PET117-Related COX Deficiency

Mendelian MONDO:0033654 Pathograph 5 Show in embeddings browser Mitochondrial Disease Inborn Error of Metabolism

PET117-related COX deficiency (mitochondrial complex IV deficiency nuclear type 19, MC4DN19) is a rare autosomal recessive nuclear form of isolated cytochrome c oxidase (COX, Complex IV) deficiency caused by biallelic loss-of-function variants in PET117. PET117 encodes a small mitochondrial protein predicted to act as a Complex IV assembly factor; loss of functional Pet117 produces an isolated Complex IV deficiency with reduced steady-state levels of individual COX subunits. The founding report described two sisters with a homozygous nonsense mutation who presented with neurodevelopmental regression and lesions of the medulla oblongata on brain MRI, a Leigh-like brainstem-predominant phenotype. Lentiviral re-expression of wild-type PET117 in patient fibroblasts restored Complex IV, confirming causality. An earlier proposed role of Pet117 in copper insertion into Complex IV could not be confirmed in patient cells. The disorder conforms to the conserved Complex IV assembly-deficiency mechanism, with the lesion localized to a defective nuclear-encoded COX assembly factor.

Ask OpenScientist

Ask a research question about PET117-Related COX Deficiency. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

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

3
Pathophys.
2
Phenotypes
5
Pathograph
1
Genes
1
Medical Actions
1
References
⚙

Pathophysiology

3
PET117 Assembly-Factor Loss and Failed Complex IV Assembly
Biallelic loss-of-function variants in PET117 abolish functional Pet117, a small mitochondrial protein predicted to act as a Complex IV assembly factor. Without Pet117, cytochrome c oxidase fails to assemble correctly and the steady-state levels of individual Complex IV subunits fall, producing an isolated Complex IV biogenesis failure. Lentiviral complementation of patient fibroblasts with wild-type PET117 restores Complex IV, situating the lesion in the nuclear-encoded assembly arm of the COX biogenesis pathway.
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.
Show evidence (3 references)
PMID:28386624 SUPPORT Human Clinical
"Whole exome sequencing revealed a homozygous nonsense mutation resulting in a premature stop codon in the gene encoding Pet117, a small protein that has previously been predicted to be a complex IV assembly factor"
Identifies a biallelic loss-of-function PET117 variant in a predicted Complex IV assembly factor as the causal lesion.
PMID:28386624 SUPPORT Human Clinical
"two sisters with a mitochondrial disease characterized by lesions in the medulla oblongata, as demonstrated by brain magnetic resonance imaging, and an isolated complex IV deficiency and reduced levels of individual complex IV subunits"
Documents the isolated Complex IV deficiency and reduced COX subunit levels that define the assembly failure.
PMID:28386624 SUPPORT In Vitro
"Lentiviral complementation of patient fibroblasts with wild-type PET117 restored the complex IV deficiency, proving that the gene defect is responsible for the complex IV deficiency in the patients"
Complementation rescue in patient fibroblasts confirms that PET117 loss causes the Complex IV deficiency.
Impaired Terminal Electron Transfer and ATP Synthesis
The isolated Complex IV deficiency blocks electron transfer from cytochrome c to molecular oxygen and the coupled proton pumping, impairing oxidative ATP synthesis. Patient tissues show an isolated Complex IV deficiency with reduced levels of individual Complex IV subunits.
mitochondrial electron transport, cytochrome c to oxygen GO:0006123 ↓ DECREASED ATP synthesis coupled electron transport GO:0042775 ↓ DECREASED
Downstream
High-Energy Tissue Dysfunction The oxidative-phosphorylation deficit injures high-energy-demand tissues, here predominantly the CNS (medulla oblongata / brainstem).
Show evidence (1 reference)
PMID:28386624 SUPPORT Human Clinical
"two sisters with a mitochondrial disease characterized by lesions in the medulla oblongata, as demonstrated by brain magnetic resonance imaging, and an isolated complex IV deficiency and reduced levels of individual complex IV subunits"
The isolated Complex IV deficiency establishes the terminal-electron-transfer deficit downstream of failed assembly.
High-Energy Tissue Dysfunction
The bioenergetic deficit manifests in high-demand tissues. In PET117-related disease the dominant phenotype is CNS involvement — neurodevelopmental regression with lesions of the medulla oblongata on brain MRI, a Leigh-like brainstem-predominant presentation in the founding sibling pair.
aerobic respiration GO:0009060 ↓ DECREASED
Downstream
Developmental regression The bioenergetic deficit in the CNS manifests as neurodevelopmental regression.
Medulla oblongata lesions Brainstem energy failure manifests as MRI-demonstrable lesions of the medulla oblongata.
Show evidence (1 reference)
PMID:28386624 SUPPORT Human Clinical
"neurodevelopmental regression and medulla oblongata lesions"
The CNS manifestations of the bioenergetic deficit in the founding patients.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for PET117-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.
●

