COX14-Related COX Deficiency

Mendelian MONDO:0033639 Pathograph 21 Show in embeddings browser Mitochondrial Disease Inborn Error of Metabolism

COX14-related COX deficiency is an autosomal recessive disorder of mitochondrial complex IV biogenesis caused by biallelic COX14 (formerly C12orf62) variants. COX14 regulates synthesis of the mitochondrial-encoded COX1 subunit in early assembly intermediates. The founding Met19Ile family had severe congenital multisystem disease with neonatal lactic acidosis, dysmorphism and brain, cardiac, hepatic and renal abnormalities. Patient-cell experiments establish a defect in COX1 translation and complex IV assembly. A corresponding mouse model reveals tissue-dependent disease and an experimental ROS-driven hepatic inflammatory pathway; its later survival and inflammatory findings are not established features of the human disorder.

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1
Inheritance
8
Pathophys.
16
Phenotypes
2
Gaps
21
Pathograph
1
Genes
8
Medical Actions
1
Datasets
4
Models
7
References
👪

Inheritance

1
Autosomal recessive
Biallelic pathogenic variants cause disease; heterozygous parents and a heterozygous sibling were unaffected in the founding family. When both parents are carriers, recurrence risks per pregnancy are 25% affected, 50% carrier and 25% unaffected non-carrier.
Show evidence (2 references)
PMID:22243966 SUPPORT Human Clinical
"The two other affected siblings had the same homozygous mutation, whereas the unaffected sibling and the parents were heterozygous carriers of the mutation."
Segregation in the family directly supports autosomal recessive inheritance.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1224/ SUPPORT BACKGROUND Other
"each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic ... carrier ... and a 25% chance of being unaffected and not a carrier."
Standard autosomal recessive recurrence risks apply when both parents carry a causative allele.
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Discussions and Knowledge Gaps

2
Does ROS-dependent mitochondrial RNA release contribute to human COX14 disease?
HUMAN MODEL MISMATCH OPEN cox14-human-model-correspondence
The knock-in mouse provides a mechanistic inflammatory pathway and ex vivo antioxidant rescue, but the human index child died neonatally and had no reported assessment of liver inflammation or retinal pathology. Survival and brain findings also differ. These observations support further investigation rather than clinical antioxidant efficacy claims.
Show evidence (1 reference)
PMID:39134548 SUPPORT Model Organism
"It is difficult to directly compare the mice phenotype to the patient pathology, as the death of the patient occurred already 24 hours after birth."
The authors explicitly limit direct human-model comparison.
Why does residual fibroblast complex IV activity coexist with a severe neonatal phenotype?
INTERPRETATION OPEN cox14-residual-activity-severity
The founding fibroblasts retain measurable complex IV activity. The mouse model demonstrates tissue-dependent protein stability and respiratory defects, but does not identify a human modifier gene or a quantitative prognostic threshold.
Show evidence (2 references)
PMID:22243966 SUPPORT In Vitro
"COX activity in immortalized subject fibroblasts was reduced to 30%-40% of that in control fibroblasts."
Residual complex IV activity is substantial in this cell system, despite the severe clinical course.
PMID:39134548 SUPPORT Model Organism
"despite the systemic defect in COX14 function, the impact on protein stability, COX1 synthesis and concomitantly amounts of complex IV differed significantly between tissues."
Tissue variation in the animal model may inform the clinical-biochemical discrepancy, without proving the human explanation.
⚙

Pathophysiology

8
COX14 Functional Deficiency
The Met19Ile allele destabilizes COX14 and reduces its capacity to regulate COX1 translation. Residual function is possible even when the protein is undetectable by immunoblotting.
COX14 hgnc:28216 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves COX14 (hgnc:28216). hgnc:28216 is a gene from the HUGO Gene Nomenclature Committee.
translation regulator activity GO:0045182 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased translation regulator activity (GO:0045182). GO:0045182 is a molecular function from the Gene Ontology.
Downstream
Reduced COX1 Translation Deficiency of the translation-regulating factor reduces production of COX1.
Show evidence (3 references)
PMID:22243966 SUPPORT In Vitro
"C12orf62 was not detectable by immunoblot analysis in subject fibroblasts, and retroviral expression of the wild-type C12orf62 cDNA rescued the biochemical phenotype."
Loss of detectable COX14 and complementation support deficiency of the protein rather than a structural COX-subunit mutation.
PMID:22243966 SUPPORT In Vitro
"the same knockdown exacerbated the biochemical phenotype, implying that the mutant protein, although not detectable by immunoblot analysis, retained some residual function."
Additional depletion worsened the patient-cell defect, arguing against a complete functional null.
PMID:27693358 SUPPORT In Vitro
"C12ORF62 acts upstream of MITRAC12 and associates with COX1 in a ribosome nascent chain complex."
Human-cell interaction and translation experiments position COX14 in early cotranslational assembly.
Reduced COX1 Translation
COX1 synthesis is selectively reduced. In patient fibroblasts this occurs without reduced mitochondrial COX mRNA abundance; it should not be described as generalized mitochondrial transcription failure.
mitochondrial translation GO:0032543 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial translation (GO:0032543). GO:0032543 is a biological process from the Gene Ontology.
Experimental models
Patient Fibroblast COX14 Complementation CELL LINE Wild-type COX14 expression restores translation and assembly in the patient-cell system.
Human Cell COX14 Translation Studies CELL LINE COX14 knockdown reduces COX1 synthesis.
Downstream
Deficient Complex IV Assembly Reduced COX1 supply and defective coordination of early assembly restrict mature complex IV formation.
Show evidence (3 references)
PMID:27693358 SUPPORT In Vitro
"the decreased level of newly synthesized COX1 observed upon C12ORF62 knockdown is apparently not a result of increased turnover but rather of reduced translation."
C12ORF62 depletion reduces COX1 synthesis; protease depletion did not explain the deficit.
PMID:22243966 SUPPORT In Vitro
"The levels of the COX mRNAs in the subject were not reduced relative to those of the controls when they were normalized to the rRNA levels"
Normal transcript abundance distinguishes this defect from depletion of COX mRNA.
PMID:22243966 SUPPORT In Vitro
"In the subject cells, although COX I was synthesized at ∼25% of control levels, the newly synthesized protein was completely stable."
In the reported pulse-chase experiment, lower COX1 synthesis coexisted with stable newly synthesized COX1.
Deficient Complex IV Assembly
The amount of mature complex IV is reduced. COX2 and COX3 incorporation into nascent complexes is inefficient, with increased turnover of these subunits in patient fibroblasts.
mitochondrial respiratory chain complex IV assembly GO:0033617 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial respiratory chain complex IV assembly (GO:0033617). GO:0033617 is a biological process from the Gene Ontology.
Experimental models
Patient Fibroblast COX14 Complementation CELL LINE Patient cells show reduced mature complex IV.
Animal models
COX14 Met19Ile Knock-in Mouse Mouse partially recapitulates The knock-in causes tissue-dependent complex IV deficiency.
Downstream
Reduced Complex IV Respiratory Capacity Deficient holoenzyme abundance reduces complex IV catalytic capacity.
Show evidence (2 references)
PMID:22243966 SUPPORT In Vitro
"Blue native polyacrylamide gel electrophoresis (BN-PAGE) analysis11 showed that the reduced activity was associated with a specific reduction in the amount of fully assembled COX, but did not identify subassemblies of the COX complex"
Patient fibroblasts directly demonstrate deficient mature complex IV assembly.
PMID:22243966 SUPPORT In Vitro
"newly synthesized COX II and III were less efficiently incorporated into the COX complex, and they were rapidly turned over after a long chase."
The assembly defect includes instability of incompletely assembled COX2 and COX3, rather than universal instability of newly synthesized COX1.
Reduced Complex IV Respiratory Capacity
Reduced complex IV activity limits terminal electron transfer and respiratory capacity. The magnitude varies by tissue and experimental system. Neither complete abolition of oxidative phosphorylation nor uniform depletion of total cellular ATP has been established.
mitochondrial electron transport, cytochrome c to oxygen GO:0006123 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased mitochondrial electron transport, cytochrome c to oxygen (GO:0006123). GO:0006123 is a biological process from the Gene Ontology.
Downstream
Lactic acidosis Impaired oxidative metabolism is a plausible contributor to the severe lactic acidosis, but the intermediate flux changes were not directly measured in the infant.
Hypertrophic cardiomyopathy Cardiac mitochondrial dysfunction provides a mechanistic explanation for the reported cardiomyopathy; the intervening developmental and metabolic steps remain unresolved.
Abnormal CNS myelination Respiratory dysfunction may contribute to the observed white-matter injury, but its cellular sequence is unresolved.
Increased Hepatocyte Mitochondrial ROS The COX14 knock-in mouse links respiratory deficiency to increased oxidant production in hepatocytes; this branch has not been demonstrated in patients.
Show evidence (2 references)
PMID:22243966 SUPPORT In Vitro
"COX activity in immortalized subject fibroblasts was reduced to 30%-40% of that in control fibroblasts."
Residual complex IV activity is substantial in this cell system, despite the severe clinical course.
PMID:39134548 SUPPORT Model Organism
"COX14M19I liver mitochondria displayed a significant reduction in respiration"
The knock-in mouse provides a tissue-level respiratory measurement.
Increased Hepatocyte Mitochondrial ROS
Mechanism confidence: Provisional
In the Met19Ile mouse model, cultured primary hepatocytes have increased mitochondrial ROS and reduced membrane potential. This is an experimental mechanism, not a documented human COX14 phenotype.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
reactive oxygen species metabolic process GO:0072593 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased reactive oxygen species metabolic process (GO:0072593). GO:0072593 is a biological process from the Gene Ontology.
Downstream
Cytosolic Mitochondrial RNA Release Antioxidant rescue supports ROS-dependent mitochondrial RNA release. The specific membrane pore or transport route has not been resolved.
Show evidence (1 reference)
PMID:39134548 SUPPORT In Vitro
"COX14M19I hepatocytes elicited markedly increased mitochondrial ROS"
Primary hepatocytes isolated from mutant mice show increased mitochondrial oxidant production.
Cytosolic Mitochondrial RNA Release
Mechanism confidence: Provisional
Mitochondrial RNA accumulates in the cytosol of mutant mouse liver cells. Mitochondrial DNA is also released, but the observed inflammatory response preferentially implicates RNA sensing. No human COX14 tissue data establish this pathway.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
Experimental models
COX14 Mutant Primary Hepatocyte Antioxidant Experiments PRIMARY CELL CULTURE NAC suppresses RNA release and downstream inflammatory markers.
Downstream
Type I Interferon Response Cytosolic mitochondrial RNA is implicated in RIG-I/MDA5-associated inflammatory signaling in mutant mouse liver.
Show evidence (2 references)
PMID:39134548 SUPPORT Model Organism
"We detected both mitochondrial RNA (mtRNA) and mitochondrial DNA (mtDNA) by qPCR in significant amounts in cytoplasmic fractions of liver cells"
Tissue fractionation and qPCR directly detect misplaced mitochondrial nucleic acids.
PMID:39134548 SUPPORT In Vitro
"treatment with NAC prevented the release of mtRNAs in hepatocytes and subsequent upregulation of ISGs at the protein level"
Antioxidant intervention in cultured mouse hepatocytes supports ROS-dependent mitochondrial RNA release.
Type I Interferon Response
Mechanism confidence: Provisional
Interferon-stimulated transcripts and proteins are elevated in COX14 mutant mouse liver, with increased RNA-sensor abundance. This sterile experimental response does not imply a viral cause of the genetic disease.
response to type I interferon GO:0034340 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased response to type I interferon (GO:0034340). GO:0034340 is a biological process from the Gene Ontology.
Downstream
Experimental Hepatic Inflammatory Injury Persistent innate signaling is implicated in liver injury in the mouse model; contribution to the human neonatal course remains untested.
Show evidence (2 references)
PMID:39134548 SUPPORT Model Organism
"We found that RNA sensors such RIG-1 and MDA5 were significantly more abundant in liver cells than DNA sensors such as STING"
Sensor abundance supports an RNA-sensing response in the mutant liver; it does not identify the RNA-release pore.
PMID:39134548 SUPPORT Model Organism
"COX14M19I liver showed a significant expression of ISGs both at RNA and protein levels"
The inflammatory response was measured at both transcript and protein levels in mouse liver.
Experimental Hepatic Inflammatory Injury
Mechanism confidence: Provisional
Focal hepatic necrosis and mononuclear infiltrates occur in the COX14 knock-in mouse. Hepatomegaly was reported in the human index child, but hepatic inflammation was not assessed, so the experimental lesion is not asserted as the cause of the human finding.
inflammatory response GO:0006954 ↑ INCREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology.
Animal models
COX14 Met19Ile Knock-in Mouse Mouse recapitulates Mutant liver develops focal necrosis and inflammatory infiltrates.
Show evidence (1 reference)
PMID:39134548 SUPPORT Model Organism
"Liver sections displayed spots of focal necrosis demarcated by mononuclear cell infiltrate."
Liver histology in COX14 Met19Ile mice demonstrates inflammatory injury.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for COX14-Related COX Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
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Phenotypes

