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Title: Genetic Rescue of Mitochondrial and Skeletal Muscle Impairment in an Induced Pluripotent Stem Cells Model of Coenzyme Q10 Deficiency.
Authors: Romero-Moya, Damià
Santos-Ocaña, Carlos
Castaño, Julio
Garrabou, Gloria
Rodríguez-Gómez, José A
Ruiz-Bonilla, Vanesa
Bueno, Clara
González-Rodríguez, Patricia
Giorgetti, Alessandra
Perdiguero, Eusebio
Prieto, Cristina
Moren-Nuñez, Constanza
Fernández-Ayala, Daniel J
Victoria Cascajo, Maria
Velasco, Iván
Canals, Josep Maria
Montero, Raquel
Yubero, Delia
Jou, Cristina
López-Barneo, José
Cardellach, Francesc
Muñoz-Cánoves, Pura
Artuch, Rafael
Navas, Plácido
Menendez, Pablo
Keywords: COQ4;CRISPR-Cas9;Coenzyme Q10;Dopaminergic and motor neurons;Induced pluripotent stem cell;Skeletal muscle
metadata.dc.subject.mesh: Ataxia
CRISPR-Cas Systems
Cell Differentiation
Child, Preschool
Dopaminergic Neurons
Electron Transport Chain Complex Proteins
Fatal Outcome
Gene Editing
Gene Expression
Genes, Lethal
Induced Pluripotent Stem Cells
Intellectual Disability
Mitochondrial Diseases
Mitochondrial Proteins
Motor Neurons
Muscle Weakness
Primary Cell Culture
Issue Date: 23-May-2017
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 four-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 (CQ4ed -iPSCs). Extensive differentiation and metabolic assays of control-iPSCs, CQ4-iPSCs and CQ4ed -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. Stem Cells 2017;35:1687-1703.
metadata.dc.identifier.doi: 10.1002/stem.2634
Appears in Collections:Producción 2020

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