Phenotypes

2
Nervous System 1
Developmental regression Developmental regression HP:0002376
Show evidence (1 reference)
PMID:28386624 SUPPORT Human Clinical
"neurodevelopmental regression and medulla oblongata lesions"
Neurodevelopmental regression was a defining feature of the founding patients.
Other 1
Medulla oblongata lesions Abnormal brainstem morphology HP:0002363
Show evidence (1 reference)
PMID:28386624 SUPPORT Human Clinical
"two sisters with a mitochondrial disease characterized by lesions in the medulla oblongata, as demonstrated by brain magnetic resonance imaging"
MRI-demonstrated medulla oblongata lesions in the founding patients.
🧬

Genetic Associations

1
PET117 pathogenic variants causing MC4DN19
Gene: PET117 hgnc:40045
Autosomal recessive
Show evidence (2 references)
PMID:28386624 SUPPORT Human Clinical
"PET117 has not been identified as a mitochondrial disease gene before"
Establishes PET117 as a novel mitochondrial disease gene.
PMID:28386624 SUPPORT In Vitro
"Although previous studies had suggested a possible role of this protein in the insertion of copper into complex IV, studies in patient fibroblasts could not confirm this"
Clarifies that the proposed copper-insertion role of Pet117 was not confirmed in patient cells.
💊

Medical Actions

1
Supportive and Metabolic Care
Action: supportive care MAXO:0000950
No curative therapy exists; management is supportive, addressing the neurodevelopmental and neurological manifestations with multidisciplinary supportive care.
{ }