16
Cardiovascular 1
Hypertrophic cardiomyopathy HP:0001639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrophic cardiomyopathy (HP:0001639). HP:0001639 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22243966 SUPPORT Human Clinical
"An autopsy revealed brain hypertrophy, diffuse alteration of the white-matter myelination, and numerous cavities in the parieto-occipital region, brainstem, and cerebellum, as well as hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal-gland hyperplasia."
Direct observation in the founding index child; this is not a population-frequency estimate.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1224/ SUPPORT BACKGROUND Other
"Common clinical features of mitochondrial disorders include ... cardiomyopathy"
The general mitochondrial-disease overview provides clinical context; the COX14-specific association rests on the primary family report.
Digestive 1
Hepatomegaly HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22243966 SUPPORT Human Clinical
"An autopsy revealed brain hypertrophy, diffuse alteration of the white-matter myelination, and numerous cavities in the parieto-occipital region, brainstem, and cerebellum, as well as hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal-gland hyperplasia."
Direct observation in the founding index child; this is not a population-frequency estimate.
Endocrine 1
Adrenal hyperplasia HP:0008221 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Adrenal hyperplasia (HP:0008221). HP:0008221 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22243966 SUPPORT Human Clinical
"An autopsy revealed brain hypertrophy, diffuse alteration of the white-matter myelination, and numerous cavities in the parieto-occipital region, brainstem, and cerebellum, as well as hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal-gland hyperplasia."
Direct observation in the founding index child; this is not a population-frequency estimate.
Eye 2
Hypotelorism HP:0000601 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotelorism (HP:0000601). HP:0000601 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22243966 SUPPORT Human Clinical
"She was dysmorphic with hypotelorism, microphthalmia, an ogival palate, and a single palmar crease on the left hand."
Direct observation in the founding index child; this is not a population-frequency estimate.
Microphthalmia HP:0000568 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microphthalmia (HP:0000568). HP:0000568 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22243966 SUPPORT Human Clinical
"She was dysmorphic with hypotelorism, microphthalmia, an ogival palate, and a single palmar crease on the left hand."
Direct observation in the founding index child; this is not a population-frequency estimate.
Genitourinary 2
Renal hypoplasia HP:0000089 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Renal hypoplasia (HP:0000089). HP:0000089 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22243966 SUPPORT Human Clinical
"An autopsy revealed brain hypertrophy, diffuse alteration of the white-matter myelination, and numerous cavities in the parieto-occipital region, brainstem, and cerebellum, as well as hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal-gland hyperplasia."
Direct observation in the founding index child; this is not a population-frequency estimate.
Ketonuria HP:0002919 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ketonuria (HP:0002919). HP:0002919 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22243966 SUPPORT Human Clinical
"which was associated with ketonuria, thus confirming the abnormal intermediary metabolism."
Direct observation in the founding index child; this is not a population-frequency estimate.
Head and Neck 1
High palate HP:0000218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is High palate (HP:0000218). HP:0000218 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22243966 SUPPORT Human Clinical
"She was dysmorphic with hypotelorism, microphthalmia, an ogival palate, and a single palmar crease on the left hand."
Direct observation in the founding index child; this is not a population-frequency estimate.
Integument 1
Single transverse palmar crease HP:0000954 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Single transverse palmar crease (HP:0000954), qualified as laterality left. HP:0000954 is a phenotype from the Human Phenotype Ontology.
Laterality: LEFT
Show evidence (1 reference)
PMID:22243966 SUPPORT Human Clinical
"She was dysmorphic with hypotelorism, microphthalmia, an ogival palate, and a single palmar crease on the left hand."
Direct observation in the founding index child; this is not a population-frequency estimate.
Metabolism 2
Lactic acidosis Congenital lactic acidosis HP:0004902 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital lactic acidosis (HP:0004902), qualified as congenital onset. HP:0004902 is a phenotype from the Human Phenotype Ontology.
Onset: CONGENITAL
Show evidence (1 reference)
PMID:22243966 SUPPORT Human Clinical
"severe congenital lactic acidosis and dysmorphic features"
Direct observation in the founding index child; this is not a population-frequency estimate.
Increased CSF lactate HP:0002490 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased CSF lactate (HP:0002490). HP:0002490 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22243966 SUPPORT Human Clinical
"Lactate concentration was 23.4 mM in the blood and 26.2 mM in the cerebrospinal fluid 16 hr after birth."
Direct observation in the founding index child; this is not a population-frequency estimate.
Nervous System 3
Megalencephaly HP:0001355 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Megalencephaly (HP:0001355). HP:0001355 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22243966 SUPPORT Human Clinical
"An autopsy revealed brain hypertrophy, diffuse alteration of the white-matter myelination, and numerous cavities in the parieto-occipital region, brainstem, and cerebellum, as well as hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal-gland hyperplasia."
Direct observation in the founding index child; this is not a population-frequency estimate.
Abnormal CNS myelination HP:0011400 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal CNS myelination (HP:0011400). HP:0011400 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22243966 SUPPORT Human Clinical
"An autopsy revealed brain hypertrophy, diffuse alteration of the white-matter myelination, and numerous cavities in the parieto-occipital region, brainstem, and cerebellum, as well as hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal-gland hyperplasia."
Direct observation in the founding index child; this is not a population-frequency estimate.
Intracranial cystic lesions HP:0010576 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intracranial cystic lesions, annotated with Intracranial cystic lesion (HP:0010576). HP:0010576 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22243966 SUPPORT Human Clinical
"An autopsy revealed brain hypertrophy, diffuse alteration of the white-matter myelination, and numerous cavities in the parieto-occipital region, brainstem, and cerebellum, as well as hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal-gland hyperplasia."
Direct observation in the founding index child; this is not a population-frequency estimate.
Prenatal and Birth 1
Oligohydramnios HP:0001562 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Oligohydramnios (HP:0001562), qualified as antenatal onset. HP:0001562 is a phenotype from the Human Phenotype Ontology.
Onset: ANTENATAL
Show evidence (1 reference)
PMID:22243966 SUPPORT Human Clinical
"Oligoamnios and septum-lucidum cysts were noted at the 28th and 37th weeks of gestation."
Direct observation in the founding index child; this is not a population-frequency estimate.
Respiratory 1
Neonatal respiratory distress HP:0002643 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neonatal respiratory distress (HP:0002643), qualified as neonatal onset. HP:0002643 is a phenotype from the Human Phenotype Ontology.
Onset: NEONATAL
Show evidence (1 reference)
PMID:22243966 SUPPORT Human Clinical
"She presented with neurological and respiratory distress immediately after birth."
Direct observation in the founding index child; this is not a population-frequency estimate.
🧬

