Clinical heterogeneity in respiratory chain complex III deficiency in childhood

Mourmans, J.; Wendel, U.; Bentlage, H.A.C.M.; Trijbels, J. M. F.; Smeitink, Jan A.M.; Coo, I.F.M. de; Gabreëls, F.J.M.; Sengers, R. C. A.; Ruitenbeek, W.

doi:10.1016/s0022-510x(97)05379-3

Cited by 55 publications

(28 citation statements)

References 34 publications

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“…Complex III deficiency represents a relatively rare cause of respiratory enzyme dysfunction (30). In our experience, among all RC enzyme-deficient patients, only 7% exhibited a complex III deficiency (21).…”

Section: Point Mutations In Mitochondrial Protein Synthesis Genesmentioning

confidence: 69%

“…In our experience, among all RC enzyme-deficient patients, only 7% exhibited a complex III deficiency (21). The clinical presentation of complex IIIdeficient patients is very heterogeneous, including myopathy, encephalomyopathy, multiple-organ disorders, cardiomyopathy, tubulopathy, and intrauterine growth retardation (21,30,31). This complex contains 11 subunits, and only one, cytochrome b, is of mitochondrial origin.…”

Section: Point Mutations In Mitochondrial Protein Synthesis Genesmentioning

confidence: 89%

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Genetic Features of Mitochondrial Respiratory Chain Disorders

Rötig¹,

Münnich²

2003

Journal of the American Society of Nephrology

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Abstract. Oxidative phosphorylation, i.e., ATP synthesis by the oxygen-consuming respiratory chain (RC), supplies most organs and tissues with a readily usable energy source, being functional before birth. Consequently, RC deficiencies can theoretically give rise to any symptom, in any organ or tissue, at any age and with any mode of inheritance, because of the twofold genetic origin of RC components (nuclear DNA and mitochondrial DNA). It was long wrongly considered that RC disorders originate from mutations of mitochondrial DNA, because for a long time only mutations or deletions of mitochondrial DNA were identified. However, the number of known disease-causing mutations in nuclear genes is steadily growing. These genes encode the various subunits of each complex, ancillary proteins functioning at different stages of holoenzyme biogenesis, including transcription, translation, chaperoning, addition of prosthetic groups, and protein assembly, and various enzymes involved in mitochondrial DNA metabolism.The mitochondrial respiratory chain (RC) catalyzes the oxidation of fuel molecules and the concomitant energy transduction into ATP via five complexes, which are embedded in the inner mitochondrial membrane (1) (Figure 1). Complex I [NADHcoenzyme Q (CoQ) reductase] carries reducing equivalents from NADH to CoQ (ubiquinone) and consists of Ͼ40 different polypeptides. Complex II (succinate-CoQ reductase) carries reducing equivalents from FADH 2 to CoQ and contains four polypeptides, including the FAD-dependent succinate dehydrogenase and iron-sulfur proteins. Complex III (reduced CoQ-cytochrome c reductase) carries electrons from CoQ to cytochrome c. It contains 11 subunits. Complex IV [cytochrome c oxidase (COX)], the terminal oxidase of the RC, catalyzes the transfer of reducing equivalents from cytochrome c to molecular oxygen. It is composed of two cytochromes (cytochromes a and a 3 ), two copper atoms, and 13 different protein subunits.During the oxidation process, electrons are transferred to oxygen via the energy-transducing complexes of the RC, i.e., complexes I, III, and IV for NADH-producing substrates; complexes II, III, and IV for succinate; and complexes III and IV for FADH 2 derived from the ␤-oxidation pathway via the electron transfer flavoprotein and the electron transfer flavoprotein-CoQ oxidoreductase system. CoQ, a highly hydrophobic quinone, and cytochrome c, a low-molecular weight hemoprotein, act as "shuttles" between the complexes. The free energy generated from the redox reactions is converted into a transmembrane proton gradient. Protons are pumped through complexes I, III, and IV of the RC, which creates a charge differential. Complex V (ATP synthase) allows protons to flow back into the mitochondrial matrix and uses the released energy to synthesize ATP. Three ATP molecules are produced for each NADH molecule oxidized.

