Mutations of the<i>SCO1</i>Gene in Mitochondrial Cytochrome<i>c</i>Oxidase Deficiency with Neonatal‐Onset Hepatic Failure and Encephalopathy

Valnot, Isabelle; Osmond, Sandrine; Gigarel, Nadine; Mehaye, Blandine; Amiel, Jeanne; Cormier‐Daire, Valérie; Münnich, Arnold; Bonnefont, Jean‐Paul; Rustin, Pierre; Rötig, Agnès

doi:10.1086/321202

Cited by 69 publications

(33 citation statements)

References 30 publications

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“…Although the P174L variant has wild-type copper binding properties, its function in vivo is severely compromised as evidenced by the pronounced CcO assembly defect in SCO1 patient tissues and fibroblasts (6,10). Overexpression of the mutant SCO1 in patient fibroblasts only partially suppressed the CcO deficiency, consistent with a loss of function mutation.…”

Section: Discussionmentioning

confidence: 99%

“…Isolated CcO deficiency, one of the most commonly recognized causes of respiratory chain defects in humans, is associated with a wide spectrum of clinical phenotypes (3,4), and autosomal recessive mutations have been identified in six nuclear genes that encode CcO assembly factors in these patients (3)(4)(5)(6)(7)(8)(9). Two such factors, SCO1 and SCO2, encode metallochaperones that play a role in the copper ion metallation of the Cu A site in CoxII.…”

mentioning

confidence: 99%

“…Mutations in either hSCO1 or hSCO2 result in pronounced CcO deficiency and lead to different, early onset, fatal clinical phenotypes (4,6,7,14). SCO2 mutations are associated with neonatal encephalocar-diomyopathy, whereas SCO1 patients present with neonatal hepatic failure and ketoacidotic coma.…”

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confidence: 99%

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The P174L Mutation in Human Sco1 Severely Compromises Cox17-dependent Metallation but Does Not Impair Copper Binding

Cobine¹,

Pierrel²,

Leary³

et al. 2006

Journal of Biological Chemistry

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Sco1 is a metallochaperone that is required for copper delivery to the Cu A site in the CoxII subunit of cytochrome c oxidase. The only known missense mutation in human Sco1, a P174L substitution in the copper-binding domain, is associated with a fatal neonatal hepatopathy; however, the molecular basis for dysfunction of the protein is unknown. Immortalized fibroblasts from a SCO1 patient show a severe deficiency in cytochrome c oxidase activity that was partially rescued by overexpression of P174L Sco1. The mutant protein retained the ability to bind Cu(I) and Cu(II) normally when expressed in bacteria, but Cox17-mediated copper transfer was severely compromised both in vitro and in a yeast cytoplasmic assay. The corresponding P153L substitution in yeast Sco1 was impaired in suppressing the phenotype of cells harboring the weakly functional C57Y allele of Cox17; however, it was functional in sco1⌬ yeast when the wild-type COX17 gene was present. Pulse-chase labeling of mitochondrial translation products in SCO1 patient fibroblasts showed no change in the rate of CoxII translation, but there was a specific and rapid turnover of CoxII protein in the chase. These data indicate that the P174L mutation attenuates a transient interaction with Cox17 that is necessary for copper transfer. They further suggest that defective Cox17-mediated copper metallation of Sco1, as well as the subsequent failure of Cu A site maturation, is the basis for the inefficient assembly of the cytochrome c oxidase complex in SCO1 patients.

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

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The P174L Mutation in Human Sco1 Severely Compromises Cox17-dependent Metallation but Does Not Impair Copper Binding

Cobine¹,

Pierrel²,

Leary³

et al. 2006

Journal of Biological Chemistry

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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: 95%

“…The fibroblast cultures which we investigated were derived from four unrelated patients with SURF1 mutations (40,41), a patient with SCO1 mutations (32), and a patient with a COX10 mutation (38). Quantitative immunoblot analysis of native gels revealed residual levels of fully assembled enzyme in all cultures but also some accumulation of subassemblies.…”

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confidence: 99%

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

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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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Histochemical Methods for the Diagnosis of Mitochondrial Diseases

2009

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Through the process of oxidative phosphorylation (OXPHOS), mitochondria provide cells with required energy in the form of ATP. The organelle possesses its own genome (mtDNA), which encodes for part of the components needed (37 genes encoding either OXPHOS structural subunits or tRNAs and rRNAs). Nonetheless, the majority of structural OXPHOS components (as well as accessory proteins and proteins required for maintenance, replication, and expression of the mtDNA) are encoded by nuclear genes. Due to the dual genetic control and the large number of proteins involved, biogenesis and assembly of the OXPHOS system is complicated, and identifying a specific gene defect can be a difficult and time consuming task. This unit describes procedures for obtaining tissue sections and cell material suitable for histological evaluation of OXPHOS activity and integrity and immunodetection of the complexes in tissue from patients suspected of mitochondrial disease. Emphasis lies on the diagnostic potential of these techniques to differentiate mtDNA from nuclear mutations.

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Mutations of theSCO1Gene in Mitochondrial CytochromecOxidase Deficiency with Neonatal‐Onset Hepatic Failure and Encephalopathy

Cited by 69 publications

References 30 publications

The P174L Mutation in Human Sco1 Severely Compromises Cox17-dependent Metallation but Does Not Impair Copper Binding

The P174L Mutation in Human Sco1 Severely Compromises Cox17-dependent Metallation but Does Not Impair Copper Binding

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

Histochemical Methods for the Diagnosis of Mitochondrial Diseases

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