Title |
Genetic Rescue of Mitochondrial and Skeletal Muscle Impairment in an Induced Pluripotent Stem Cells Model of Coenzyme Q10 Deficiency
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Published in |
Stem Cells, May 2017
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DOI | 10.1002/stem.2634 |
Pubmed ID | |
Authors |
Damià Romero‐Moya, Carlos Santos‐Ocaña, Julio Castaño, Gloria Garrabou, José A. Rodríguez‐Gómez, Vanesa Ruiz‐Bonilla, Clara Bueno, Patricia González‐Rodríguez, Alessandra Giorgetti, Eusebio Perdiguero, Cristina Prieto, Constanza Moren‐Nuñez, Daniel J. Fernández‐Ayala, Maria Victoria Cascajo, Iván Velasco, Josep Maria Canals, Raquel Montero, Delia Yubero, Cristina Jou, José López‐Barneo, Francesc Cardellach, Pura Muñoz‐Cánoves, Rafael Artuch, Plácido Navas, Pablo Menendez |
Abstract |
Coenzyme Q10 (CoQ10 ) plays a crucial role in mitochondria as an electron carrier within the mitochondrial respiratory chain (MRC), and is an essential antioxidant. Mutations in genes responsible for CoQ10 biosynthesis (COQ genes) cause primary CoQ10 deficiency, a rare and heterogeneous mitochondrial disorder with no clear genotype-phenotype association, mainly affecting tissues with high-energy demand including brain and skeletal muscle (SkM). Here, we report a 4-year old girl diagnosed with minor mental retardation and lethal rhabdomyolysis harboring a heterozygous mutation (c.483G>C (E161D)) in COQ4. The patient's fibroblasts showed a decrease in [CoQ10 ], CoQ10 biosynthesis, MRC activity affecting complexes I/II+III, and respiration defects. Bona fide induced pluripotent stem cell (iPSCs) lines carrying the COQ4 mutation (CQ4-iPSCs) were generated, characterized and genetically edited using the CRISPR-Cas9 system (CQ4(ed) -iPSCs). Extensive differentiation and metabolic assays of control-iPSCs, CQ4-iPSCs and CQ4(ed) -iPSCs demonstrated a genotype association, reproducing the disease phenotype. The COQ4 mutation in iPSC was associated with CoQ10 deficiency, metabolic dysfunction, and respiration defects. iPSC differentiation into SkM was compromised, and the resulting SkM also displayed respiration defects. Remarkably, iPSC differentiation in dopaminergic or motor neurons was unaffected. This study offers an unprecedented iPSC model recapitulating CoQ10 deficiency-associated functional and metabolic phenotypes caused by COQ4 mutation. This article is protected by copyright. All rights reserved. |
X Demographics
Geographical breakdown
Country | Count | As % |
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Spain | 4 | 40% |
Unknown | 6 | 60% |
Demographic breakdown
Type | Count | As % |
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Members of the public | 7 | 70% |
Practitioners (doctors, other healthcare professionals) | 2 | 20% |
Scientists | 1 | 10% |
Mendeley readers
Geographical breakdown
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Unknown | 79 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
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Researcher | 13 | 16% |
Student > Master | 9 | 11% |
Student > Ph. D. Student | 8 | 10% |
Student > Bachelor | 8 | 10% |
Other | 6 | 8% |
Other | 22 | 28% |
Unknown | 13 | 16% |
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Biochemistry, Genetics and Molecular Biology | 25 | 32% |
Medicine and Dentistry | 10 | 13% |
Neuroscience | 7 | 9% |
Agricultural and Biological Sciences | 7 | 9% |
Pharmacology, Toxicology and Pharmaceutical Science | 5 | 6% |
Other | 8 | 10% |
Unknown | 17 | 22% |