COX14-Related COX Deficiency

Mendelian MONDO:0033639 Pathograph 5 Show in embeddings browser Mitochondrial Disease Inborn Error of Metabolism

COX14-related COX deficiency (mitochondrial complex IV deficiency nuclear type 10, MC4DN10) is a rare autosomal recessive nuclear form of isolated cytochrome c oxidase (COX, Complex IV) deficiency caused by biallelic variants in COX14 (formerly C12orf62). COX14 is a very small (~6 kDa) single-pass mitochondrial inner-membrane protein that coordinates the early steps of Complex IV assembly with the synthesis of the mtDNA-encoded core subunit COX I (MT-CO1), the subunit that nucleates holoenzyme assembly. Loss of COX14 uncouples COX I synthesis from assembly, leaving the nascent enzyme complex unstable and producing an isolated Complex IV deficiency. It was first identified in an index subject who presented with severe congenital lactic acidosis and dysmorphic features and a fatal neonatal course. It conforms to the conserved Complex IV assembly-deficiency mechanism, with the lesion localized to failed coordination of COX I synthesis with holoenzyme assembly.

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Pathophysiology

COX14 Loss and Failed Complex IV Assembly

Biallelic COX14 (C12orf62) variants cause loss of a small mitochondrial inner-membrane Complex IV biogenesis factor that couples synthesis of the core mtDNA-encoded subunit COX I to holoenzyme assembly. In its absence COX I synthesis is decreased, COX assembly is impaired, and the nascent enzyme complex is unstable, yielding isolated Complex IV biogenesis failure.

mitochondrial respiratory chain complex IV assembly GO:0033617 ↓ DECREASED

Downstream

Impaired Terminal Electron Transfer and ATP Synthesis Failure to assemble Complex IV yields a catalytically deficient holoenzyme.

Dysmorphic facial features Severe congenital mitochondrial dysfunction can perturb early development, producing dysmorphic facial features through developmental intermediates.

Show evidence (3 references)

PMID:22243966 SUPPORT Human Clinical

"(COX)-assembly defect and a specific decrease in the synthesis of COX"

Establishes the COX-assembly defect with reduced synthesis of COX I, the lesion underlying isolated Complex IV biogenesis failure.

PMID:22243966 SUPPORT In Vitro

"the nascent enzyme complex was unstable"

Patient fibroblasts show impaired COX assembly with an unstable nascent enzyme complex, demonstrating failed biogenesis.

PMID:22243966 SUPPORT In Vitro

"C12orf62 is required for coordination of the early steps of COX assembly with"

Defines COX14 (C12orf62) as required to coordinate the early steps of COX assembly, consistent with an assembly-factor role.

Impaired Terminal Electron Transfer and ATP Synthesis

Deficient Complex IV blocks electron transfer from cytochrome c to oxygen and proton pumping, collapsing oxidative ATP synthesis and preferentially injuring high-energy tissue.

mitochondrial electron transport, cytochrome c to oxygen GO:0006123 ↓ DECREASED ATP synthesis coupled electron transport GO:0042775 ↓ DECREASED

Downstream

Lactic Acidosis and Metabolic Decompensation Loss of oxidative ATP synthesis forces anaerobic glycolysis and lactate accumulation.

Show evidence (1 reference)

PMID:22243966 SUPPORT Human Clinical

"(COX)-assembly defect and a specific decrease in the synthesis of COX"

The index subject's COX-assembly defect produces a functional Complex IV deficiency, the biochemical basis for impaired terminal electron transfer and ATP synthesis.

Lactic Acidosis and Metabolic Decompensation

With oxidative phosphorylation blocked, pyruvate is shunted to lactate, elevating blood lactate; in COX14-related disease this presented as a severe congenital lactic acidosis with a fatal neonatal course.

lactate biosynthetic process GO:0019249 ↑ INCREASED

Downstream

Lactic acidosis Lactate overproduction manifests clinically as lactic acidosis.

Show evidence (1 reference)

PMID:22243966 SUPPORT Human Clinical

"cause fatal neonatal lactic acidosis"

COX14 mutations cause a fatal neonatal lactic acidosis, the metabolic consequence of failed oxidative ATP synthesis.

