Cytochrome c oxidase-deficient patients have distinct subunit assembly profiles.
Cytochrome c oxidase (COX) deficiency is the most common respiratory chain defect in childhood and is clinically heterogeneous. We report a study of six patients with COX deficiencies. Two of the patients had as yet undefined defects, three patients had Surf-1 mutations, and one patient had a 15-base pair deletion in the COX III subunit. We show that quantitative measurements of steady-state levels of subunits by monoclonal antibody reactivity, when used in combination with a discontinuous sucrose gradient methods, provide an improved diagnosis of COX deficiencies by distinguishing between kinetic, stability, and assembly defects. The two mutants of undefined etiology had a full complement of subunits with one stable and the other partially unstable to detergent solubilization. Both are likely to carry mutations in nuclear-encoded subunits of the complex. The three Surf-1 mutants and the COX III mutant each had reduced steady-state levels of subunits but variable associations of the residual subunits. This information, as well as aiding in diagnosis, helps in understanding the genotype-phenotype relationships of COX deficiencies and provides insight into the mechanism of assembly of the enzyme complex.
Hanson
B J
BJ
Institute of Molecular Biology, University of Oregon, Eugene, Oregon 97403, USA.
Carrozzo
R
R
Piemonte
F
F
Tessa
A
A
Robinson
B H
BH
Capaldi
R A
RA
D000293:Adolescent; D020739:Brain Diseases, Metabolic, Inborn / Q000201:enzymology / Q000235:genetics; D002460:Cell Line; D002499:Centrifugation, Density Gradient; D002675:Child, Preschool; D030401:Cytochrome-c Oxidase Deficiency; D003937:Diagnosis, Differential; D003576:Electron Transport Complex IV / Q000737:chemistry* / Q000235:genetics; D004795:Enzyme Stability; D005347:Fibroblasts / Q000201:enzymology; D006801:Humans; D007223:Infant; D007700:Kinetics; D007888:Leigh Disease / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics; D017240:Mitochondrial Myopathies / Q000201:enzymology / Q000235:genetics; D021122:Protein Subunits; D017384:Sequence Deletion
D021122:Protein Subunits; D003576:Electron Transport Complex IV