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Title: The molecular basis of cytochrome oxidase deficiency in childhood
Author: Rahman, Shamima
Awarding Body: University of London
Current Institution: University College London (University of London)
Date of Award: 2002
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The mitochondrial respiratory chain and oxidative phosphorylation system (complexes I-V) produce ATP by aerobic metabolism. Complex IV or cytochrome c oxidase (COX) catalyses transfer of electrons from reduced cytochrome c to molecular oxygen, coupled with proton pumping across the inner mitochondrial membrane. Human COX has 13 polypeptide subunits. Three subunits (I, II and III) constitute the enzyme's catalytic core and are encoded on the mitochondrial genome. The remaining subunits are nuclear-encoded. COX deficiency, either total or partial, is the most commonly recognised respiratory chain defect in childhood. This may be an isolated defect, or combined with deficiencies of other respiratory chain components. Clinical presentations are heterogeneous but most patients with COX deficiency remain uncharacterised at the molecular level. COX subunit expression patterns were analysed in 5 patients with known mitochondrial DNA (mtDNA) mutations and 36 uncharacterised patients. A specific pattern of COX subunit loss was identified in COX deficiency secondary to mtDNA mutations. This suggested that immunohistochemistry using monoclonal antibodies may distinguish between mtDNA defects and nuclear defects in COX deficiency. Subsequent sequence analysis, targeted by immunohistochemistry findings, led to identification of a missense mutation of COX subunit II that causes defective assembly and myopathy. Characterisation of this mutation provided information about assembly of the metal centres of COX. Thus identification of naturally occurring COX mutations allows insight into structure-function relationships within the enzyme. The majority of children with COX deficiency did not have selective loss of mtDNA- encoded subunits, suggesting that nuclear gene defects account for many cases of childhood-onset COX deficiency. One nuclear gene SURF1 is responsible for COX assembly or maintenance. Four patients had homozygous SURF1 mutations, associated with reduced expression of both mtDNA- and nuclear-encoded COX subunits. Studying patterns of subunit expression in COX-deficient patients is fundamental to understanding the pathogenesis of respiratory chain enzyme deficiencies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available