Genetic Associations

1
COX14 pathogenic variants
Gene: COX14 hgnc:28216 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is COX14 (hgnc:28216). hgnc:28216 is a gene from the HUGO Gene Nomenclature Committee.
Autosomal recessive
Show evidence (3 references)
PMID:22243966 SUPPORT Human Clinical
"a homozygous missense mutation (c.88G>A) ... predicting an amino acid change from methionine to isoleucine (p.Met19Ile)"
The source identifies the patient allele; nucleotide numbering is retained as reported rather than reassigned to a modern transcript.
PMID:22243966 SUPPORT Human Clinical
"The two other affected siblings had the same homozygous mutation, whereas the unaffected sibling and the parents were heterozygous carriers of the mutation."
Segregation in the family directly supports autosomal recessive inheritance.
PMID:22243966 SUPPORT In Vitro
"C12orf62 was not detectable by immunoblot analysis in subject fibroblasts, and retroviral expression of the wild-type C12orf62 cDNA rescued the biochemical phenotype."
Loss of detectable COX14 and complementation support deficiency of the protein rather than a structural COX-subunit mutation.
💊

Medical Actions

8
Acute Supportive and Metabolic Care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
Severe neonatal decompensation requires individualized intensive care, correction of metabolic derangements and specialist management of cardiorespiratory and multisystem dysfunction. The founding report does not establish a specific effective drug or bicarbonate regimen.
Target Phenotypes: Congenital lactic acidosis HP:0004902 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Congenital lactic acidosis (HP:0004902), qualified as congenital onset. HP:0004902 is a phenotype from the Human Phenotype Ontology. Neonatal respiratory distress HP:0002643 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Neonatal respiratory distress (HP:0002643), qualified as neonatal onset. HP:0002643 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28749475 SUPPORT BACKGROUND Other
"Treatment during acute decompensation should include dextrose-containing IV fluids, stopping exposure to potentially toxic medications, and correction of any metabolic derangements."
General mitochondrial-disease guidance; no COX14-specific clinical efficacy study is implied.
Prevention of Catabolism
Action: Nutritional SupportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. NCIT:C15433
Platform: Other
Avoid prolonged fasting and provide individualized nutrition and glucose-containing fluids during illness or procedures. Glucose delivery requires particular caution when an alternative pyruvate-metabolism disorder is suspected, during a ketogenic diet, or after prior adverse responses to glucose.
Show evidence (1 reference)
PMID:28749475 SUPPORT BACKGROUND Other
"Mitochondrial patients should take precautions to prevent entering catabolism, especially when exposed to medical stressors, including avoiding prolonged fasting and receiving dextrose-containing IV fluids before, during, and after procedures and surgeries."
General mitochondrial-disease guidance; no COX14-specific clinical efficacy study is implied.
Respiratory Support
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Platform: Other
Respiratory distress warrants specialist ventilatory assessment and support according to the infant’s physiology. Neuromuscular, central, aspiration and cardiac contributors may need evaluation.
Target Phenotypes: Neonatal respiratory distress HP:0002643 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Neonatal respiratory distress (HP:0002643), qualified as neonatal onset. HP:0002643 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28749475 SUPPORT BACKGROUND Other
"Ventilatory assessment should include evaluation for aspiration, atelectasis, and infection, and account for underlying issues of abnormal tone, as well as nerve and muscle disease."
General mitochondrial-disease guidance; no COX14-specific clinical efficacy study is implied.
Cardiac and Multisystem Surveillance
Platform: Other
Assess cardiomyopathy and other organ complications with the relevant specialists. General mitochondrial guidance emphasizes regular cardiac surveillance; a fixed long-term COX14 surveillance interval has not been established.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1224/ SUPPORT BACKGROUND Other
"These focus on regular surveillance to detect complications and their management using standard approaches that are not usually specific to mitochondrial disorders. Regular cardiac evaluation and monitoring for diabetes are particularly important."
General mitochondrial-disease guidance; no COX14-specific clinical efficacy study is implied.
Medication and Anesthesia Precautions
Platform: Other
Review potentially mitochondrial-toxic medications and anesthetic plans individually. General guidance advises avoiding or limiting prolonged propofol exposure and using caution with valproate, metformin and selected antibiotics. These are broader mitochondrial-disease precautions; the POLG-specific valproate contraindication should not be inferred solely from a COX14 diagnosis.
Show evidence (2 references)
PMID:28749475 SUPPORT BACKGROUND Other
"Mitochondrial patients may be at a higher risk for propofol infusion syndrome and propofol use should be avoided or limited to short procedures."
General mitochondrial-disease guidance; no COX14-specific clinical efficacy study is implied.
PMID:28749475 SUPPORT BACKGROUND Other
"The following medications should be avoided in patients with mitochondrial disease when possible and, if given, they should be used with caution: valproic acid; statins; metformin; high-dose acetaminophen; and selected antibiotics, including aminoglycosides, linezolid, tetracycline,..."
General consensus cautions are not evidence of specific toxicity in COX14 patients.
Genetic Counseling and Reproductive Planning
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Platform: Other
Confirm familial pathogenic variants, offer carrier testing and explain autosomal recessive recurrence risks. Prenatal and preimplantation genetic testing are possible once causative familial variants are known.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1224/ SUPPORT BACKGROUND Other
"Once the ... have been identified in an affected family member, ... prenatal testing ... for a pregnancy at increased risk and ... preimplantation genetic testing ... are possible."
General mitochondrial-disease guidance; no COX14-specific clinical efficacy study is implied.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1224/ SUPPORT BACKGROUND Other
"each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic ... carrier ... and a 25% chance of being unaffected and not a carrier."
Standard autosomal recessive recurrence risks apply when both parents carry a causative allele.
N-acetylcysteine in Experimental Hepatocytes
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: N-acetyl-L-cysteine CHEBI:28939 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses N-acetyl-L-cysteine (CHEBI:28939). CHEBI:28939 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Preclinical antioxidant intervention in cultured primary hepatocytes from COX14 Met19Ile mice reduced the ROS-associated inflammatory response. This experiment does not establish treatment efficacy, dosing or safety in human COX14 deficiency.
Mechanism Target:
INHIBITS Increased Hepatocyte Mitochondrial ROS — Ex vivo antioxidant effect in mutant mouse hepatocytes; human benefit is untested.
Show evidence (2 references)
PMID:39134548 SUPPORT In Vitro
"treatment with NAC prevented the release of mtRNAs in hepatocytes and subsequent upregulation of ISGs at the protein level"
Intervention was performed ex vivo in primary mouse hepatocytes; this is not an in vivo treatment or a clinical trial.
PMID:39134548 SUPPORT In Vitro
"In addition, we could show that the NAC treatments reduced the mitochondrial superoxide levels"
Direct measurement of reduced mitochondrial superoxide supports the antioxidant effect on this target, distinct from the downstream RNA-release readout.
Show evidence (1 reference)
PMID:39134548 SUPPORT In Vitro
"treatment with NAC prevented the release of mtRNAs in hepatocytes and subsequent upregulation of ISGs at the protein level"
Intervention was performed ex vivo in primary mouse hepatocytes; this is not an in vivo treatment or a clinical trial.
MitoTEMPO in Experimental Hepatocytes
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: MitoTEMPO CHEBI:232424 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses MitoTEMPO (CHEBI:232424). CHEBI:232424 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Preclinical antioxidant intervention in cultured primary hepatocytes from COX14 Met19Ile mice reduced the ROS-associated inflammatory response. This experiment does not establish treatment efficacy, dosing or safety in human COX14 deficiency.
Mechanism Target:
INHIBITS Increased Hepatocyte Mitochondrial ROS — Ex vivo antioxidant effect in mutant mouse hepatocytes; human benefit is untested.
Show evidence (2 references)
PMID:39134548 SUPPORT In Vitro
"Similar results as seen for NAC were obtained with Mito-TEMPO"
Intervention was performed ex vivo in primary mouse hepatocytes; this is not an in vivo treatment or a clinical trial.
PMID:39134548 SUPPORT In Vitro
"in a complementary approach we utilized Mito-TEMPO, which acts on superoxide as a superoxide dismutase mimetic. Similar results as seen for NAC were obtained with Mito-TEMPO"
The authors state the superoxide-directed pharmacology and a similar experimental response to NAC in cultured mutant mouse hepatocytes.
Show evidence (1 reference)
PMID:39134548 SUPPORT In Vitro
"Similar results as seen for NAC were obtained with Mito-TEMPO"
Intervention was performed ex vivo in primary mouse hepatocytes; this is not an in vivo treatment or a clinical trial.
🔬

Diagnosis

3
Molecular Genetic Diagnosis
Evaluate severe congenital lactic acidosis with multisystem abnormalities using mitochondrial/nuclear gene testing, including COX14. Urgent trio exome or genome sequencing may be appropriate. Assess segregation and variant pathogenicity; a COX14 VUS alone does not establish this diagnosis.
Show evidence (3 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1224/ SUPPORT BACKGROUND Other
"Molecular genetic testing is used to establish the diagnosis."
General mitochondrial-disease diagnostic guidance.
PMID:36513735 SUPPORT BACKGROUND Other
"For urgent paediatric referrals where samples from a parent–child trio can be obtained, gene-agnostic WES or WGS, where data is analysed with no gene panels or other preconceptions about where variants associated with a condition are located, is an appropriate testing strategy."
Consensus guidance supports rapid broad testing in critically ill infants, without claiming COX14-specific diagnostic yield.
PMID:22243966 SUPPORT Human Clinical
"The two other affected siblings had the same homozygous mutation, whereas the unaffected sibling and the parents were heterozygous carriers of the mutation."
Segregation in the family directly supports autosomal recessive inheritance.
Functional Assessment of Complex IV
Respiratory-chain enzyme assays, blue-native electrophoresis and mitochondrial translation studies can clarify an uncertain genetic result. The founding fibroblasts retained complex IV activity despite a fatal neonatal phenotype; fibroblast activity is not a direct prognostic scale.
Show evidence (3 references)
PMID:22243966 SUPPORT In Vitro
"COX activity in immortalized subject fibroblasts was reduced to 30%-40% of that in control fibroblasts."
Residual complex IV activity is substantial in this cell system, despite the severe clinical course.
PMID:22243966 SUPPORT In Vitro
"Blue native polyacrylamide gel electrophoresis (BN-PAGE) analysis11 showed that the reduced activity was associated with a specific reduction in the amount of fully assembled COX, but did not identify subassemblies of the COX complex"
Patient fibroblasts directly demonstrate deficient mature complex IV assembly.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1224/ SUPPORT BACKGROUND Other
"In many individuals in whom ... molecular genetic testing ... does not yield or confirm a diagnosis, further investigation of suspected mitochondrial disease can involve a range of different clinical tests, including muscle biopsy for respiratory chain function."
Functional studies complement inconclusive molecular testing; biopsy is not required before sequencing.
Metabolic and Multisystem Assessment
Assess lactate and acid-base status, respiratory function and cardiac, neurologic, hepatic and renal involvement. Organ assessment should be driven by the presentation; the founding case had abnormalities across these systems.
Show evidence (2 references)
PMID:22243966 SUPPORT Human Clinical
"An autopsy revealed brain hypertrophy, diffuse alteration of the white-matter myelination, and numerous cavities in the parieto-occipital region, brainstem, and cerebellum, as well as hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal-gland hyperplasia."
Autopsy defined the multisystem burden in the index child.
PMID:28749475 SUPPORT BACKGROUND Other
"Initial triage stratification of critically ill mitochondrial patients should include a systemic assessment of all body systems since the disease is multisystemic and patients may develop new organ system involvement during an acute decompensation."
General critical-care guidance supports systematic assessment.
📈