Source YAML

click to show 
name: PET117-Related COX Deficiency
category: Mendelian
creation_date: "2026-06-21T00:00:00Z"
synonyms:
- PET117 deficiency
- Mitochondrial complex IV deficiency, nuclear type 19
- MC4DN19
- PET117-related cytochrome c oxidase deficiency
description: >
  PET117-related COX deficiency (mitochondrial complex IV deficiency nuclear
  type 19, MC4DN19) is a rare autosomal recessive nuclear form of isolated
  cytochrome c oxidase (COX, Complex IV) deficiency caused by biallelic
  loss-of-function variants in PET117. PET117 encodes a small mitochondrial
  protein predicted to act as a Complex IV assembly factor; loss of functional
  Pet117 produces an isolated Complex IV deficiency with reduced steady-state
  levels of individual COX subunits. The founding report described two sisters
  with a homozygous nonsense mutation who presented with neurodevelopmental
  regression and lesions of the medulla oblongata on brain MRI, a Leigh-like
  brainstem-predominant phenotype. Lentiviral re-expression of wild-type PET117
  in patient fibroblasts restored Complex IV, confirming causality. An earlier
  proposed role of Pet117 in copper insertion into Complex IV could not be
  confirmed in patient cells. The disorder conforms to the conserved Complex IV
  assembly-deficiency mechanism, with the lesion localized to a defective
  nuclear-encoded COX assembly factor.
disease_term:
  preferred_term: PET117-related COX deficiency (MC4DN19)
  term:
    id: MONDO:0033654
    label: mitochondrial complex IV deficiency, nuclear type 19
parents:
- Mitochondrial Disease
- Inborn Error of Metabolism
references:
- reference: PMID:28386624
  title: "Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions."
pathophysiology:
- name: PET117 Assembly-Factor Loss and Failed Complex IV Assembly
  conforms_to: "complex_iv_assembly_deficiency#Complex IV Biogenesis Failure"
  description: >
    Biallelic loss-of-function variants in PET117 abolish functional Pet117, a
    small mitochondrial protein predicted to act as a Complex IV assembly
    factor. Without Pet117, cytochrome c oxidase fails to assemble correctly and
    the steady-state levels of individual Complex IV subunits fall, producing an
    isolated Complex IV biogenesis failure. Lentiviral complementation of patient
    fibroblasts with wild-type PET117 restores Complex IV, situating the lesion
    in the nuclear-encoded assembly arm of the COX biogenesis pathway.
  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:28386624
    reference_title: "Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Whole exome sequencing revealed a homozygous nonsense mutation resulting in a premature stop codon in the gene encoding Pet117, a small protein that has previously been predicted to be a complex IV assembly factor"
    explanation: Identifies a biallelic loss-of-function PET117 variant in a predicted Complex IV assembly factor as the causal lesion.
  - reference: PMID:28386624
    reference_title: "Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two sisters with a mitochondrial disease characterized by lesions in the medulla oblongata, as demonstrated by brain magnetic resonance imaging, and an isolated complex IV deficiency and reduced levels of individual complex IV subunits"
    explanation: Documents the isolated Complex IV deficiency and reduced COX subunit levels that define the assembly failure.
  - reference: PMID:28386624
    reference_title: "Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Lentiviral complementation of patient fibroblasts with wild-type PET117 restored the complex IV deficiency, proving that the gene defect is responsible for the complex IV deficiency in the patients"
    explanation: Complementation rescue in patient fibroblasts confirms that PET117 loss causes the Complex IV deficiency.
  downstream:
  - target: Impaired Terminal Electron Transfer and ATP Synthesis
    causal_link_type: DIRECT
    description: Failure to assemble Complex IV yields a catalytically deficient holoenzyme.
    evidence:
    - reference: PMID:28386624
      reference_title: "Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "indicating a pivotal role of this protein in the proper functioning of complex IV"
      explanation: Links the assembly defect to loss of proper Complex IV function.
- name: Impaired Terminal Electron Transfer and ATP Synthesis
  conforms_to: "complex_iv_assembly_deficiency#Impaired Terminal Electron Transfer and ATP Synthesis"
  description: >
    The isolated Complex IV deficiency blocks electron transfer from cytochrome c
    to molecular oxygen and the coupled proton pumping, impairing oxidative ATP
    synthesis. Patient tissues show an isolated Complex IV deficiency with reduced
    levels of individual Complex IV subunits.
  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:28386624
    reference_title: "Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two sisters with a mitochondrial disease characterized by lesions in the medulla oblongata, as demonstrated by brain magnetic resonance imaging, and an isolated complex IV deficiency and reduced levels of individual complex IV subunits"
