Top

Published in:

01-01-2012 | Original Article

Combined OXPHOS complex I and IV defect, due to mutated complex I assembly factor C20ORF7

Authors: Ann Saada, Shimon Edvardson, Avraham Shaag, Wendy K. Chung, Reeval Segel, Chaya Miller, Chaim Jalas, Orly Elpeleg

Published in: Journal of Inherited Metabolic Disease | Issue 1/2012

Abstract

Defects of the mitochondrial oxidative phosphorylation (OXPHOS) system are frequent causes of neurological disorders in children. Linkage analysis and DNA sequencing identified a new founder p.G250V substitution in the C20ORF7 complex I chaperone in five Ashkenazi Jewish patients from two families with a combined OXPHOS complex I and IV defect presenting with Leigh's syndrome in infancy. Complementation with the wild type gene restored complex I, but only partially complex IV activity. Although the pathogenic mechanism remains elusive, a C20ORF7 defect should be considered not only in isolated complex I deficiency, but also in combination with decreased complex IV. Given the significant 1:290 carrier rate for the p.G250V mutation among Ashkenazi Jews, this mutation should be screened in all Ashkenazi patients with Leigh's syndrome prior to muscle biopsy.

Available only for authorised users

Barghuti F, Elian K, Gomori JM et al. (2008) The unique neuroradiology of complex I deficiency due to NDUFA12L defect. Mol Genet Metab 94:78–82PubMedCrossRef

Calvo SE, Tucker EJ, Compton AG et al. (2010) High-throughput, pooled sequencing identifies mutations in NUBPL and FOXRED1 in human complex I deficiency. Nat Genet 42:851–858PubMedCrossRef

Carroll J, Fearnley IM, Skehel JM et al. (2005) The post-translational modifications of the nuclear encoded subunits of complex I from bovine heart mitochondria. Mol Cell Proteomics 4:693–699PubMedCrossRef

Carroll J, Fearnley IM, Skehel JM, Shannon RJ, Hirst J, Walker JE (2006) Bovine complex I is a complex of 45 different subunits. J Biol Chem 281:32724–132727PubMedCrossRef

DiMauro S, Schon EA (1998) Nuclear power and mitochondrial disease. Nat Genet 19:214–215PubMedCrossRef

Dunning CJ, McKenzie M, Sugiana C (2007) Human CIA30 is involved in the early assembly of mitochondrial complex I and mutations in its gene cause disease. EMBO J 26:3227–3237PubMedCrossRef

Edvardson S, Shaag A, Kolesnikova O et al. (2007) Deleterious mutation in the mitochondrial arginyl-transfer RNA synthetase gene is associated with pontocerebellar hypoplasia. Am J Hum Genet 81:857–862PubMedCrossRef

Fassone E, Duncan AJ, Taanman JW, Pagnamenta AT, Sadowski MI, Holand T, Qasim W, Rutland P, Calvo SE, Mootha VK, Bitner-Glindzicz M, Rahman S (2010) FOXRED1, encoding an FAD-dependent oxidoreductase complex-I-specific molecular chaperone, is mutated in infantile-onset mitochondrial encephalopathy. Hum Mol Genet 19:4837–4847PubMedCrossRef

Gerards M, Sluiter W, van den Bosch BJ et al. (2010) Defective complex I assembly due to C20orf7 mutations as a new cause of Leigh syndrome. J Med Genet 47:507–551PubMedCrossRef

Gerards M, van den Bosch BJ, Danhauser K, Serre V, van Weeghel M, Wanders RJ, Nicolaes GA, Sluiter W, Schoonderwoerd K, Scholte HR, Prokisch H, Rötig A, de Coo IF, Smeets HJ (2011) Riboflavin-responsive oxidative phosphorylation complex I deficiency caused by defective ACAD9: new function for an old gene. Brain 134:210–209PubMedCrossRef

Haack TB, Danhauser K, Haberberger B et al. (2010) Exome sequencing identifies ACAD9 mutations as a cause of complex I deficiency. Nat Genet 42:1131–1134PubMedCrossRef

Janssen RJ, Nijtmans LG, van den Heuvel LP, Smeitink JA (2006) Mitochondrial complex I: structure, function and pathology. J Inherit Metab Dis 29:499–51PubMedCrossRef

Jones CN, Miller C, Tenenbaum A, Spremulli LL, Saada A (2009) Antibiotic effects on mitochondrial translation and in patients with mitochondrial translational defects. Mitochondrion 9:429–437PubMedCrossRef