Progression

1
Fatal neonatal course in the founding family
The founding index child died 24 hours after birth. This observation describes the reported severe family and does not establish an invariant outcome for all possible COX14 genotypes.
Show evidence (1 reference)
PMID:22243966 SUPPORT Human Clinical
"Lactate concentration was 23.4 mM in the blood and 26.2 mM in the cerebrospinal fluid 16 hr after birth. Death occurred 24 hr after birth."
The primary family report documents neonatal mortality in the index child.
📊

Related Datasets

1
Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver geo:GSE269535
Bulk liver transcriptomics comparing wild-type and homozygous COX14 Met19Ile mice. The experimental dataset supports study of the interferon response and metabolic gene-expression changes; it contains no human patient cohort.
Mus musculus BULK RNA SEQ
Conditions: Wild-type mouse liver Homozygous COX14 Met19Ile mouse liver
PMID:39134548
Show evidence (1 reference)
PMID:39134548 SUPPORT Model Organism
"we addressed changes in the gene expression pattern by RNA sequencing (RNA-seq) of wild type and COX14M19I mice liver samples."
The primary paper describes the model, tissue and assay; GEO accession resolution was separately verified.
🧫

Experimental Models

3
Patient Fibroblast COX14 Complementation CELL_LINE
Patient fibroblasts demonstrate reduced COX1 synthesis and complex IV assembly, with rescue by wild-type COX14. These experiments establish biochemical causality without reproducing the full neonatal multisystem phenotype.
Cell source
Immortalized fibroblasts from the index patient and controls
Publication
PMID:22243966
Pathograph links
Deficient Complex IV Assembly recapitulates fidelity: high observes: molecular Patient cells show reduced mature complex IV.
Limitations: Residual fibroblast activity does not predict neonatal tissue severity.
Show evidence (1 reference)
PMID:22243966 SUPPORT In Vitro
"Blue native polyacrylamide gel electrophoresis (BN-PAGE) analysis11 showed that the reduced activity was associated with a specific reduction in the amount of fully assembled COX, but did not identify subassemblies of the COX complex"
Patient fibroblasts directly demonstrate deficient mature complex IV assembly.
Reduced COX1 Translation rescues fidelity: high observes: molecular Wild-type COX14 expression restores translation and assembly in the patient-cell system.
Limitations: Retroviral complementation is not a tested clinical gene therapy.
Show evidence (1 reference)
PMID:22243966 SUPPORT In Vitro
"it completely rescued the COX-assembly defect ... COX I translation in the PULSE assay ... and COX activity (92% of control) in subject fibroblasts."
Functional complementation confirms the causal protein defect.
Show evidence (1 reference)
PMID:22243966 SUPPORT In Vitro
"C12orf62 was not detectable by immunoblot analysis in subject fibroblasts, and retroviral expression of the wild-type C12orf62 cDNA rescued the biochemical phenotype."
Loss of detectable COX14 and complementation support deficiency of the protein rather than a structural COX-subunit mutation.
Human Cell COX14 Translation Studies CELL_LINE
Knockdown, complementation and immunoisolation connect COX14 to COX1-translating ribosomes and nascent-chain assembly intermediates.
Cell source
HEK293-derived human cell lines
Publication
PMID:27693358
Pathograph links
Reduced COX1 Translation perturbs fidelity: moderate observes: molecular COX14 knockdown reduces COX1 synthesis.
Limitations: Knockdown and tagged-protein systems differ from the homozygous patient missense allele.
Show evidence (1 reference)
PMID:27693358 SUPPORT In Vitro
"the decreased level of newly synthesized COX1 observed upon C12ORF62 knockdown is apparently not a result of increased turnover but rather of reduced translation."
C12ORF62 depletion reduces COX1 synthesis; protease depletion did not explain the deficit.
Show evidence (1 reference)
PMID:27693358 SUPPORT In Vitro
"We conclude that the COX1 translation intermediates initially associate with C12ORF62, and MITRAC12 is recruited sequentially."
The experiments resolve the order of early assembly-factor recruitment.
COX14 Mutant Primary Hepatocyte Antioxidant Experiments PRIMARY_CELL_CULTURE
Cultured mutant hepatocytes permit measurement of ROS, membrane potential, mitochondrial RNA release and interferon-stimulated gene expression, with antioxidant intervention.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
Cell source
Primary hepatocytes isolated from homozygous COX14 Met19Ile mice
Publication
PMID:39134548
Pathograph links
Cytosolic Mitochondrial RNA Release rescues fidelity: moderate observes: cellular NAC suppresses RNA release and downstream inflammatory markers.
Limitations: Ex vivo rescue does not establish benefit in a living mouse or patient.
Show evidence (1 reference)
PMID:39134548 SUPPORT In Vitro
"treatment with NAC prevented the release of mtRNAs in hepatocytes and subsequent upregulation of ISGs at the protein level"
Antioxidant intervention in cultured mouse hepatocytes supports ROS-dependent mitochondrial RNA release.
Findings
Fatostatin did not reduce interferon-stimulated gene expression, in contrast to antioxidant rescue.
Show evidence (1 reference)
PMID:39134548 SUPPORT In Vitro
"The treatment with Fatostatin did not alter the expression of ISGs, demonstrating that SERBP-mediated cholesterol biosynthesis did not contribute to the inflammatory response"
The negative pharmacologic result distinguishes the proposed ROS pathway from a cholesterol-biosynthesis explanation.
Show evidence (2 references)
PMID:39134548 SUPPORT In Vitro
"COX14M19I hepatocytes elicited markedly increased mitochondrial ROS"
Primary hepatocytes isolated from mutant mice show increased mitochondrial oxidant production.
PMID:39134548 SUPPORT In Vitro
"treatment with NAC prevented the release of mtRNAs in hepatocytes and subsequent upregulation of ISGs at the protein level"
Antioxidant intervention in cultured mouse hepatocytes supports ROS-dependent mitochondrial RNA release.
🐁

Animal Models

1
COX14 Met19Ile Knock-in Mouse
The patient-corresponding allele causes reduced complex IV assembly and respiration with tissue-dependent severity. Mice show partial pre-weaning mortality and progressive liver, cardiac, retinal and muscle abnormalities among survivors. The inflammatory liver branch is a model-derived hypothesis for human disease.
Species
Mouse
Genotype
Homozygous Cox14 p.Met19Ile knock-in
Publication
PMID:39134548
Pathograph links
Deficient Complex IV Assembly partially recapitulates fidelity: moderate observes: organism The knock-in causes tissue-dependent complex IV deficiency.
Limitations: Many mice survive to adulthood; no apparent brain phenotype was detected, unlike the severe human neonatal presentation.
Show evidence (1 reference)
PMID:39134548 SUPPORT Model Organism
"complex IV activity and amount were significantly reduced in mutant mitochondria isolated from different tissues"
The animal reproduces the proximal respiratory-chain defect.
Experimental Hepatic Inflammatory Injury recapitulates fidelity: moderate observes: organism Mutant liver develops focal necrosis and inflammatory infiltrates.
Limitations: Inflammation was not assessed in the human index case; human applicability is unresolved.
Show evidence (1 reference)
PMID:39134548 SUPPORT Model Organism
"Liver sections displayed spots of focal necrosis demarcated by mononuclear cell infiltrate."
Liver histology in COX14 Met19Ile mice demonstrates inflammatory injury.
Show evidence (4 references)
PMID:39134548 SUPPORT Model Organism
"Moreover, 26% of the COX14M19I animals experienced pre-weaning mortality as compared to that in the wild type."
Partial early mortality differs from the reported human neonatal course.
PMID:39134548 SUPPORT Model Organism
"Brain and muscle displayed similar complex IV reduction, yet a brain phenotype was not apparent in our analyses."
A biochemical defect did not imply the same organ phenotype as in the human case.
PMID:39134548 SUPPORT Model Organism
"While cardiac defects were also apparent in the COX14M19I mouse, information on inflammation and retinal state of the patient are not available."
Human inflammatory and retinal phenotypes remain unestablished.
+ 1 more reference
{ }