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Section: Point Mutations In Mitochondrial Protein Synthesis Genesmentioning

confidence: 69%

Section: Point Mutations In Mitochondrial Protein Synthesis Genesmentioning

confidence: 89%

Genetic Features of Mitochondrial Respiratory Chain Disorders

Rötig¹,

Münnich²

2003

Journal of the American Society of Nephrology

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“…In contrast, deficiencies in complex III of the respiratory chain are rare, with very few patients with an isolated complex III defect being reported. The estimated incidence of complex III deficiency accounts for approximately 2% of the respiratory chain diseases in Netherlands (Mourmans et al, 1997), and 15% of these diseases in France (Ristin et al, 1994). In a majority of the cases, disease onset is during infancy and early childhood; however, adults have also been affected in a small number of cases.…”

Section: Discussionmentioning

confidence: 99%

“…In a majority of the cases, disease onset is during infancy and early childhood; however, adults have also been affected in a small number of cases. A previous study of complex III deficiency in 6 patients showed that the clinical onset of the disease had occurred prior to the age of 15 months in 5 patients, and after 7 years in 1 patient (Mourmans et al, 1997). Blazquez summarized the clinical and biochemical characteristics of 14 previously reported patients with complex III deficiency, caused by mutations in the BCS1L gene.…”

Section: Discussionmentioning

confidence: 99%

Respiratory chain complex III deficiency in patients with tRNA-leu mutation

Jiang

Wang

2015

Genet. Mol. Res.

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ABSTRACT. The aim of this study was to investigate the clinical and genetic profiles of mitochondrial disease resulting from deficiencies in the respiratory chain complex III. Three patients, aged between 8 months and 12 years, were recruited for this study. The activities of mitochondrial respiratory chain complexes in the peripheral leucocytes were spectrophotometrically measured. The entire mitochondrial DNA (mtDNA) sequence was analyzed. Samples obtained from the three patients and their families were subjected to restriction fragment length polymorphism and gene sequencing analyses. mtDNA copy numbers of all patients and their mothers were analyzed. The patients displayed nervous system impairment, including motor and mental developmental delay, hypotonia, and motor regression. Two patients also suffered from Leigh syndrome. Assay of the mitochondrial respiratory chain enzymes revealed an isolated complex III deficiency in the three patients. The m.3243 A>G mutation was detected in all patients and their mothers. The mutation loads were 48.3, 57.2, and 45.5% in the patients, and 20.5, 16.4, and 23.6% in their respective mothers. The leukocyte mtDNA copy numbers of the patients and their mothers were within the control range. The clinical manifestation and genetics were observed to be very heterogeneous. Patient carrying an m.3243 A>G mutation may biochemically display a deficiency in the mitochondrial respiratory chain complex III.

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“…1 Ubiquinol-cytochrome c oxidoreductase (EC 1.10.2.2) or complex III (CIII) deficiency represents a relatively rare cause of respiratory chain dysfunction. 2 CIII catalyses electron transfer between coenzyme Q and cytochrome c, thereby translocating protons across the mitochondrial inner membrane.…”

Section: Introductionmentioning

confidence: 99%

The deleterious G15498A mutation in mitochondrial DNA-encoded cytochrome b may remain clinically silent in homoplasmic carriers

et al. 2004

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We report on a patient with severe growth retardation and IgF1 deficiency, in which a mitochondrial abnormality was suspected. An isolated mitochondrial respiratory chain complex III deficiency was found in blood lymphocytes and skin fibroblasts. Sequence analysis of the cytochrome b, which is the only mitochondrial DNA-encoded subunit of complex III, revealed a homoplasmic G15498A mutation, resulting in the substitution of a highly conserved amino acid (glycine 251 into an aspartic acid). The mutation was found to be homoplasmic in all tissues examined from the mother and her brother (lymphocytes, fibroblasts, hair roots and buccal cells). Complex III deficiency was also demonstrated in these cells. Nevertheless, the mother and the brother were asymptomatic. This mutation had been considered as a cardiomyopathy-generating mutation in a previously reported case, and its pathogenicity has been demonstrated recently in yeast. However, it seems not to fulfil the classical criteria for pathogenicity of a mitochondrial DNA mutation, especially the heteroplasmic status, and to be clinically silent, albeit present, in nonaffected relatives. We suggest that other factors are contributing to the clinical variability expression of the G15498A mtDNA mutation.

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Clinical heterogeneity in respiratory chain complex III deficiency in childhood

Cited by 55 publications

References 34 publications

Genetic Features of Mitochondrial Respiratory Chain Disorders

Genetic Features of Mitochondrial Respiratory Chain Disorders

Respiratory chain complex III deficiency in patients with tRNA-leu mutation

The deleterious G15498A mutation in mitochondrial DNA-encoded cytochrome b may remain clinically silent in homoplasmic carriers

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