Pathogenicity of two COQ7 mutations and responses to 2,4-dihydroxybenzoate bypass treatment.
J Cell Mol Med
; 21(10): 2329-2343, 2017 10.
Article
en En
| MEDLINE
| ID: mdl-28409910
ABSTRACT
Primary ubiquinone (co-enzyme Q) deficiency results in a wide range of clinical features due to mitochondrial dysfunction. Here, we analyse and characterize two mutations in the ubiquinone biosynthetic gene COQ7. One mutation from the only previously identified patient (V141E), and one (L111P) from a 6-year-old girl who presents with spasticity and bilateral sensorineural hearing loss. We used patient fibroblast cell lines and a heterologous expression system to show that both mutations lead to loss of protein stability and decreased levels of ubiquinone that correlate with the severity of mitochondrial dysfunction. The severity of L111P is enhanced by the particular COQ7 polymorphism (T103M) that the patient carries, but not by a mitochondrial DNA mutation (A1555G) that is also present in the patient and that has been linked to aminoglycoside-dependent hearing loss. We analysed treatment with the unnatural biosynthesis precursor 2,4-dihydroxybenzoate (DHB), which can restore ubiquinone synthesis in cells completely lacking the enzymatic activity of COQ7. We find that the treatment is not beneficial for every COQ7 mutation and its outcome depends on the extent of enzyme activity loss.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Paraplejía Espástica Hereditaria
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Ubiquinona
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Sistema Enzimático del Citocromo P-450
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Fibroblastos
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Pérdida Auditiva
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Hidroxibenzoatos
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Oxigenasas de Función Mixta
Tipo de estudio:
Diagnostic_studies
/
Prognostic_studies
Límite:
Animals
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Child
/
Female
/
Humans
Idioma:
En
Revista:
J Cell Mol Med
Asunto de la revista:
BIOLOGIA MOLECULAR
Año:
2017
Tipo del documento:
Article
País de afiliación:
Canadá