Source YAML

click to show 
name: COX14-Related COX Deficiency
category: Mendelian
creation_date: '2026-06-17T00:00:00Z'
synonyms:
- COX14 deficiency
- Mitochondrial complex IV deficiency, nuclear type 10
- MC4DN10
- COX14-related cytochrome c oxidase deficiency
- C12orf62-related complex IV deficiency
disease_term:
  preferred_term: COX14-related COX deficiency (MC4DN10)
  term:
    id: MONDO:0033639
    label: mitochondrial complex IV deficiency, nuclear type 10
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
updated_date: '2026-10-03T00:00:00Z'
description: COX14-related COX deficiency is an autosomal recessive disorder of mitochondrial complex IV biogenesis caused by biallelic COX14 (formerly C12orf62) variants. COX14 regulates synthesis of the mitochondrial-encoded COX1 subunit in early assembly intermediates. The founding Met19Ile family had severe congenital multisystem disease with neonatal lactic acidosis, dysmorphism and brain, cardiac, hepatic and renal abnormalities. Patient-cell experiments establish a defect in COX1 translation and complex IV assembly. A corresponding mouse model reveals tissue-dependent disease and an experimental ROS-driven hepatic inflammatory pathway; its later survival and inflammatory findings are not established features of the human disorder.
references:
- reference: PMID:22243966
  title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
- reference: PMID:27693358
  title: Mitochondrial Protein Synthesis Adapts to Influx of Nuclear-Encoded Protein.
- reference: PMID:39134548
  title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1224/
  title: Primary Mitochondrial Disorders Overview - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
- reference: PMID:20301403
  title: Primary Mitochondrial Disorders Overview.
  tags:
  - GeneReviews
- reference: PMID:28749475
  title: 'Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society.'
- reference: PMID:36513735
  title: 'Genetic testing for mitochondrial disease: the United Kingdom best practice guidelines.'
pathophysiology:
- name: COX14 Functional Deficiency
  biological_scale: MOLECULAR
  description: The Met19Ile allele destabilizes COX14 and reduces its capacity to regulate COX1 translation. Residual function is possible even when the protein is undetectable by immunoblotting.
  genes:
  - &id007
    preferred_term: COX14
    term:
      id: hgnc:28216
      label: COX14
  molecular_functions:
  - preferred_term: translation regulator activity
    term:
      id: GO:0045182
      label: translation regulator activity
    modifier: DECREASED
  evidence:
  - &id009
    reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: C12orf62 was not detectable by immunoblot analysis in subject fibroblasts, and retroviral expression of the wild-type C12orf62 cDNA rescued the biochemical phenotype.
    explanation: Loss of detectable COX14 and complementation support deficiency of the protein rather than a structural COX-subunit mutation.
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: the same knockdown exacerbated the biochemical phenotype, implying that the mutant protein, although not detectable by immunoblot analysis, retained some residual function.
    explanation: Additional depletion worsened the patient-cell defect, arguing against a complete functional null.
  - reference: PMID:27693358
    reference_title: Mitochondrial Protein Synthesis Adapts to Influx of Nuclear-Encoded Protein.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: C12ORF62 acts upstream of MITRAC12 and associates with COX1 in a ribosome nascent chain complex.
    explanation: Human-cell interaction and translation experiments position COX14 in early cotranslational assembly.
  downstream:
  - target: Reduced COX1 Translation
    causal_link_type: DIRECT
    description: Deficiency of the translation-regulating factor reduces production of COX1.
    evidence:
    - &id001
      reference: PMID:27693358
      reference_title: Mitochondrial Protein Synthesis Adapts to Influx of Nuclear-Encoded Protein.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: the decreased level of newly synthesized COX1 observed upon C12ORF62 knockdown is apparently not a result of increased turnover but rather of reduced translation.
      explanation: C12ORF62 depletion reduces COX1 synthesis; protease depletion did not explain the deficit.
- name: Reduced COX1 Translation
  biological_scale: MOLECULAR
  description: COX1 synthesis is selectively reduced. In patient fibroblasts this occurs without reduced mitochondrial COX mRNA abundance; it should not be described as generalized mitochondrial transcription failure.
  biological_processes:
  - preferred_term: mitochondrial translation
    term:
      id: GO:0032543
      label: mitochondrial translation
    modifier: DECREASED
  evidence:
  - *id001
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: The levels of the COX mRNAs in the subject were not reduced relative to those of the controls when they were normalized to the rRNA levels
    explanation: Normal transcript abundance distinguishes this defect from depletion of COX mRNA.
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: In the subject cells, although COX I was synthesized at ∼25% of control levels, the newly synthesized protein was completely stable.
    explanation: In the reported pulse-chase experiment, lower COX1 synthesis coexisted with stable newly synthesized COX1.
  downstream:
  - target: Deficient Complex IV Assembly
    causal_link_type: DIRECT
    description: Reduced COX1 supply and defective coordination of early assembly restrict mature complex IV formation.
    evidence:
    - &id002
      reference: PMID:22243966
      reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Blue native polyacrylamide gel electrophoresis (BN-PAGE) analysis11 showed that the reduced activity was associated with a specific reduction in the amount of fully assembled COX, but did not identify subassemblies of the COX complex
      explanation: Patient fibroblasts directly demonstrate deficient mature complex IV assembly.
- name: Deficient Complex IV Assembly
  biological_scale: MOLECULAR
  conforms_to: complex_iv_assembly_deficiency#Complex IV Biogenesis Failure
  description: The amount of mature complex IV is reduced. COX2 and COX3 incorporation into nascent complexes is inefficient, with increased turnover of these subunits in patient fibroblasts.
  biological_processes:
  - preferred_term: mitochondrial respiratory chain complex IV assembly
    term:
      id: GO:0033617
      label: mitochondrial respiratory chain complex IV assembly
    modifier: DECREASED
  evidence:
  - *id002
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: newly synthesized COX II and III were less efficiently incorporated into the COX complex, and they were rapidly turned over after a long chase.
    explanation: The assembly defect includes instability of incompletely assembled COX2 and COX3, rather than universal instability of newly synthesized COX1.
  downstream:
  - target: Reduced Complex IV Respiratory Capacity
    causal_link_type: DIRECT
    description: Deficient holoenzyme abundance reduces complex IV catalytic capacity.
    evidence:
    - &id003
      reference: PMID:22243966
      reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: COX activity in immortalized subject fibroblasts was reduced to 30%-40% of that in control fibroblasts.
      explanation: Residual complex IV activity is substantial in this cell system, despite the severe clinical course.
- name: Reduced Complex IV Respiratory Capacity
  biological_scale: CELLULAR
  description: Reduced complex IV activity limits terminal electron transfer and respiratory capacity. The magnitude varies by tissue and experimental system. Neither complete abolition of oxidative phosphorylation nor uniform depletion of total cellular ATP has been established.
  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
  evidence:
  - *id003
  - reference: PMID:39134548
    reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: COX14M19I liver mitochondria displayed a significant reduction in respiration
    explanation: The knock-in mouse provides a tissue-level respiratory measurement.
  downstream:
  - target: Lactic acidosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Impaired oxidative metabolism is a plausible contributor to the severe lactic acidosis, but the intermediate flux changes were not directly measured in the infant.
    evidence:
    - reference: PMID:22243966
      reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: severe congenital lactic acidosis and dysmorphic features associated with a cytochrome c oxidase (COX)-assembly defect
      explanation: Clinical-biochemical association supports the link without a measured ATP or glycolytic-flux result.
      directness: INDIRECT
  - target: Hypertrophic cardiomyopathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cardiac mitochondrial dysfunction provides a mechanistic explanation for the reported cardiomyopathy; the intervening developmental and metabolic steps remain unresolved.
  - target: Abnormal CNS myelination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Respiratory dysfunction may contribute to the observed white-matter injury, but its cellular sequence is unresolved.
  - target: Increased Hepatocyte Mitochondrial ROS
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The COX14 knock-in mouse links respiratory deficiency to increased oxidant production in hepatocytes; this branch has not been demonstrated in patients.
    evidence:
    - &id004
      reference: PMID:39134548
      reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: COX14M19I hepatocytes elicited markedly increased mitochondrial ROS
      explanation: Primary hepatocytes isolated from mutant mice show increased mitochondrial oxidant production.
- name: Increased Hepatocyte Mitochondrial ROS
  biological_scale: CELLULAR
  description: In the Met19Ile mouse model, cultured primary hepatocytes have increased mitochondrial ROS and reduced membrane potential. This is an experimental mechanism, not a documented human COX14 phenotype.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  biological_processes:
  - preferred_term: reactive oxygen species metabolic process
    term:
      id: GO:0072593
      label: reactive oxygen species metabolic process
    modifier: INCREASED
  evidence:
  - *id004
  downstream:
  - target: Cytosolic Mitochondrial RNA Release
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Antioxidant rescue supports ROS-dependent mitochondrial RNA release. The specific membrane pore or transport route has not been resolved.
    evidence:
    - &id005
      reference: PMID:39134548
      reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: treatment with NAC prevented the release of mtRNAs in hepatocytes and subsequent upregulation of ISGs at the protein level
      explanation: Antioxidant intervention in cultured mouse hepatocytes supports ROS-dependent mitochondrial RNA release.
  mechanism_confidence: PROVISIONAL
- name: Cytosolic Mitochondrial RNA Release
  biological_scale: CELLULAR
  description: Mitochondrial RNA accumulates in the cytosol of mutant mouse liver cells. Mitochondrial DNA is also released, but the observed inflammatory response preferentially implicates RNA sensing. No human COX14 tissue data establish this pathway.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:39134548
    reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: We detected both mitochondrial RNA (mtRNA) and mitochondrial DNA (mtDNA) by qPCR in significant amounts in cytoplasmic fractions of liver cells
    explanation: Tissue fractionation and qPCR directly detect misplaced mitochondrial nucleic acids.
  - *id005
  downstream:
  - target: Type I Interferon Response
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cytosolic mitochondrial RNA is implicated in RIG-I/MDA5-associated inflammatory signaling in mutant mouse liver.
    evidence:
    - &id006
      reference: PMID:39134548
      reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: We found that RNA sensors such RIG-1 and MDA5 were significantly more abundant in liver cells than DNA sensors such as STING
      explanation: Sensor abundance supports an RNA-sensing response in the mutant liver; it does not identify the RNA-release pore.
