Loss of the smallest subunit of cytochrome c oxidase, COX8A, causes Leigh-like syndrome and epilepsy.
Brain
; 139(Pt 2): 338-45, 2016 Feb.
Article
en En
| MEDLINE
| ID: mdl-26685157
ABSTRACT
Isolated cytochrome c oxidase (complex IV) deficiency is one of the most frequent respiratory chain defects in humans and is usually caused by mutations in proteins required for assembly of the complex. Mutations in nuclear-encoded structural subunits are very rare. In a patient with Leigh-like syndrome presenting with leukodystrophy and severe epilepsy, we identified a homozygous splice site mutation in COX8A, which codes for the ubiquitously expressed isoform of subunit VIII, the smallest nuclear-encoded subunit of complex IV. The mutation, affecting the last nucleotide of intron 1, leads to aberrant splicing, a frame-shift in the highly conserved exon 2, and decreased amount of the COX8A transcript. The loss of the wild-type COX8A protein severely impairs the stability of the entire cytochrome c oxidase enzyme complex and manifests in isolated complex IV deficiency in skeletal muscle and fibroblasts, similar to the frequent c.845_846delCT mutation in the assembly factor SURF1 gene. Stability and activity of complex IV could be rescued in the patient's fibroblasts by lentiviral expression of wild-type COX8A. Our findings demonstrate that COX8A is indispensable for function of human complex IV and its mutation causes human disease.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Enfermedad de Leigh
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Complejo IV de Transporte de Electrones
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Subunidades de Proteína
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Epilepsia
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Límite:
Child
/
Female
/
Humans
Idioma:
En
Revista:
Brain
Año:
2016
Tipo del documento:
Article
País de afiliación:
Alemania