CYTOCHROME OXIDASE ASSEMBLY GENES IN HUMAN DISEASE

Cytochrome c oxidase (COX), or complex IV of the mitochondrial respiratory chain, is a copper- and heme-containing metalloprotein composed of 13 subunits, 3 encoded by mitochondrial DNA (mtDNA) and 10 by nuclear DNA (nDNA). A number of COX-deficiency disorders are associated with point mutations in mtDNA-encoded COX subunits, but almost nothing is known regarding the molecular basis of mendelian-inherited COX deficiency disorders, which display widely varying phenotypes, including both generalized and tissue-specific clinical presentations. In particular, no mutation in any of the 10 nDNA-encoded COX subunits has yet been found. We have now identified mutations in the human SC02 gene, encoding a putative copper-transport protein that is required for the assembly of the COX holoprotein, in three patients with a newly-identified clinical entity characterized by fatal cardioencephalomyopathy and COX deficiency limited to clinically-affected tissues. We propose to follow up on this exciting finding in four areas: (1) we will clarify the unexpectedly complex patterns of transcription and protein expression of the two known human SCO genes (hSCO1 and hSCO2); (2) we will study hSCO2 deficiency in two cellular models in which SCO function is compromised, namely, in patient cells harboring hSC02 mutations and in yeast cells harboring SCO1/SCO2 null mutations; (3) we will create mouse models of hSCO2 deficiency (both knock-out and knock-in mice); and (4) we will search for mutations in hSCO1 and hSCO2, and in other COX-assembly genes as well, in a large series of candidate patient tissues available to us and our colleagues here at Columbia.