Homozygosity (E140K) in
            <i>SCO2</i>
            causes delayed infantile onset of cardiomyopathy and neuropathy

Jaksch, Michaela; Horvath, Rita; Horn, Nina; Auer, Dorothee P.; Macmillan, Carol; Peters, Janny L.; Gerbitz, Klaus-Dieter; Kraegeloh‐Mann, Ingeborg; Muntau, Ania C.; Karcagi, V.; Kálmánchey, R.; Lochmüller, Hanns; Shoubridge, Eric A.; Freisinger, Peter

doi:10.1212/wnl.57.8.1440

Cited by 80 publications

(68 citation statements)

References 22 publications

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“…Two patients have been described with complex III defects, one had a mutation in cytochrome b subunit of complex III and the other was without a recognized mutation but a defect in enzyme activity (Majoie et al, 2002;Seijo-Martinez et al, 2003). At least 5 patients with defects in complex IV have demonstrated white matter changes (Zafeiriou et al, 1995;Rahman et al, 2001;Jaksch et al, 2001). One patient with multiple ETC defects with leukodystrophy has been reported (Moroni et al, 2002).…”

Section: Isolated Electron Transport Chain Disordersmentioning

confidence: 99%

Neuroimaging of mitochondrial disease

2008

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Section: Isolated Electron Transport Chain Disordersmentioning

confidence: 99%

Neuroimaging of mitochondrial disease

2008

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“…It is not clear why two SCO proteins are present in human mitochondria. Mutations in SCO2 have been reported in several unrelated patients (18,30,31), but only a single family with SCO1 mutations has been described (32). The patients from this family carried a frameshift mutation on one allele, introducing a premature termination codon, and a missense mutation on the other allele, resulting in a proline to leucine replacement immediately adjacent to the CXXXC motif.…”

mentioning

confidence: 94%

Cytochrome c Oxidase Subassemblies in Fibroblast Cultures from Patients Carrying Mutations in COX10, SCO1, or SURF1

Williams

Valnot

Rustin

et al. 2004

Journal of Biological Chemistry

127

135

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Cytochrome c oxidase contains two redox-active copper centers (Cu A and Cu B ) and two redox-active heme A moieties. Assembly of the enzyme relies on several assembly factors in addition to the constituent subunits and prosthetic groups. We studied fibroblast cultures from patients carrying mutations in the assembly factors COX10, SCO1, or SURF1. COX10 is involved in heme A biosynthesis. SCO1 is required for formation of the Cu A center. The function of SURF1 is unknown. Immunoblot analysis of native gels demonstrated severely decreased levels of holoenzyme in the patient cultures compared with controls. In addition, the blots revealed the presence of five subassemblies: three subassemblies involving the core subunit MTCO1 but apparently no other subunits; a subassembly containing subunits MTCO1, COX4, and COX5A; and a subassembly containing at least subunits MTCO1, MTCO2, MTCO3, COX4, and COX5A. As some of the subassemblies correspond to known assembly intermediates of human cytochrome c oxidase, we think that these subassemblies are probably assembly intermediates that accumulate in patient cells. The MTCO1⅐COX4⅐COX5A subassembly was not detected in COX10-deficient cells, which suggests that heme A incorporation into MTCO1 occurs prior to association of MTCO1 with COX4 and COX5A. SCO1-deficient cells contained accumulated levels of the MTCO1⅐COX4⅐COX5A subassembly, suggesting that MTCO2 associates with the MTCO1⅐COX4⅐COX5A subassembly after the Cu A center of MTCO2 is formed. Assembly in SURF1-deficient cells appears to stall at the same stage as in SCO1-deficient cells, pointing to a role for SURF1 in promoting the association of MTCO2 with the MTCO1⅐COX4⅐COX5A subassembly.

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“…Both encode mt proteins (Petruzzella et al, 1998;Paret et al, 1999), which are essential for mt function as shown by the recent detection of mutations associated with fatal COX deficiencies. Mutations in hSCO2 were reported in infants who suffered from a fatal disorder with hypertrophic cardiomyopathy as the predominant symptom (Papadopoulou et al, 1999;Jaksch et al, 2000Jaksch et al, , 2001a whereas the key symptoms of the infant patients carrying mutations in the hSCO1 gene were hepatic failure and ketoacidotic coma (Valnot et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

Molecular characterization of Saccharomyces cerevisiae Sco2p reveals a high degree of redundancy with Sco1p

Lode¹,

Paret²,

Rödel³

2002

Yeast

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The Saccharomyces cerevisiae gene SCO1 has been shown to play an essential role in the transfer of copper to the Cu A -centre of the mitochondrial cytochrome c oxidase subunit Cox2p. By contrast, the function of Sco2p, the gene product of the highly homologous SCO2 gene, remains to be elucidated. Deletion of the SCO2 gene does not affect growth on a variety of carbon sources, including glycerol, lactate and ethanol. We report here, that Sco2p is anchored in the mitochondrial membrane by a single transmembrane segment and displays a similar tripartite structure as Sco1p. Most parts of Sco1p can be replaced by the homologous parts of Sco2p without loss of function. A short stretch of 13 amino acids, immediately adjacent to the transmembrane region, is crucial for Sco1p function and cannot be replaced by its Sco2p counterpart. We propose that this region is relevant for the correct spatial orientation of the C-terminal part of the protein. Immunoprecipitation and in vitro binding assays show that Sco2p interacts with the C-terminal portion of Cox2p. This interaction is neither dependent on bound copper ions nor on the presence of Sco1p. Furthermore we report on in vitro binding assays which show that Sco2p can form homomeric complexes, but also heteromeric complexes with Sco1p. Our data suggest that Sco2p is involved in the transfer of copper to Cox2p, but that this activity is insufficient for oxidative growth and not able to substitute for Sco1p activity.

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Homozygosity (E140K) in SCO2 causes delayed infantile onset of cardiomyopathy and neuropathy

Abstract: The clinical spectrum of SCO2 deficiency includes the delayed development of hypertrophic obstructive cardiomyopathy and severe neurogenic muscular atrophy. There is increased copper uptake in patients' fibroblasts indicating that the G1541A mutation effects cellular copper metabolism.

Cited by 80 publications

References 22 publications

Neuroimaging of mitochondrial disease

Neuroimaging of mitochondrial disease

Cytochrome c Oxidase Subassemblies in Fibroblast Cultures from Patients Carrying Mutations in COX10, SCO1, or SURF1

Molecular characterization of Saccharomyces cerevisiae Sco2p reveals a high degree of redundancy with Sco1p

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