  mechanism_confidence: PROVISIONAL
- name: Type I Interferon Response
  biological_scale: CELLULAR
  description: Interferon-stimulated transcripts and proteins are elevated in COX14 mutant mouse liver, with increased RNA-sensor abundance. This sterile experimental response does not imply a viral cause of the genetic disease.
  biological_processes:
  - preferred_term: response to type I interferon
    term:
      id: GO:0034340
      label: response to type I interferon
    modifier: INCREASED
  evidence:
  - *id006
  - reference: PMID:39134548
    reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: COX14M19I liver showed a significant expression of ISGs both at RNA and protein levels
    explanation: The inflammatory response was measured at both transcript and protein levels in mouse liver.
  downstream:
  - target: Experimental Hepatic Inflammatory Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Persistent innate signaling is implicated in liver injury in the mouse model; contribution to the human neonatal course remains untested.
    evidence:
    - reference: PMID:39134548
      reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Sensing of the “foreign“ mitochondrial RNAs in the cytoplasm instigated the inflammation and subsequent liver pathology.
      explanation: The authors interpret the experimental pathway as a contributor to hepatic pathology.
      directness: INDIRECT
  mechanism_confidence: PROVISIONAL
- name: Experimental Hepatic Inflammatory Injury
  biological_scale: TISSUE
  description: Focal hepatic necrosis and mononuclear infiltrates occur in the COX14 knock-in mouse. Hepatomegaly was reported in the human index child, but hepatic inflammation was not assessed, so the experimental lesion is not asserted as the cause of the human finding.
  biological_processes:
  - preferred_term: inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  evidence:
  - &id015
    reference: PMID:39134548
    reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Liver sections displayed spots of focal necrosis demarcated by mononuclear cell infiltrate.
    explanation: Liver histology in COX14 Met19Ile mice demonstrates inflammatory injury.
  mechanism_confidence: PROVISIONAL
phenotypes:
- name: Lactic acidosis
  description: Profound neonatal metabolic acidosis with marked blood lactate elevation was the presenting metabolic feature.
  phenotype_term: &id010
    preferred_term: Congenital lactic acidosis
    term:
      id: HP:0004902
      label: Congenital lactic acidosis
    onset:
      onset_category: CONGENITAL
  evidence:
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: severe congenital lactic acidosis and dysmorphic features
    explanation: Direct observation in the founding index child; this is not a population-frequency estimate.
- name: Neonatal respiratory distress
  description: Respiratory distress occurred immediately after birth in the index child.
  phenotype_term: &id011
    preferred_term: Neonatal respiratory distress
    term:
      id: HP:0002643
      label: Neonatal respiratory distress
    onset:
      onset_category: NEONATAL
  evidence:
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She presented with neurological and respiratory distress immediately after birth.
    explanation: Direct observation in the founding index child; this is not a population-frequency estimate.
- name: Hypotelorism
  description: Closely spaced eyes were part of the congenital dysmorphism.
  phenotype_term:
    preferred_term: Hypotelorism
    term:
      id: HP:0000601
      label: Hypotelorism
  evidence:
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She was dysmorphic with hypotelorism, microphthalmia, an ogival palate, and a single palmar crease on the left hand.
    explanation: Direct observation in the founding index child; this is not a population-frequency estimate.
- name: Microphthalmia
  description: Small eyes were reported in the index child.
  phenotype_term:
    preferred_term: Microphthalmia
    term:
      id: HP:0000568
      label: Microphthalmia
  evidence:
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She was dysmorphic with hypotelorism, microphthalmia, an ogival palate, and a single palmar crease on the left hand.
    explanation: Direct observation in the founding index child; this is not a population-frequency estimate.
- name: High palate
  description: The index child had an ogival palate.
  phenotype_term:
    preferred_term: High palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She was dysmorphic with hypotelorism, microphthalmia, an ogival palate, and a single palmar crease on the left hand.
    explanation: Direct observation in the founding index child; this is not a population-frequency estimate.
- name: Single transverse palmar crease
  description: A single palmar crease was reported on the left hand.
  phenotype_term:
    preferred_term: Single transverse palmar crease
    term:
      id: HP:0000954
      label: Single transverse palmar crease
    laterality: LEFT
  evidence:
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: She was dysmorphic with hypotelorism, microphthalmia, an ogival palate, and a single palmar crease on the left hand.
    explanation: Direct observation in the founding index child; this is not a population-frequency estimate.
- name: Megalencephaly
  description: Brain hypertrophy was reported at autopsy; the source does not characterize cortical dysplasia.
  phenotype_term:
    preferred_term: Megalencephaly
    term:
      id: HP:0001355
      label: Megalencephaly
  evidence:
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: An autopsy revealed brain hypertrophy, diffuse alteration of the white-matter myelination, and numerous cavities in the parieto-occipital region, brainstem, and cerebellum, as well as hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal-gland hyperplasia.
    explanation: Direct observation in the founding index child; this is not a population-frequency estimate.
- name: Abnormal CNS myelination
  description: Diffuse white-matter myelination abnormalities were reported. The source does not resolve delayed myelination, hypomyelination or demyelination.
  phenotype_term:
    preferred_term: Abnormal CNS myelination
    term:
      id: HP:0011400
      label: Abnormal CNS myelination
  evidence:
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: An autopsy revealed brain hypertrophy, diffuse alteration of the white-matter myelination, and numerous cavities in the parieto-occipital region, brainstem, and cerebellum, as well as hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal-gland hyperplasia.
    explanation: Direct observation in the founding index child; this is not a population-frequency estimate.
- name: Intracranial cystic lesions
  description: Multiple cavities involved the parieto-occipital region, brainstem and cerebellum. Septum-lucidum cysts had also been identified prenatally.
  phenotype_term:
    preferred_term: Intracranial cystic lesions
    term:
      id: HP:0010576
      label: Intracranial cystic lesion
  evidence:
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: An autopsy revealed brain hypertrophy, diffuse alteration of the white-matter myelination, and numerous cavities in the parieto-occipital region, brainstem, and cerebellum, as well as hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal-gland hyperplasia.
    explanation: Direct observation in the founding index child; this is not a population-frequency estimate.
- name: Hepatomegaly
  description: Enlargement of the liver was found at autopsy; inflammatory histology was not reported in this infant.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: An autopsy revealed brain hypertrophy, diffuse alteration of the white-matter myelination, and numerous cavities in the parieto-occipital region, brainstem, and cerebellum, as well as hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal-gland hyperplasia.
    explanation: Direct observation in the founding index child; this is not a population-frequency estimate.
- name: Hypertrophic cardiomyopathy
  description: Hypertrophic cardiomyopathy was identified in the neonatal index case.
  phenotype_term:
    preferred_term: Hypertrophic cardiomyopathy
    term:
      id: HP:0001639
      label: Hypertrophic cardiomyopathy
  evidence:
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: An autopsy revealed brain hypertrophy, diffuse alteration of the white-matter myelination, and numerous cavities in the parieto-occipital region, brainstem, and cerebellum, as well as hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal-gland hyperplasia.
    explanation: Direct observation in the founding index child; this is not a population-frequency estimate.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1224/
    reference_title: Primary Mitochondrial Disorders Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Common clinical features of mitochondrial disorders include ... cardiomyopathy
    explanation: The general mitochondrial-disease overview provides clinical context; the COX14-specific association rests on the primary family report.
    quote_role: BACKGROUND
- name: Renal hypoplasia
  description: Hypoplastic kidneys were reported; this structural finding does not by itself establish renal tubular acidosis.
  phenotype_term:
    preferred_term: Renal hypoplasia
    term:
      id: HP:0000089
      label: Renal hypoplasia
  evidence:
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: An autopsy revealed brain hypertrophy, diffuse alteration of the white-matter myelination, and numerous cavities in the parieto-occipital region, brainstem, and cerebellum, as well as hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal-gland hyperplasia.
    explanation: Direct observation in the founding index child; this is not a population-frequency estimate.
- name: Adrenal hyperplasia
  description: Adrenal enlargement was observed at autopsy. A steroidogenic congenital adrenal hyperplasia syndrome or hormonal dysfunction was not demonstrated.
  phenotype_term:
    preferred_term: Adrenal hyperplasia
    term:
      id: HP:0008221
      label: Adrenal hyperplasia
  evidence:
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: An autopsy revealed brain hypertrophy, diffuse alteration of the white-matter myelination, and numerous cavities in the parieto-occipital region, brainstem, and cerebellum, as well as hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal-gland hyperplasia.
    explanation: Direct observation in the founding index child; this is not a population-frequency estimate.
- name: Ketonuria
  description: Urinary ketones accompanied the severe neonatal metabolic acidosis.
  phenotype_term:
    preferred_term: Ketonuria
    term:
      id: HP:0002919
      label: Ketonuria
  evidence:
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: which was associated with ketonuria, thus confirming the abnormal intermediary metabolism.
    explanation: Direct observation in the founding index child; this is not a population-frequency estimate.
- name: Increased CSF lactate
  description: CSF lactate was markedly elevated in the index child.
  phenotype_term:
    preferred_term: Increased CSF lactate
    term:
      id: HP:0002490
      label: Increased CSF lactate
  evidence:
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Lactate concentration was 23.4 mM in the blood and 26.2 mM in the cerebrospinal fluid 16 hr after birth.
    explanation: Direct observation in the founding index child; this is not a population-frequency estimate.
- name: Oligohydramnios
  description: Reduced amniotic fluid was recorded during the index pregnancy; recurrence across COX14 genotypes is unknown.
  phenotype_term:
    preferred_term: Oligohydramnios
    term:
      id: HP:0001562
      label: Oligohydramnios
    onset:
      onset_category: ANTENATAL
  evidence:
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Oligoamnios and septum-lucidum cysts were noted at the 28th and 37th weeks of gestation.
    explanation: Direct observation in the founding index child; this is not a population-frequency estimate.
inheritance:
- name: Autosomal recessive
