COQ4 mutations cause a broad spectrum of mitochondrial disorders associated with CoQ10 deficiency

Gloria Brea-Calvo, Tobias B. Haack, Daniela Karall, Akira Ohtake, Federica Invernizzi, Rosalba Carrozzo, Laura Kremer, Sabrina Dusi, Christine Fauth, Sabine Scholl-Bürgi, Elisabeth Graf, Uwe Ahting, Nicoletta Resta, Nicola Laforgia, Daniela Verrigni, Yasushi Okazaki, Masakazu Kohda, Diego Martinelli, Peter Freisinger, Tim M. StromThomas Meitinger, Costanza Lamperti, Atilano Lacson, Placido Navas, Johannes A. Mayr, Enrico Bertini, Kei Murayama, Massimo Zeviani, Holger Prokisch, Daniele Ghezzi

Research output: Contribution to journalArticle

Abstract

Primary coenzyme Q10 (CoQ10) deficiencies are rare, clinically heterogeneous disorders caused by mutations in several genes encoding proteins involved in CoQ10 biosynthesis. CoQ10 is an essential component of the electron transport chain (ETC), where it shuttles electrons from complex I or II to complex III. By whole-exome sequencing, we identified five individuals carrying biallelic mutations in COQ4. The precise function of human COQ4 is not known, but it seems to play a structural role in stabilizing a multiheteromeric complex that contains most of the CoQ10 biosynthetic enzymes. The clinical phenotypes of the five subjects varied widely, but four had a prenatal or perinatal onset with early fatal outcome. Two unrelated individuals presented with severe hypotonia, bradycardia, respiratory insufficiency, and heart failure; two sisters showed antenatal cerebellar hypoplasia, neonatal respiratory-distress syndrome, and epileptic encephalopathy. The fifth subject had an early-onset but slowly progressive clinical course dominated by neurological deterioration with hardly any involvement of other organs. All available specimens from affected subjects showed reduced amounts of CoQ10 and often displayed a decrease in CoQ10-dependent ETC complex activities. The pathogenic role of all identified mutations was experimentally validated in a recombinant yeast model; oxidative growth, strongly impaired in strains lacking COQ4, was corrected by expression of human wild-type COQ4 cDNA but failed to be corrected by expression of COQ4 cDNAs with any of the mutations identified in affected subjects. COQ4 mutations are responsible for early-onset mitochondrial diseases with heterogeneous clinical presentations and associated with CoQ10 deficiency.

Original languageEnglish
Pages (from-to)309-317
Number of pages9
JournalAmerican Journal of Human Genetics
Volume96
Issue number2
DOIs
Publication statusPublished - Feb 5 2015

Fingerprint

coenzyme Q10
Mitochondrial Diseases
Mutation
Electron Transport
Respiratory Insufficiency
Complementary DNA
Exome
Newborn Respiratory Distress Syndrome
Muscle Hypotonia
Fatal Outcome
Electron Transport Complex III
Brain Diseases
Bradycardia
Heart Failure
Yeasts
Coenzyme Q10 Deficiency
Electrons
Phenotype
Enzymes
Growth

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

COQ4 mutations cause a broad spectrum of mitochondrial disorders associated with CoQ10 deficiency. / Brea-Calvo, Gloria; Haack, Tobias B.; Karall, Daniela; Ohtake, Akira; Invernizzi, Federica; Carrozzo, Rosalba; Kremer, Laura; Dusi, Sabrina; Fauth, Christine; Scholl-Bürgi, Sabine; Graf, Elisabeth; Ahting, Uwe; Resta, Nicoletta; Laforgia, Nicola; Verrigni, Daniela; Okazaki, Yasushi; Kohda, Masakazu; Martinelli, Diego; Freisinger, Peter; Strom, Tim M.; Meitinger, Thomas; Lamperti, Costanza; Lacson, Atilano; Navas, Placido; Mayr, Johannes A.; Bertini, Enrico; Murayama, Kei; Zeviani, Massimo; Prokisch, Holger; Ghezzi, Daniele.

In: American Journal of Human Genetics, Vol. 96, No. 2, 05.02.2015, p. 309-317.

Research output: Contribution to journalArticle

Brea-Calvo, G, Haack, TB, Karall, D, Ohtake, A, Invernizzi, F, Carrozzo, R, Kremer, L, Dusi, S, Fauth, C, Scholl-Bürgi, S, Graf, E, Ahting, U, Resta, N, Laforgia, N, Verrigni, D, Okazaki, Y, Kohda, M, Martinelli, D, Freisinger, P, Strom, TM, Meitinger, T, Lamperti, C, Lacson, A, Navas, P, Mayr, JA, Bertini, E, Murayama, K, Zeviani, M, Prokisch, H & Ghezzi, D 2015, 'COQ4 mutations cause a broad spectrum of mitochondrial disorders associated with CoQ10 deficiency', American Journal of Human Genetics, vol. 96, no. 2, pp. 309-317. https://doi.org/10.1016/j.ajhg.2014.12.023
Brea-Calvo, Gloria ; Haack, Tobias B. ; Karall, Daniela ; Ohtake, Akira ; Invernizzi, Federica ; Carrozzo, Rosalba ; Kremer, Laura ; Dusi, Sabrina ; Fauth, Christine ; Scholl-Bürgi, Sabine ; Graf, Elisabeth ; Ahting, Uwe ; Resta, Nicoletta ; Laforgia, Nicola ; Verrigni, Daniela ; Okazaki, Yasushi ; Kohda, Masakazu ; Martinelli, Diego ; Freisinger, Peter ; Strom, Tim M. ; Meitinger, Thomas ; Lamperti, Costanza ; Lacson, Atilano ; Navas, Placido ; Mayr, Johannes A. ; Bertini, Enrico ; Murayama, Kei ; Zeviani, Massimo ; Prokisch, Holger ; Ghezzi, Daniele. / COQ4 mutations cause a broad spectrum of mitochondrial disorders associated with CoQ10 deficiency. In: American Journal of Human Genetics. 2015 ; Vol. 96, No. 2. pp. 309-317.
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AU - Brea-Calvo, Gloria

AU - Haack, Tobias B.

AU - Karall, Daniela

AU - Ohtake, Akira

AU - Invernizzi, Federica

AU - Carrozzo, Rosalba

AU - Kremer, Laura

AU - Dusi, Sabrina

AU - Fauth, Christine

AU - Scholl-Bürgi, Sabine

AU - Graf, Elisabeth

AU - Ahting, Uwe

AU - Resta, Nicoletta

AU - Laforgia, Nicola

AU - Verrigni, Daniela

AU - Okazaki, Yasushi

AU - Kohda, Masakazu

AU - Martinelli, Diego

AU - Freisinger, Peter

AU - Strom, Tim M.

AU - Meitinger, Thomas

AU - Lamperti, Costanza

AU - Lacson, Atilano

AU - Navas, Placido

AU - Mayr, Johannes A.

AU - Bertini, Enrico

AU - Murayama, Kei

AU - Zeviani, Massimo

AU - Prokisch, Holger

AU - Ghezzi, Daniele

PY - 2015/2/5

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