Kirby DM, Crawford M, Cleary MA, Dahl HH, Dennett X, Thorburn DR (1999) Respiratory chain complex I deficiency: an underdiagnosed energy generation isorder. Neurology 52:1255–1264PubMed

Lazarou M, Thorburn DR, Ryan MT, McKenzie M (2009) Assembly of mitochondrial complex I and defects in disease. Biochim Biophys Acta 1793:78–88PubMedCrossRef

Mckenzie M, Ryan MT (2010) Assembly factors of human mitochondrial complex I and their defects in disease. IUBMB Life 62:497–502PubMedCrossRef

Nouws J, Nijtmans L, Houten SM et al. (2010) Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I. Cell Metab 12:283–294PubMedCrossRef

Ogilvie I, Kennaway NG, Shoubridge EA (2005) A molecular chaperone for mitochondrial complex I assembly is mutated in a progressive encephalopathy. J Clin Invest 115:2784–2792PubMedCrossRef

Pagliarini DJ, Calvo SE, Chang B et al. (2008) A mitochondrial protein compendium elucidates complex I disease biology. Cell 134:112–12324PubMedCrossRef

Pogozelski WK, Hamel CJ, Woeller CF et al. (2003) Quantification of total mitochondrial DNA and the 4977-bp common deletion in Pearson's syndrome lymphoblasts using a fluorogenic 5'-nuclease (TaqMan) real-time polymerase chain reaction assay and plasmid external calibration standards. Mitochondrion 2:415–427PubMedCrossRef

Saada A, Bar-Meir M, Belaiche C, Miller C, Elpeleg O (2004) Evaluation of enzymatic assays and compounds affecting ATP production in mitochondrial respiratory chain complex I deficiency. Anal Biochem 335:66–72PubMedCrossRef

Saada A, Edvardson S, Rapoport M et al. (2008) C6ORF66 is an assembly factor of mitochondrial complex I. Am J Hum Genet 82:32–38PubMedCrossRef

Saada A, Vogel RO, Hoefs SJ et al. (2009) Mutations in NDUFAF3 (C3ORF60), encoding an NDUFAF4 (C6ORF66)-interacting complex I assembly protein, cause fatal neonatal mitochondrial disease. Am J Hum Genet 84:718–727PubMedCrossRef

Schaefer AM, McFarland R, Blakely EL et al. (2008) Prevalence of mitochondrial DNA disease in adults. Ann Neurol 63:35–39PubMedCrossRef

Sheftel AD, Stehling O, Pierik AJ et al. (2009) Human ind1, an iron-sulfur cluster assembly factor for respiratory complex I. Mol Cell Biol 29:6059–6073PubMedCrossRef

Skladal D, Halliday J, Thorburn DR (2003) Minimum birth prevalence of mitochondrial respiratory chain disorders in children. Brain 126:1905–1912PubMedCrossRef

Sugiana C, Pagliarini DJ, McKenzie M et al. (2008) Mutation of C20orf7 disrupts complex I assembly and causes lethal neonatal mitochondrial disease. Am J Hum Genet 83:468–478PubMedCrossRef

Vince JE, Wong WW, Khan N et al. (2007) IAP antagonists target cIAP1 to induce TNFalpha-dependent apoptosis. Cell 131:682–693PubMedCrossRef

Title: Combined OXPHOS complex I and IV defect, due to mutated complex I assembly factor C20ORF7
Authors: Ann Saada
Shimon Edvardson
Avraham Shaag
Wendy K. Chung
Reeval Segel
Chaya Miller
Chaim Jalas
Orly Elpeleg
Publication date: 01-01-2012
Publisher: Springer Netherlands
Published in: Journal of Inherited Metabolic Disease / Issue 1/2012
Print ISSN: 0141-8955
Electronic ISSN: 1573-2665
DOI: https://doi.org/10.1007/s10545-011-9348-y

ACC 2024 Congress Coverage

Heart Failure Video

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Combined OXPHOS complex I and IV defect, due to mutated complex I assembly factor C20ORF7

Abstract

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 1/2012

Variability in the clinical management of fatty acid oxidation disorders: results of a survey of Canadian metabolic physicians

Treatment by oral creatine, L-arginine and L-glycine in six severely affected patients with creatine transporter defect

Propionic acidemia: neonatal versus selective metabolic screening

Mutation analysis in 54 propionic acidemia patients

Interrupting the mechanisms of brain injury in a model of maple syrup urine disease encephalopathy

Inborn errors of ketogenesis and ketone body utilization

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

Incentivised to exercise

New intervention for STEMI-related cardiogenic shock

» View more highlights on the ACC 2024 congress hub page