  description: Biallelic pathogenic variants cause disease; heterozygous parents and a heterozygous sibling were unaffected in the founding family. When both parents are carriers, recurrence risks per pregnancy are 25% affected, 50% carrier and 25% unaffected non-carrier.
  evidence:
  - &id008
    reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The two other affected siblings had the same homozygous mutation, whereas the unaffected sibling and the parents were heterozygous carriers of the mutation.
    explanation: Segregation in the family directly supports autosomal recessive inheritance.
  - &id012
    reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1224/
    reference_title: Primary Mitochondrial Disorders Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: each sib of an affected individual has at conception a 25% chance of being affected, a 50% chance of being an asymptomatic ... carrier ... and a 25% chance of being unaffected and not a carrier.
    explanation: Standard autosomal recessive recurrence risks apply when both parents carry a causative allele.
    quote_role: BACKGROUND
genetic:
- name: COX14 pathogenic variants
  gene_term: *id007
  inheritance:
  - name: Autosomal recessive
    evidence:
    - *id008
  features: The established founding allele is homozygous p.Met19Ile, reported with the historical nucleotide designation c.88G>A. It affects the conserved transmembrane region and greatly reduces protein abundance. The family does not establish a broad genotype-phenotype series, population penetrance or modifier genes.
  evidence:
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a homozygous missense mutation (c.88G>A) ... predicting an amino acid change from methionine to isoleucine (p.Met19Ile)
    explanation: The source identifies the patient allele; nucleotide numbering is retained as reported rather than reassigned to a modern transcript.
  - *id008
  - *id009
diagnosis:
- name: Molecular Genetic Diagnosis
  description: Evaluate severe congenital lactic acidosis with multisystem abnormalities using mitochondrial/nuclear gene testing, including COX14. Urgent trio exome or genome sequencing may be appropriate. Assess segregation and variant pathogenicity; a COX14 VUS alone does not establish this diagnosis.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1224/
    reference_title: Primary Mitochondrial Disorders Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Molecular genetic testing is used to establish the diagnosis.
    explanation: General mitochondrial-disease diagnostic guidance.
    quote_role: BACKGROUND
  - reference: PMID:36513735
    reference_title: 'Genetic testing for mitochondrial disease: the United Kingdom best practice guidelines.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: For urgent paediatric referrals where samples from a parent–child trio can be obtained, gene-agnostic WES or WGS, where data is analysed with no gene panels or other preconceptions about where variants associated with a condition are located, is an appropriate testing strategy.
    explanation: Consensus guidance supports rapid broad testing in critically ill infants, without claiming COX14-specific diagnostic yield.
    quote_role: BACKGROUND
  - *id008
- name: Functional Assessment of Complex IV
  description: Respiratory-chain enzyme assays, blue-native electrophoresis and mitochondrial translation studies can clarify an uncertain genetic result. The founding fibroblasts retained complex IV activity despite a fatal neonatal phenotype; fibroblast activity is not a direct prognostic scale.
  evidence:
  - *id003
  - *id002
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1224/
    reference_title: Primary Mitochondrial Disorders Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: In many individuals in whom ... molecular genetic testing ... does not yield or confirm a diagnosis, further investigation of suspected mitochondrial disease can involve a range of different clinical tests, including muscle biopsy for respiratory chain function.
    explanation: Functional studies complement inconclusive molecular testing; biopsy is not required before sequencing.
    quote_role: BACKGROUND
- name: Metabolic and Multisystem Assessment
  description: Assess lactate and acid-base status, respiratory function and cardiac, neurologic, hepatic and renal involvement. Organ assessment should be driven by the presentation; the founding case had abnormalities across these systems.
  evidence:
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: An autopsy revealed brain hypertrophy, diffuse alteration of the white-matter myelination, and numerous cavities in the parieto-occipital region, brainstem, and cerebellum, as well as hepatomegaly, hypertrophic cardiomyopathy, renal hypoplasia, and adrenal-gland hyperplasia.
    explanation: Autopsy defined the multisystem burden in the index child.
  - reference: PMID:28749475
    reference_title: 'Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Initial triage stratification of critically ill mitochondrial patients should include a systemic assessment of all body systems since the disease is multisystemic and patients may develop new organ system involvement during an acute decompensation.
    explanation: General critical-care guidance supports systematic assessment.
    quote_role: BACKGROUND
treatments:
- name: Acute Supportive and Metabolic Care
  description: Severe neonatal decompensation requires individualized intensive care, correction of metabolic derangements and specialist management of cardiorespiratory and multisystem dysfunction. The founding report does not establish a specific effective drug or bicarbonate regimen.
  therapeutic_modality: OTHER
  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: OTHER
    snippet: Treatment during acute decompensation should include dextrose-containing IV fluids, stopping exposure to potentially toxic medications, and correction of any metabolic derangements.
    explanation: General mitochondrial-disease guidance; no COX14-specific clinical efficacy study is implied.
    quote_role: BACKGROUND
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - *id010
  - *id011
  notes: Dextrose-containing fluids require individual assessment and the same pyruvate-metabolism, ketogenic-diet and glucose-intolerance exceptions described under Prevention of Catabolism.
- name: Prevention of Catabolism
  description: Avoid prolonged fasting and provide individualized nutrition and glucose-containing fluids during illness or procedures. Glucose delivery requires particular caution when an alternative pyruvate-metabolism disorder is suspected, during a ketogenic diet, or after prior adverse responses to glucose.
  therapeutic_modality: OTHER
  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: OTHER
    snippet: Mitochondrial patients should take precautions to prevent entering catabolism, especially when exposed to medical stressors, including avoiding prolonged fasting and receiving dextrose-containing IV fluids before, during, and after procedures and surgeries.
    explanation: General mitochondrial-disease guidance; no COX14-specific clinical efficacy study is implied.
    quote_role: BACKGROUND
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
- name: Respiratory Support
  description: Respiratory distress warrants specialist ventilatory assessment and support according to the infant’s physiology. Neuromuscular, central, aspiration and cardiac contributors may need evaluation.
  therapeutic_modality: OTHER
  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: OTHER
    snippet: Ventilatory assessment should include evaluation for aspiration, atelectasis, and infection, and account for underlying issues of abnormal tone, as well as nerve and muscle disease.
    explanation: General mitochondrial-disease guidance; no COX14-specific clinical efficacy study is implied.
    quote_role: BACKGROUND
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - *id011
- name: Cardiac and Multisystem Surveillance
  description: Assess cardiomyopathy and other organ complications with the relevant specialists. General mitochondrial guidance emphasizes regular cardiac surveillance; a fixed long-term COX14 surveillance interval has not been established.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1224/
    reference_title: Primary Mitochondrial Disorders Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: These focus on regular surveillance to detect complications and their management using standard approaches that are not usually specific to mitochondrial disorders. Regular cardiac evaluation and monitoring for diabetes are particularly important.
    explanation: General mitochondrial-disease guidance; no COX14-specific clinical efficacy study is implied.
    quote_role: BACKGROUND
- name: Medication and Anesthesia Precautions
  description: Review potentially mitochondrial-toxic medications and anesthetic plans individually. General guidance advises avoiding or limiting prolonged propofol exposure and using caution with valproate, metformin and selected antibiotics. These are broader mitochondrial-disease precautions; the POLG-specific valproate contraindication should not be inferred solely from a COX14 diagnosis.
  therapeutic_modality: OTHER
  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: OTHER
    snippet: Mitochondrial patients may be at a higher risk for propofol infusion syndrome and propofol use should be avoided or limited to short procedures.
    explanation: General mitochondrial-disease guidance; no COX14-specific clinical efficacy study is implied.
    quote_role: BACKGROUND
  - reference: PMID:28749475
    reference_title: 'Patient care standards for primary mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: 'The following medications should be avoided in patients with mitochondrial disease when possible and, if given, they should be used with caution: valproic acid; statins; metformin; high-dose acetaminophen; and selected antibiotics, including aminoglycosides, linezolid, tetracycline, azithromycin, and erythromycin.'
    explanation: General consensus cautions are not evidence of specific toxicity in COX14 patients.
    quote_role: BACKGROUND
- name: Genetic Counseling and Reproductive Planning
  description: Confirm familial pathogenic variants, offer carrier testing and explain autosomal recessive recurrence risks. Prenatal and preimplantation genetic testing are possible once causative familial variants are known.
  therapeutic_modality: OTHER
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1224/
    reference_title: Primary Mitochondrial Disorders Overview - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Once the ... have been identified in an affected family member, ... prenatal testing ... for a pregnancy at increased risk and ... preimplantation genetic testing ... are possible.
    explanation: General mitochondrial-disease guidance; no COX14-specific clinical efficacy study is implied.
    quote_role: BACKGROUND
  - *id012
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
- name: N-acetylcysteine in Experimental Hepatocytes
  description: Preclinical antioxidant intervention in cultured primary hepatocytes from COX14 Met19Ile mice reduced the ROS-associated inflammatory response. This experiment does not establish treatment efficacy, dosing or safety in human COX14 deficiency.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: N-acetyl-L-cysteine
      term:
        id: CHEBI:28939
        label: N-acetyl-L-cysteine
  target_mechanisms:
  - target: Increased Hepatocyte Mitochondrial ROS
    treatment_effect: INHIBITS
    description: Ex vivo antioxidant effect in mutant mouse hepatocytes; human benefit is untested.
    evidence:
    - &id013
      reference: PMID:39134548
      reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: treatment with NAC prevented the release of mtRNAs in hepatocytes and subsequent upregulation of ISGs at the protein level
      explanation: Intervention was performed ex vivo in primary mouse hepatocytes; this is not an in vivo treatment or a clinical trial.
    - reference: PMID:39134548
      reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: In addition, we could show that the NAC treatments reduced the mitochondrial superoxide levels
      explanation: Direct measurement of reduced mitochondrial superoxide supports the antioxidant effect on this target, distinct from the downstream RNA-release readout.