    explanation: The isolated Complex IV deficiency establishes the terminal-electron-transfer deficit downstream of failed assembly.
  downstream:
  - target: High-Energy Tissue Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: The oxidative-phosphorylation deficit injures high-energy-demand tissues, here predominantly the CNS (medulla oblongata / brainstem).
- name: High-Energy Tissue Dysfunction
  conforms_to: "complex_iv_assembly_deficiency#High-Energy Tissue Dysfunction"
  description: >
    The bioenergetic deficit manifests in high-demand tissues. In PET117-related
    disease the dominant phenotype is CNS involvement — neurodevelopmental
    regression with lesions of the medulla oblongata on brain MRI, a Leigh-like
    brainstem-predominant presentation in the founding sibling pair.
  biological_processes:
  - preferred_term: aerobic respiration
    term:
      id: GO:0009060
      label: aerobic respiration
    modifier: DECREASED
  evidence:
  - reference: PMID:28386624
    reference_title: "Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurodevelopmental regression and medulla oblongata lesions"
    explanation: The CNS manifestations of the bioenergetic deficit in the founding patients.
  downstream:
  - target: Developmental regression
    causal_link_type: DIRECT
    description: The bioenergetic deficit in the CNS manifests as neurodevelopmental regression.
  - target: Medulla oblongata lesions
    causal_link_type: DIRECT
    description: Brainstem energy failure manifests as MRI-demonstrable lesions of the medulla oblongata.
phenotypes:
- name: Developmental regression
  description: >
    Neurodevelopmental regression, a presenting feature of the founding sibling
    pair with PET117-related Complex IV deficiency.
  phenotype_term:
    preferred_term: Developmental regression
    term:
      id: HP:0002376
      label: Developmental regression
  evidence:
  - reference: PMID:28386624
    reference_title: "Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurodevelopmental regression and medulla oblongata lesions"
    explanation: Neurodevelopmental regression was a defining feature of the founding patients.
- name: Medulla oblongata lesions
  description: >
    Lesions of the medulla oblongata demonstrated on brain magnetic resonance
    imaging, a hallmark of the founding sibling pair (a Leigh-like
    brainstem-predominant pattern).
  phenotype_term:
    preferred_term: Medulla oblongata lesions
    term:
      id: HP:0002363
      label: Abnormal brainstem morphology
  evidence:
  - reference: PMID:28386624
    reference_title: "Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "two sisters with a mitochondrial disease characterized by lesions in the medulla oblongata, as demonstrated by brain magnetic resonance imaging"
    explanation: MRI-demonstrated medulla oblongata lesions in the founding patients.
genetic:
- name: PET117 pathogenic variants causing MC4DN19
  gene_term:
    preferred_term: PET117
    term:
      id: hgnc:40045
      label: PET117
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:28386624
      reference_title: "Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Whole exome sequencing revealed a homozygous nonsense mutation resulting in a premature stop codon in the gene encoding Pet117, a small protein that has previously been predicted to be a complex IV assembly factor"
      explanation: A homozygous nonsense PET117 variant in two affected sisters establishes autosomal recessive inheritance.
  features: >
    Biallelic PET117 variants cause MC4DN19. The founding sibling pair carried a
    homozygous nonsense mutation producing a premature stop codon in PET117.
    PET117 had not previously been identified as a mitochondrial disease gene.
    Lentiviral re-expression of wild-type PET117 in patient fibroblasts restored
    Complex IV, confirming pathogenicity. An earlier proposed role of Pet117 in
    copper insertion into Complex IV could not be confirmed in patient cells.
  evidence:
  - reference: PMID:28386624
    reference_title: "Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PET117 has not been identified as a mitochondrial disease gene before"
    explanation: Establishes PET117 as a novel mitochondrial disease gene.
  - reference: PMID:28386624
    reference_title: "Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Although previous studies had suggested a possible role of this protein in the insertion of copper into complex IV, studies in patient fibroblasts could not confirm this"
    explanation: Clarifies that the proposed copper-insertion role of Pet117 was not confirmed in patient cells.
treatments:
- name: Supportive and Metabolic Care
  description: >
    No curative therapy exists; management is supportive, addressing the
    neurodevelopmental and neurological manifestations with multidisciplinary
    supportive care.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
📚

References & Deep Research

References

1
PMID:28386624
Mutated PET117 causes complex IV deficiency and is associated with neurodevelopmental regression and medulla oblongata lesions.
No top-level findings curated for this source.