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Pathograph

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

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Phenotypes

Head and Neck 1

Dysmorphic facial features Abnormal facial shape HP:0001999

Show evidence (1 reference)

PMID:22243966 SUPPORT Human Clinical

"congenital lactic acidosis and dysmorphic features"

Dysmorphic features accompanied the presenting lactic acidosis in the index subject.

Metabolism 1

Lactic acidosis Lactic acidosis HP:0003128

Onset: CONGENITAL

Show evidence (1 reference)

PMID:22243966 SUPPORT Human Clinical

"congenital lactic acidosis and dysmorphic features"

The index subject presented with severe congenital lactic acidosis.

🧬

Genetic Associations

COX14 pathogenic variants causing MC4DN10

Gene: COX14 hgnc:28216

Autosomal recessive

Show evidence (2 references)

PMID:22243966 SUPPORT Human Clinical

"homozygous missense mutation (c.88G>A) in C12orf62"

Identifies the homozygous COX14 (C12orf62) missense variant as the causal lesion.

PMID:22243966 SUPPORT In Vitro

"wild-type C12orf62 cDNA rescued the biochemical phenotype"

Retroviral re-expression of wild-type COX14 (C12orf62) rescued the biochemical defect, confirming causality.

💊

Medical Actions

Supportive and Metabolic Care

Action: supportive care MAXO:0000950

No curative therapy exists; management is supportive, addressing the severe metabolic (lactic) acidosis, including bicarbonate buffering of acute decompensation, alongside multidisciplinary supportive care.