  evidence:
  - *id013
- name: MitoTEMPO in Experimental Hepatocytes
  description: Preclinical antioxidant intervention in cultured primary hepatocytes from COX14 Met19Ile mice reduced the ROS-associated inflammatory response. This experiment does not establish treatment efficacy, dosing or safety in human COX14 deficiency.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: MitoTEMPO
      term:
        id: CHEBI:232424
        label: MitoTEMPO
  target_mechanisms:
  - target: Increased Hepatocyte Mitochondrial ROS
    treatment_effect: INHIBITS
    description: Ex vivo antioxidant effect in mutant mouse hepatocytes; human benefit is untested.
    evidence:
    - &id014
      reference: PMID:39134548
      reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Similar results as seen for NAC were obtained with Mito-TEMPO
      explanation: Intervention was performed ex vivo in primary mouse hepatocytes; this is not an in vivo treatment or a clinical trial.
    - reference: PMID:39134548
      reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: in a complementary approach we utilized Mito-TEMPO, which acts on superoxide as a superoxide dismutase mimetic. Similar results as seen for NAC were obtained with Mito-TEMPO
      explanation: The authors state the superoxide-directed pharmacology and a similar experimental response to NAC in cultured mutant mouse hepatocytes.
  evidence:
  - *id014
experimental_models:
- name: Patient Fibroblast COX14 Complementation
  experimental_model_type: CELL_LINE
  publication: PMID:22243966
  cell_source: Immortalized fibroblasts from the index patient and controls
  description: Patient fibroblasts demonstrate reduced COX1 synthesis and complex IV assembly, with rescue by wild-type COX14. These experiments establish biochemical causality without reproducing the full neonatal multisystem phenotype.
  modeled_mechanisms:
  - target: Deficient Complex IV Assembly
    relationship: RECAPITULATES
    description: Patient cells show reduced mature complex IV.
    limitations: Residual fibroblast activity does not predict neonatal tissue severity.
    fidelity: HIGH
    model_scale: MOLECULAR
    evidence:
    - *id002
  - target: Reduced COX1 Translation
    relationship: RESCUES
    description: Wild-type COX14 expression restores translation and assembly in the patient-cell system.
    limitations: Retroviral complementation is not a tested clinical gene therapy.
    fidelity: HIGH
    model_scale: MOLECULAR
    evidence:
    - reference: PMID:22243966
      reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: it completely rescued the COX-assembly defect ... COX I translation in the PULSE assay ... and COX activity (92% of control) in subject fibroblasts.
      explanation: Functional complementation confirms the causal protein defect.
  evidence:
  - *id009
- name: Human Cell COX14 Translation Studies
  experimental_model_type: CELL_LINE
  publication: PMID:27693358
  cell_source: HEK293-derived human cell lines
  description: Knockdown, complementation and immunoisolation connect COX14 to COX1-translating ribosomes and nascent-chain assembly intermediates.
  modeled_mechanisms:
  - target: Reduced COX1 Translation
    relationship: PERTURBS
    description: COX14 knockdown reduces COX1 synthesis.
    limitations: Knockdown and tagged-protein systems differ from the homozygous patient missense allele.
    fidelity: MODERATE
    model_scale: MOLECULAR
    evidence:
    - *id001
  evidence:
  - reference: PMID:27693358
    reference_title: Mitochondrial Protein Synthesis Adapts to Influx of Nuclear-Encoded Protein.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: We conclude that the COX1 translation intermediates initially associate with C12ORF62, and MITRAC12 is recruited sequentially.
    explanation: The experiments resolve the order of early assembly-factor recruitment.
- name: COX14 Mutant Primary Hepatocyte Antioxidant Experiments
  experimental_model_type: PRIMARY_CELL_CULTURE
  publication: PMID:39134548
  cell_source: Primary hepatocytes isolated from homozygous COX14 Met19Ile mice
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  description: Cultured mutant hepatocytes permit measurement of ROS, membrane potential, mitochondrial RNA release and interferon-stimulated gene expression, with antioxidant intervention.
  modeled_mechanisms:
  - target: Cytosolic Mitochondrial RNA Release
    relationship: RESCUES
    description: NAC suppresses RNA release and downstream inflammatory markers.
    limitations: Ex vivo rescue does not establish benefit in a living mouse or patient.
    fidelity: MODERATE
    model_scale: CELLULAR
    evidence:
    - *id005
  evidence:
  - *id004
  - *id005
  findings:
  - statement: Fatostatin did not reduce interferon-stimulated gene expression, in contrast to antioxidant rescue.
    evidence:
    - reference: PMID:39134548
      reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: The treatment with Fatostatin did not alter the expression of ISGs, demonstrating that SERBP-mediated cholesterol biosynthesis did not contribute to the inflammatory response
      explanation: The negative pharmacologic result distinguishes the proposed ROS pathway from a cholesterol-biosynthesis explanation.
animal_models:
- name: COX14 Met19Ile Knock-in Mouse
  species: Mouse
  genotype: Homozygous Cox14 p.Met19Ile knock-in
  description: The patient-corresponding allele causes reduced complex IV assembly and respiration with tissue-dependent severity. Mice show partial pre-weaning mortality and progressive liver, cardiac, retinal and muscle abnormalities among survivors. The inflammatory liver branch is a model-derived hypothesis for human disease.
  publication: PMID:39134548
  modeled_mechanisms:
  - target: Deficient Complex IV Assembly
    relationship: PARTIALLY_RECAPITULATES
    description: The knock-in causes tissue-dependent complex IV deficiency.
    limitations: Many mice survive to adulthood; no apparent brain phenotype was detected, unlike the severe human neonatal presentation.
    fidelity: MODERATE
    model_scale: ORGANISM
    evidence:
    - reference: PMID:39134548
      reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: complex IV activity and amount were significantly reduced in mutant mitochondria isolated from different tissues
      explanation: The animal reproduces the proximal respiratory-chain defect.
  - target: Experimental Hepatic Inflammatory Injury
    relationship: RECAPITULATES
    description: Mutant liver develops focal necrosis and inflammatory infiltrates.
    limitations: Inflammation was not assessed in the human index case; human applicability is unresolved.
    fidelity: MODERATE
    model_scale: ORGANISM
    evidence:
    - *id015
  evidence:
  - reference: PMID:39134548
    reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Moreover, 26% of the COX14M19I animals experienced pre-weaning mortality as compared to that in the wild type.
    explanation: Partial early mortality differs from the reported human neonatal course.
  - reference: PMID:39134548
    reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Brain and muscle displayed similar complex IV reduction, yet a brain phenotype was not apparent in our analyses.
    explanation: A biochemical defect did not imply the same organ phenotype as in the human case.
  - reference: PMID:39134548
    reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: While cardiac defects were also apparent in the COX14M19I mouse, information on inflammation and retinal state of the patient are not available.
    explanation: Human inflammatory and retinal phenotypes remain unestablished.
  - reference: PMID:39134548
    reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: Histological analysis of heart, skeletal muscle, liver, and eye indicated that these tissues were affected by the COX14 mutation
    explanation: The model extends to multiple tissues, but these animal findings must not be used as sole evidence for human retinal or muscle phenotypes.
discussions:
- discussion_id: cox14-human-model-correspondence
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: Does ROS-dependent mitochondrial RNA release contribute to human COX14 disease?
  rationale: The knock-in mouse provides a mechanistic inflammatory pathway and ex vivo antioxidant rescue, but the human index child died neonatally and had no reported assessment of liver inflammation or retinal pathology. Survival and brain findings also differ. These observations support further investigation rather than clinical antioxidant efficacy claims.
  evidence:
  - reference: PMID:39134548
    reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: It is difficult to directly compare the mice phenotype to the patient pathology, as the death of the patient occurred already 24 hours after birth.
    explanation: The authors explicitly limit direct human-model comparison.
- discussion_id: cox14-residual-activity-severity
  kind: INTERPRETATION
  status: OPEN
  prompt: Why does residual fibroblast complex IV activity coexist with a severe neonatal phenotype?
  rationale: The founding fibroblasts retain measurable complex IV activity. The mouse model demonstrates tissue-dependent protein stability and respiratory defects, but does not identify a human modifier gene or a quantitative prognostic threshold.
  evidence:
  - *id003
  - reference: PMID:39134548
    reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: despite the systemic defect in COX14 function, the impact on protein stability, COX1 synthesis and concomitantly amounts of complex IV differed significantly between tissues.
    explanation: Tissue variation in the animal model may inform the clinical-biochemical discrepancy, without proving the human explanation.
datasets:
- accession: geo:GSE269535
  title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver
  description: Bulk liver transcriptomics comparing wild-type and homozygous COX14 Met19Ile mice. The experimental dataset supports study of the interferon response and metabolic gene-expression changes; it contains no human patient cohort.
  data_type: BULK_RNA_SEQ
  organism:
    preferred_term: Mus musculus
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  conditions:
  - Wild-type mouse liver
  - Homozygous COX14 Met19Ile mouse liver
  publication: PMID:39134548
  evidence:
  - reference: PMID:39134548
    reference_title: Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: we addressed changes in the gene expression pattern by RNA sequencing (RNA-seq) of wild type and COX14M19I mice liver samples.
    explanation: The primary paper describes the model, tissue and assay; GEO accession resolution was separately verified.
progression:
- phase: Fatal neonatal course in the founding family
  notes: The founding index child died 24 hours after birth. This observation describes the reported severe family and does not establish an invariant outcome for all possible COX14 genotypes.
  evidence:
  - reference: PMID:22243966
    reference_title: Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Lactate concentration was 23.4 mM in the blood and 26.2 mM in the cerebrospinal fluid 16 hr after birth. Death occurred 24 hr after birth.
    explanation: The primary family report documents neonatal mortality in the index child.
📚

References & Deep Research

References

7
PMID:22243966
Mutations in C12orf62, a factor that couples COX I synthesis with cytochrome c oxidase assembly, cause fatal neonatal lactic acidosis.
No top-level findings curated for this source.
PMID:27693358
Mitochondrial Protein Synthesis Adapts to Influx of Nuclear-Encoded Protein.
No top-level findings curated for this source.
PMID:39134548
Defective mitochondrial COX1 translation due to loss of COX14 function triggers ROS-induced inflammation in mouse liver.
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1224/
Primary Mitochondrial Disorders Overview - GeneReviews® - NCBI Bookshelf
No top-level findings curated for this source.
PMID:20301403
Primary Mitochondrial Disorders Overview.
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.
PMID:36513735
Genetic testing for mitochondrial disease: the United Kingdom best practice guidelines.
No top-level findings curated for this source.