: >-
An abnormal electromyogram is recorded for the adolescent patient; this is an investigation finding.
phenotype_term:
preferred_term: EMG abnormality
term:
id: HP:0003457
label: EMG abnormality
evidence:
- reference: >-
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z
reference_title: curation results for Gene-Disease Validity
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Male ... Age of Report: ... 17 Years ... HPO terms(s): ... EMG abnormality (HP:0003457) ... Hypotonia
(HP:0001252) ... Increased circulating lactate concentration (HP:0002151) ... Muscle weakness (HP:0001324)
... Waddling gait (HP:0002515)
explanation: >-
ClinGen records the adolescent compound-heterozygous patient with abnormal EMG, elevated lactate and
waddling gait.
genetic:
- name: COX6A2
gene_term:
preferred_term: COX6A2
term:
id: hgnc:2279
label: COX6A2
inheritance:
- name: Autosomal recessive
inheritance_term:
preferred_term: Autosomal recessive inheritance
term:
id: HP:0000007
label: Autosomal recessive inheritance
description: >-
The two founding patients carried homozygous or compound-heterozygous missense variants; the compound
allelic phase was confirmed by cloning PCR products.
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The variants detected were homozygous c.117C > A (p.Ser39Arg) and compound heterozygous c.117C > A
(p.Ser39Arg) and c.127T > C (p.Cys43Arg).
explanation: >-
The reported alleles were homozygous p.Ser39Arg and compound heterozygous p.Ser39Arg/p.Cys43Arg.
- reference: >-
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z
reference_title: curation results for Gene-Disease Validity
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The allelic phases of the compound heterozygous variants in P2 were confirmed by cloning their PCR
products
explanation: ClinGen records phase confirmation for the second patient.
features: >-
The founding missense alleles are c.117C>A (p.Ser39Arg) and c.127T>C (p.Cys43Arg), described on NM_005205.4
in ClinGen. Both perturb protein stability in allele-expression assays. Two probands do not establish penetrance
or a general genotype-severity rule.
variants:
- name: c.117C>A (p.Ser39Arg)
description: Homozygous in the infantile proband and in trans with p.Cys43Arg in the surviving proband.
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The variants detected were homozygous c.117C > A (p.Ser39Arg) and compound heterozygous c.117C > A
(p.Ser39Arg) and c.127T > C (p.Cys43Arg).
explanation: >-
The reported alleles were homozygous p.Ser39Arg and compound heterozygous p.Ser39Arg/p.Cys43Arg.
- reference: >-
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z
reference_title: curation results for Gene-Disease Validity
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
HeLa studies with COX6A2-fused EGFPs with WT and Ser39Arg mutation show transport to mitochondria,
but dramatically reduced expression of protein after blocking de novo protein synthesis compared to
WT at 2,4,6 hours
explanation: >-
ClinGen summarizes the allele-expression experiments: mitochondrial targeting was retained but mutant
protein decayed more rapidly after translation blockade.
- name: c.127T>C (p.Cys43Arg)
description: Compound heterozygous with p.Ser39Arg in the surviving proband.
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The variants detected were homozygous c.117C > A (p.Ser39Arg) and compound heterozygous c.117C > A
(p.Ser39Arg) and c.127T > C (p.Cys43Arg).
explanation: >-
The reported alleles were homozygous p.Ser39Arg and compound heterozygous p.Ser39Arg/p.Cys43Arg.
gene_disease_validity:
- validity_classification: MODERATE
classified_by: CLINGEN
external_id: CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z
notes: >-
Mitochondrial Diseases Gene Curation Expert Panel, 18 March 2024, SOP10. ClinGen evaluates the broader
primary mitochondrial disease entity (MONDO:0044970), encompassing this COX6A2 phenotype.
evidence:
- reference: CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z
reference_title: COX6A2 / mitochondrial disease (Moderate)
supports: SUPPORT
evidence_source: OTHER
snippet: In summary, there is moderate evidence to support this gene-disease relationship.
explanation: This is the externally assigned ClinGen tier, not a new dismech classification.
evidence:
- reference: PMID:31155743
reference_title: COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The variants detected were homozygous c.117C > A (p.Ser39Arg) and compound heterozygous c.117C > A (p.Ser39Arg)
and c.127T > C (p.Cys43Arg).
explanation: >-
The reported alleles were homozygous p.Ser39Arg and compound heterozygous p.Ser39Arg/p.Cys43Arg.
- reference: >-
url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z
reference_title: curation results for Gene-Disease Validity
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
HeLa studies with COX6A2-fused EGFPs with WT and Ser39Arg mutation show transport to mitochondria, but
dramatically reduced expression of protein after blocking de novo protein synthesis compared to WT at
2,4,6 hours
explanation: >-
ClinGen summarizes the allele-expression experiments: mitochondrial targeting was retained but mutant
protein decayed more rapidly after translation blockade.
treatments:
- name: Supportive rehabilitation and multidisciplinary care
description: >-
Primary mitochondrial disease consensus recommends rehabilitation and individualized specialist care to
maintain mobility and function. Application to COX6A2 disease is extrapolated from that broader guidance;
disease-specific clinical efficacy data are lacking.
treatment_term:
preferred_term: Supportive care
term:
id: NCIT:C15747
label: Supportive Care
evidence:
- reference: PMID:28749475
reference_title: >-
Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial
Medicine Society.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Evaluation and care by a rehabilitation medicine specialist and therapy are used to maintain safety,
mobility, and an active lifestyle.
explanation: >-
This general mitochondrial care recommendation supports symptom-directed rehabilitation, rather than
a proven COX6A2-specific treatment.
directness: INDIRECT
target_phenotypes:
- preferred_term: Limb muscle weakness
term:
id: HP:0003690
label: Limb muscle weakness
- preferred_term: Hypotonia
term:
id: HP:0001252
label: Hypotonia
- name: L-carnitine and trimetazidine (preclinical)
description: >-
L-carnitine at 200 micromolar and trimetazidine at 50 micromolar were tested individually and together
in engineered knockout cardiomyocytes. The combination gave the largest ATP-content recovery and ROS reduction,
and improved respiration and calcium transients. These cell-culture concentrations and results do not establish
clinical dosing, safety or efficacy in COX6A2 disease.
therapeutic_modality: SMALL_MOLECULE
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: L-carnitine
term:
id: CHEBI:16347
label: (R)-carnitine
- preferred_term: Trimetazidine
term:
id: CHEBI:94789
label: 1-[(2,3,4-trimethoxyphenyl)methyl]piperazine
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The ATP content of KO cardiomyocytes following LC, TMZ, and LC + TMZ treatment was restored to varying
degrees, of which LC + TMZ exhibited the greatest effect (Fig. 7A).
explanation: >-
The ATP-content assay documents the energy deficit and its partial restoration by metabolic compounds
in knockout cardiomyocytes.
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
We examined the concentration gradient of the therapeutic drugs and determined the optimal concentration
of LC 200 µmol/L and TMZ 50 µmol/L.
explanation: These concentrations were chosen for cell-culture experiments.
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Similarly, ROS levels in cardiomyocytes were determined after treatment with the three regimens, and
the LC + TMZ group exhibited the greatest reduction in ROS (Fig. 7B).
explanation: The combined treatment most strongly reduced the ROS readout.
target_mechanisms:
- target: Reduced Cardiomyocyte ATP Content
description: The compounds partially restore measured cellular ATP content.
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The ATP content of KO cardiomyocytes following LC, TMZ, and LC + TMZ treatment was restored to varying
degrees, of which LC + TMZ exhibited the greatest effect (Fig. 7A).
explanation: >-
The ATP-content assay documents the energy deficit and its partial restoration by metabolic compounds
in knockout cardiomyocytes.
- target: Reduced Cardiomyocyte Respiration
description: Combined treatment improves the respiratory phenotype in the knockout cells.
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
The results indicated that combination treatment of the KO myocardial cells improved energy metabolism
(Fig. 7C–E),
explanation: Combined treatment improves Seahorse respiratory measurements.
- target: Altered Cardiomyocyte Calcium Transients
description: The combined intervention partially restores calcium-transient parameters.
evidence:
- reference: PMID:38072986
reference_title: >-
COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Finally, we measured the calcium transients of cardiomyocytes following treatment, and after drug intervention,
the level of calcium transport in cardiomyocytes was restored to a certain extent (Fig. 7F, G).
explanation: Calcium-transient measurements improve after intervention.

