Complementation analysis of systemic cytochrome oxidase deficiency presenting as Leigh syndrome

Brown, Ruth; Brown, Garry K.

doi:10.1007/bf01799168

Cited by 28 publications

(12 citation statements)

References 16 publications

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“…At the same time, three complementation groups were shown to exist for classic COX deficiency with Leigh syndrome (21). This strongly suggested that the genes responsible were coding for factors involved in assembly of the COX multisubunit enzyme, so approaches were used to narrow down the search area by the use of single chromosome transfer (22,23), sequencing candidate genes (24), and linkage analysis (25,26).…”

Section: Resolution Of the Genetic Defectsmentioning

confidence: 99%

Human Cytochrome Oxidase Deficiency

Robinson

2000

Pediatr Res

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Section: Resolution Of the Genetic Defectsmentioning

confidence: 99%

Human Cytochrome Oxidase Deficiency

Robinson

2000

Pediatr Res

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“…However, in the French Canadian form of LS-COX -in Saguenay Lac Saint Jean, sequencing of all nuclear COX subunit genes revealed that two patients exhibited a mutation in the COX VIc subunit gene but the phenotype-genotype relationship of this mutation was not firmly established (Lee et al 1998). Brown and Brown (1996) were the first to show by somatic cell genetics that many LS-COX -patients belong to a single complementation group, suggesting that a single gene is responsible for these cases. Recently, Zhu et al (1998) and Tiranti et al (1998) have mapped the gene defect in COX deficiency associated with LS to chromosome band 9q34 by complementation of the respiratory chain deficiency in LS-COX -patient fibroblasts.…”

Section: Introductionmentioning

confidence: 98%

Missense mutations in SURF1 associated with deficient cytochrome c oxidase assembly in Leigh syndrome patients

et al. 2000

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We have studied the fibroblasts of three patients suffering from Leigh syndrome associated with cytochrome c oxidase deficiency (LS-COX-). Their mitochondrial DNA was functional and all nuclear COX subunits had a normal sequence. The expression of transcripts encoding mitochondrial and nuclear COX subunits was normal or slightly increased. Similarly, the OXA1 transcript coding for a protein involved in COX assembly was increased. However, several COX-protein subunits were severely depressed, indicating deficient COX assembly. Surf1, a factor involved in COX biogenesis, was recently reported as mutated in LS-COX- patients, all mutations predicting a truncated protein. Sequence analysis of SURF1 gene in our three patients revealed seven heterozygous mutations, six of which were new : an insertion, a nonsense mutation, a splicing mutation of intron 7 in addition to three missense mutations. The mutation G385 A (Gly124-->Glu) changes a Gly that is strictly conserved in Surfl homologs of 12 species. The substitution G618 C (Asp202-->His), changing an Asp that is conserved only in mammals, appears to be a polymorphism. The mutation T751 C changes Ile246 to Thr, a position at which a hydrophobic amino acid is conserved in all eukaryotic and some bacterial species. Replacing Ile246 by Thr disrupts a predicted beta sheet structure present in all higher eukaryotes. COX activity could be restored in fibroblasts of the three patients by complementation with a retroviral vector containing normal SURF1 cDNA. These mutations identify domains essential to Surf1 protein structure and/or function.

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“…A common complementation group was identified in peroxisomal biogenesis disorders (20) and in respiratory chain complex IV deficiency (21,22). In both these examples, identification of several unrelated patients within individual complementation groups facilitated subsequent identification of the causative genes, PEX1 (23,24) and SURF1 (25,26), by somatic cell genetic, genomic, or candidate gene studies.…”

Section: Introductionmentioning

confidence: 99%

NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency

Kirby¹,

Salemi²,

Sugiana³

et al. 2004

J. Clin. Invest.

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Complex I deficiency, the most common respiratory chain defect, is genetically heterogeneous: mutations in 8 nuclear and 7 mitochondrial DNA genes encoding complex I subunits have been described. However, these genes account for disease in only a minority of complex I-deficient patients. We investigated whether there may be an unknown common gene by performing functional complementation analysis of cell lines from 10 unrelated patients. Two of the patients were found to have mitochondrial DNA mutations. The other 8 represented 7 different (nuclear) complementation groups, all but 1 of which showed abnormalities of complex I assembly. It is thus unlikely that any one unknown gene accounts for a large proportion of complex I cases. The 2 patients sharing a nuclear complementation group had a similar abnormal complex I assembly profile and were studied further by homozygosity mapping, chromosome transfers, and microarray expression analysis. NDUFS6, a complex I subunit gene not previously associated with complex I deficiency, was grossly underexpressed in the 2 patient cell lines. Both patients had homozygous mutations in this gene, one causing a splicing abnormality and the other a large deletion. This integrated approach to gene identification offers promise for identifying other unknown causes of respiratory chain disorders.

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Complementation analysis of systemic cytochrome oxidase deficiency presenting as Leigh syndrome

Cited by 28 publications

References 16 publications

Human Cytochrome Oxidase Deficiency

Human Cytochrome Oxidase Deficiency

Missense mutations in SURF1 associated with deficient cytochrome c oxidase assembly in Leigh syndrome patients

NDUFS6 mutations are a novel cause of lethal neonatal mitochondrial complex I deficiency

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