{ }

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
description: >
  COX14-related COX deficiency (mitochondrial complex IV deficiency nuclear
  type 10, MC4DN10) is a rare autosomal recessive nuclear form of isolated
  cytochrome c oxidase (COX, Complex IV) deficiency caused by biallelic variants
  in COX14 (formerly C12orf62). COX14 is a very small (~6 kDa) single-pass
  mitochondrial inner-membrane protein that coordinates the early steps of
  Complex IV assembly with the synthesis of the mtDNA-encoded core subunit COX I
  (MT-CO1), the subunit that nucleates holoenzyme assembly. Loss of COX14
  uncouples COX I synthesis from assembly, leaving the nascent enzyme complex
  unstable and producing an isolated Complex IV deficiency. It was first
  identified in an index subject who presented with severe congenital lactic
  acidosis and dysmorphic features and a fatal neonatal course. It conforms to
  the conserved Complex IV assembly-deficiency mechanism, with the lesion
  localized to failed coordination of COX I synthesis with holoenzyme assembly.
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
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."
pathophysiology:
- name: COX14 Loss and Failed Complex IV Assembly
  conforms_to: "complex_iv_assembly_deficiency#Complex IV Biogenesis Failure"
  description: >
    Biallelic COX14 (C12orf62) variants cause loss of a small mitochondrial
    inner-membrane Complex IV biogenesis factor that couples synthesis of the
    core mtDNA-encoded subunit COX I to holoenzyme assembly. In its absence COX I
    synthesis is decreased, COX assembly is impaired, and the nascent enzyme
    complex is unstable, yielding isolated Complex IV biogenesis failure.
  biological_processes:
  - preferred_term: mitochondrial respiratory chain complex IV assembly
    term:
      id: GO:0033617
      label: mitochondrial respiratory chain complex IV assembly
    modifier: DECREASED
  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: "(COX)-assembly defect and a specific decrease in the synthesis of COX"
    explanation: Establishes the COX-assembly defect with reduced synthesis of COX I, the lesion underlying isolated Complex IV biogenesis failure.
  - 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 nascent enzyme complex was unstable"
    explanation: Patient fibroblasts show impaired COX assembly with an unstable nascent enzyme complex, demonstrating failed biogenesis.
  - 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 is required for coordination of the early steps of COX assembly with"
    explanation: Defines COX14 (C12orf62) as required to coordinate the early steps of COX assembly, consistent with an assembly-factor role.
  downstream:
  - target: Impaired Terminal Electron Transfer and ATP Synthesis
    causal_link_type: DIRECT
    description: Failure to assemble Complex IV yields a catalytically deficient holoenzyme.
  - target: Dysmorphic facial features
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Severe congenital mitochondrial dysfunction can perturb early development,
      producing dysmorphic facial features through developmental intermediates.
- name: Impaired Terminal Electron Transfer and ATP Synthesis
  conforms_to: "complex_iv_assembly_deficiency#Impaired Terminal Electron Transfer and ATP Synthesis"
  description: >
    Deficient Complex IV blocks electron transfer from cytochrome c to oxygen
    and proton pumping, collapsing oxidative ATP synthesis and preferentially
    injuring high-energy tissue.
  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
  - preferred_term: ATP synthesis coupled electron transport
    term:
      id: GO:0042775
      label: mitochondrial ATP synthesis coupled electron transport
    modifier: DECREASED
  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: "(COX)-assembly defect and a specific decrease in the synthesis of COX"
    explanation: The index subject's COX-assembly defect produces a functional Complex IV deficiency, the biochemical basis for impaired terminal electron transfer and ATP synthesis.
  downstream:
  - target: Lactic Acidosis and Metabolic Decompensation
    causal_link_type: DIRECT
    description: Loss of oxidative ATP synthesis forces anaerobic glycolysis and lactate accumulation.
- name: Lactic Acidosis and Metabolic Decompensation
  conforms_to: "complex_iv_assembly_deficiency#Lactic Acidosis and Metabolic Decompensation"
  description: >
    With oxidative phosphorylation blocked, pyruvate is shunted to lactate,
    elevating blood lactate; in COX14-related disease this presented as a severe
    congenital lactic acidosis with a fatal neonatal course.
  biological_processes:
  - preferred_term: lactate biosynthetic process
    term:
      id: GO:0019249
      label: lactate biosynthetic process
    modifier: INCREASED
  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: "cause fatal neonatal lactic acidosis"
    explanation: COX14 mutations cause a fatal neonatal lactic acidosis, the metabolic consequence of failed oxidative ATP synthesis.
  downstream:
  - target: Lactic acidosis
    causal_link_type: DIRECT
    description: Lactate overproduction manifests clinically as lactic acidosis.
phenotypes:
- name: Lactic acidosis
  description: >
    Severe congenital (neonatal-onset) lactic acidosis, the presenting metabolic
    feature of COX14-related Complex IV deficiency.
  phenotype_term:
    preferred_term: Lactic acidosis
    term:
      id: HP:0003128
      label: 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: "congenital lactic acidosis and dysmorphic features"
    explanation: The index subject presented with severe congenital lactic acidosis.
- name: Dysmorphic facial features
  description: >
    Dysmorphic features were noted in the index subject alongside the severe
    congenital lactic acidosis.
  phenotype_term:
    preferred_term: Dysmorphic facial features
    term:
      id: HP:0001999
      label: Abnormal facial shape
  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: "congenital lactic acidosis and dysmorphic features"
    explanation: Dysmorphic features accompanied the presenting lactic acidosis in the index subject.
genetic:
- name: COX14 pathogenic variants causing MC4DN10
  gene_term:
    preferred_term: COX14
    term:
      id: hgnc:28216
      label: COX14
  inheritance:
  - name: Autosomal recessive
    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: "homozygous missense mutation (c.88G>A) in C12orf62"
      explanation: A homozygous COX14 (C12orf62) missense mutation in the index subject establishes autosomal recessive inheritance.
  features: >
    Biallelic COX14 (C12orf62) variants cause MC4DN10. The index family carried a
    homozygous missense variant (c.88G>A) in C12orf62; loss of the protein in
    patient fibroblasts and rescue by wild-type cDNA confirmed pathogenicity.
  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: "homozygous missense mutation (c.88G>A) in C12orf62"
    explanation: Identifies the homozygous COX14 (C12orf62) missense variant as the causal lesion.
  - 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: "wild-type C12orf62 cDNA rescued the biochemical phenotype"
    explanation: Retroviral re-expression of wild-type COX14 (C12orf62) rescued the biochemical defect, confirming causality.
treatments:
- name: Supportive and Metabolic Care
  description: >
    No curative therapy exists; management is supportive, addressing the severe
    metabolic (lactic) acidosis, including bicarbonate buffering of acute
    decompensation, alongside multidisciplinary supportive care.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care

📚

References & Deep Research

References

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.

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Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Source YAML

References & Deep Research

References