📚

References & Deep Research

References

PMID:31155743

COX6A2 variants cause a muscle-specific cytochrome c oxidase deficiency.

No top-level findings curated for this source.

PMID:38072986

COX6A2 deficiency leads to cardiac remodeling in human pluripotent stem cell-derived cardiomyocytes.

No top-level findings curated for this source.

PMID:23460811

Mice deficient in the respiratory chain gene Cox6a2 are protected against high-fat diet-induced obesity and insulin resistance.

No top-level findings curated for this source.

PMID:11788423

Cardiac dysfunction in mice lacking cytochrome-c oxidase subunit VIaH.

No top-level findings curated for this source.

PMID:28749475

Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society.

No top-level findings curated for this source.

CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z

COX6A2 / mitochondrial disease (Moderate)

No top-level findings curated for this source.

url:https://www.embopress.org/doi/full/10.15252/embj.2020105759

Complex IV subunit isoform COX6A2 protects fast‐spiking interneurons from oxidative stress and supports their function | The EMBO Journal | Springer Nature Link

No top-level findings curated for this source.

url:https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_c09fbc40-dc5e-4cbd-80d1-1f918fffdceb-2024-03-18T040000.000Z

curation results for Gene-Disease Validity

No top-level findings curated for this source.

PMID:32744742

Complex IV subunit isoform COX6A2 protects fast-spiking interneurons from oxidative stress and supports their function.

No top-level findings curated for this source.

Ask OpenScientist

OpenScientist Report

Classifications

Inheritance

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Diagnosis

Related Datasets

Experimental Models

Animal Models

Source YAML

References & Deep Research

References