A microdeletion in cytochrome c oxidase (COX) subunit III associated with COX deficiency and recurrent myoglobinuria

Keightley, J. Andrew; Hoffbuhr, Kristen C.; Burton, Miriam D.; Salas, V. M.; Johnston, Wendy; Penn, Andrew M.; Buist, Neil R. M.; Kennaway, Nancy G.

doi:10.1038/ng0496-410

Cited by 190 publications

(96 citation statements)

References 47 publications

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“…These results were consistent with the level of mutation found in the patient's leukocytes (1%; Ref. 16). …”

Section: Creation and Characterization Of Transmitochondrial Cellsupporting

confidence: 81%

“…Since the patient's skeletal muscle harbored high levels of mutated mtDNA (92%; Ref. 16), these results suggested that the COX III mutation was absent or present at very low levels in muscle satellite cells (undifferentiated muscle precursor cells), in contrast to the skeletal muscle. Alternatively, it is possible that satellite cells and myoblasts containing high levels of mutation were selected against during culture because of a growth disadvantage.…”

Section: Discussionmentioning

confidence: 93%

“…PCR analysis of mutation levels was performed as described previously (16). Amplified DNA fragments of the wild-type (85 bp) or the mutated mtDNA (70 bp) were differentiated by size after electrophoresis through 10% polyacrylamide gels.…”

Section: Methodsmentioning

confidence: 99%

“…The first documented COX gene mutation (encoded by mtDNA or nuclear DNA) associated with COX deficiency was a 15-bp deletion (9480del15) in the mtDNA-encoded COX III gene (16). This in-frame deletion removed 5 amino acids (92del-Phe-Phe-Phe-Ala-Gly) from a conserved transmembrane region of the COX III polypeptide, one of two regions that contact COX I in the holoenzyme (4).…”

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confidence: 99%

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A Pathogenic 15-Base Pair Deletion in Mitochondrial DNA-encoded Cytochrome c Oxidase Subunit III Results in the Absence of Functional Cytochrome c Oxidase

Hoffbuhr¹,

Davidson²,

Filiano³

et al. 2000

Journal of Biological Chemistry

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A 15-base pair, in-frame, deletion (9480del15) in the mitochondrial DNA (mtDNA)-encoded cytochrome c oxidase subunit III (COX III) gene was identified previously in a patient with recurrent episodes of myoglobinuria and an isolated COX deficiency. Transmitochondrial cell lines harboring 0, 97, and 100% of the 9480del15 deletion were created by fusing human cells lacking mtDNA ( 0 cells) with platelet and lymphocyte fractions isolated from the patient. The COX III gene mutation resulted in a severe respiratory chain defect in all mutant cell lines. Cells homoplasmic for the mutation had no detectable COX activity or respiratory ATP synthesis, and required uridine and pyruvate supplementation for growth, a phenotype similar to 0 cells. The cells with 97% mutated mtDNA exhibited severe reductions in both COX activity (6% of wild-type levels) and rates of ATP synthesis (9% of wild-type). The COX III polypeptide in the mutant cells, although translated at rates similar to wild-type, had reduced stability. There was no evidence for assembly of COX

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“…These results were consistent with the level of mutation found in the patient's leukocytes (1%; Ref. 16). …”

Section: Creation and Characterization Of Transmitochondrial Cellsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 93%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

A Pathogenic 15-Base Pair Deletion in Mitochondrial DNA-encoded Cytochrome c Oxidase Subunit III Results in the Absence of Functional Cytochrome c Oxidase

Hoffbuhr¹,

Davidson²,

Filiano³

et al. 2000

Journal of Biological Chemistry

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“…This clinical variability is probably due to the number of nuclear genes involved in the expression, maturation, and assembly of the 13 COX subunits (Taanman 1997). So far, COX deficiency has been ascribed to mutations of either mtDNA-encoded COX subunits (Keightley et al 1996;Comi et al 1998;Hanna et al 1998;Bruno et al 1999;Clark et al 1999;Rahman et al 1999;Hoffbuhr et al 2000) or nuclear genes involved in assembly of functional complexes-namely, SURF1, SCO2, and COX10. Indeed, mutations in the nuclear SURF1 gene (MIM 185620 and MIM 256000) usually cause Leigh subacute necrotizing encephalomyopathy (Zhu et al 1998;Tiranti et al 1999;Poyau et al 2000) and have occasionally been associated with other clinical presentations (von Kleist-Retzow et al, in press).…”

Section: Introductionmentioning

confidence: 99%

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

Valnot¹,

Osmond²,

Gigarel³

et al. 2000

Am. J Hum. Genet.

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Cytochrome c oxidase (COX) catalyzes both electron transfer from cytochrome c to molecular oxygen and the concomitant vectorial proton pumping across the inner mitochondrial membrane. Studying a large family with multiple cases of neonatal ketoacidotic comas and isolated COX deficiency, we have mapped the disease locus to chromosome 17p13.1, in a region encompassing two candidate genes involved in COX assembly-namely, SCO1 and COX10. Mutation screening revealed compound heterozygosity for SCO1 gene mutations in the patients. The mutated allele, inherited from the father, harbored a 2-bp frameshift deletion (DGA; nt 363-364) resulting in both a premature stop codon and a highly unstable mRNA. The maternally inherited mutation (C520T) changed a highly conserved proline into a leucine in the protein (P174L). This proline, adjacent to the CxxxC copper-binding domain of SCO1, is likely to play a crucial role in the tridimentional structure of the domain. Interestingly, the clinical presentation of SCO1-deficient patients markedly differs from that of patients harboring mutations in other COX assembly and/or maturation genes.

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Mitochondrial anomalies in a Swiss family with autosomal dominant myoglobinuria

et al. 1997

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We report on a Swiss family in which 10 individuals of both sexes in 4 successive generations suffered from myoglobinuria, precipitated by febrile illness. It is the second family described with autosomal dominant inheritance of myoglobinuria. Four individuals suffered acute renal failure, which in two was reversible only after dialysis. In a recent case, a mitochondrial disorder was suspected because of an abnormal increase in lactate levels during an exercise test and because of a subsarcolemmal accumulation of mitochondria in a muscle biopsy, associated with a lack of cytochrome C oxidase in some muscle fibers. No mutation in the mitochondrial DNA was identified. Along with the inheritance pattern, these findings suggest that the myoglobinuria in this family is caused by a nuclear-encoded mutation affecting the respiratory chain.

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A microdeletion in cytochrome c oxidase (COX) subunit III associated with COX deficiency and recurrent myoglobinuria

Cited by 190 publications

References 47 publications

A Pathogenic 15-Base Pair Deletion in Mitochondrial DNA-encoded Cytochrome c Oxidase Subunit III Results in the Absence of Functional Cytochrome c Oxidase

A Pathogenic 15-Base Pair Deletion in Mitochondrial DNA-encoded Cytochrome c Oxidase Subunit III Results in the Absence of Functional Cytochrome c Oxidase

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

Mitochondrial anomalies in a Swiss family with autosomal dominant myoglobinuria

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