Exercise Intolerance Due to Mutations in the Cytochrome<i>b</i>Gene of Mitochondrial DNA

Andreu, Antoni L.; Hanna, Michael G.; Reichmann, Heinz; Bruno, Claudio; Penn, Alan; Tanji, Kurenai; Pallotti, Francesco; Iwata, So; Bonilla, Eduardo; Lach, Bolesław; Morgan‐Hughes, J. A.; Shanske, Sara; Sue, Carolyn M.; Pulkes, Teeratorn; Siddiqui, Asra Tus Saleha; Clark, John B.; Land, John M.; Iwata, Momi; Schäefer, Jochen; DiMauro, Salvatore

doi:10.1056/nejm199909303411404

Cited by 387 publications

(234 citation statements)

References 23 publications

Supporting

Mentioning

229

Contrasting

Unclassified

Order By: Relevance

“…This concept has now been revised because, in the past few years, several pathogenic mutations in protein-coding genes have broken the canonical laws of mitochondrial genetics. In particular, we and others have observed many mutations in the cyt b gene that are neither generalized (they are only present in differentiated skeletal-muscle) nor maternally inherited (all cases were sporadic) (33,34,39). Studies in cell culture suggest that these mutations arose as spontaneous events during embryogenesis.…”

Section: Discussionmentioning

confidence: 91%

A Missense Mutation in the Mitochondrial Cytochrome b Gene in a Revisited Case with Histiocytoid Cardiomyopathy

et al. 2000

Self Cite

View full text Add to dashboard Cite

Section: Discussionmentioning

confidence: 91%

A Missense Mutation in the Mitochondrial Cytochrome b Gene in a Revisited Case with Histiocytoid Cardiomyopathy

et al. 2000

Self Cite

View full text Add to dashboard Cite

“…Among a dozen mutations mapped to the human cytochrome b gene, only two have been investigated in the yeast system (11). The G34S mutation has been observed in a patient suffering from exercise intolerance (31) and the substitution of the corresponding glycine by aspartate in yeast leads to a total defect of the bc1 complex activity at 28°C (32). The G339E mutation is responsible for a human myopathy and the same mutation totally abolishes the bc1 complex assembly in yeast at 28°C (33,34).…”

Section: Discussionmentioning

confidence: 99%

A Pathogenic Cytochrome b Mutation Reveals New Interactions between Subunits of the Mitochondrial bc1Complex

Saint-Georges¹,

Bonnefoy²,

Rago³

et al. 2002

Journal of Biological Chemistry

View full text Add to dashboard Cite

Energy transduction in mitochondria involves five oligomeric complexes embedded within the inner membrane. They are composed of catalytic and noncatalytic subunits, the role of these latter proteins often being difficult to assign. One of these complexes, the bc1 complex, is composed of three catalytic subunits including cytochrome b and seven or eight noncatalytic subunits. Recently, several mutations in the human cytochrome b gene have been linked to various diseases. We have studied in detail the effects of a cardiomyopathy generating mutation G252D in yeast. This mutation disturbs the biogenesis of the bc1 complex at 36°C and decreases the steady-state level of the noncatalytic subunit Qcr9p. In addition, the G252D mutation and the deletion of QCR9 show synergetic defects that can be partially bypassed by suppressor mutations at position 252 and by a new cytochrome b mutation, P174T. Altogether, our results suggest that the supernumerary subunit Qcr9p enhances or stabilizes the interactions between the catalytic subunits, this role being essential at high temperature.Numerous cellular functions are performed by oligomeric complexes composed of catalytic and noncatalytic subunits and the role of these latter proteins is often difficult to assign. Energy transduction in mitochondria involves five oligomeric complexes that are embedded within the inner membrane. One of these complexes, the bc1 complex is composed of three catalytic and seven or eight noncatalytic subunits (for review, see Ref. 1). The three catalytic subunits, cytochrome b, cytochrome c1, and the Rieske iron-sulfur protein (Rieske) are conserved in the bacterial equivalents of this complex. However, several noncatalytic subunits are present in the mitochondrial bc1 complexes and are often referred to as supernumerary subunits although some are required for the enzymatic activity. In Saccharomyces cerevisiae the bc1 complex contains seven supernumerary subunits that are conserved in the mammalian enzyme. The mammalian bc1 complex presents an additional subunit that has no equivalent in yeast. The mitochondrial bc1 complexes from bovine, chicken, and yeast have been crystallized (2-5) and an analysis of these structures reveals that the general shape, size, and topology of the complexes are similar in the three organisms.

show abstract

“…Four probes were designed for the analysis of the m.1606G4A mutation in the MT-RNR1 (12S ribosomal RNA) gene causing ataxia, myoclonus and deafness to avoid interference by the mtSNP m.1598G4A, which is found in haplogroups B5b, N9b1 and N1b in the Japanese population (frequency: 4.2%). 21 Similarly, for the detection of the m.15498G4A mutation in the MT-CYB (cytochrome b) gene, 22 two pairs of probes were designed to avoid interference by the mtSNP m.15497G4A, which is characteristic of haplogroup G1a in the Japanese population (frequency: 3.7%). The detection of the m.12706T4C mutation in the MT-ND5 gene can be inhibited by the presence of mtSNP m.12705C4T, which is found in haplogroups A and N9a, as well as in macrohaplogroup M among the Japanese population (frequency, 81%).…”

Section: Materials and Methods Patientsmentioning

confidence: 99%

Extensive and rapid screening for major mitochondrial DNA point mutations in patients with hereditary hearing loss

et al. 2010

View full text Add to dashboard Cite

Sensorineural hearing loss (HL) is one of the most frequent clinical features in patients with mitochondrial diseases caused by mitochondrial DNA (mtDNA) mutations, and hearing is impaired in over half of all cases with mitochondrial disorders. This study analyzed 373 patients with suspected hereditary HL using an extensive and rapid suspension-array screening system for 29 major mtDNA mutations, including the m.1555A4G homoplasmic mutation in the MT-RNR1 gene, which causes non-syndromic sensorineural HL and aminoglycoside-induced HL, and the m.3243A4G heteroplasmic mutation in the MT-TL1 gene. This method is rapid and suitable for large-scale screening because universal 96-well plates are available for use, and because an analysis of each plate can be completed within 1 h. This system detected five different mtDNA mutations in 24 of the 373 (6.4%) patients. The m.1555A4G and m.3243A4G mutations were detected in 11 (2.9%) and 9 (2.7%) patients, respectively. In addition, three mutations, that is, m.8348A4G in the MT-TK gene, m.11778G4A in the MT-ND4 gene and 15498G4A in the MT-CYB gene were detected in one patient for each. This screening system is useful for the genetic diagnosis and epidemiological study of both syndromic and non-syndromic HL.

show abstract

Exercise Intolerance Due to Mutations in the CytochromebGene of Mitochondrial DNA

Abstract: The sporadic form of mitochondrial myopathy is associated with somatic mutations in the cytochrome b gene of mtDNA. This myopathy is one cause of the common and often elusive syndrome of exercise intolerance.

Cited by 387 publications

References 23 publications

A Missense Mutation in the Mitochondrial Cytochrome b Gene in a Revisited Case with Histiocytoid Cardiomyopathy

A Missense Mutation in the Mitochondrial Cytochrome b Gene in a Revisited Case with Histiocytoid Cardiomyopathy

A Pathogenic Cytochrome b Mutation Reveals New Interactions between Subunits of the Mitochondrial bc1Complex

Extensive and rapid screening for major mitochondrial DNA point mutations in patients with hereditary hearing loss

Contact Info

Product

Resources

About