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EMBO Mol Med. 2015 May;7(5):670-87. doi: 10.15252/emmm.201404632.

The clinical heterogeneity of coenzyme Q10 deficiency results from genotypic differences in the Coq9 gene.

Author information

1
Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain Centro de Investigación Biomédica, Instituto de Biotecnología, Parque Tecnológico de Ciencias de la Salud, Granada, Spain.
2
Department of Neurology, Columbia University Medical Center, New York, NY, USA.
3
Departamento de Farmacología, Facultad de Medicina, Universidad de Granada, Granada, Spain Centro de Investigación Biomédica, Instituto de Neurociencias, Parque Tecnológico de Ciencias de la Salud, Granada, Spain.
4
Departamento de Fisiología, Facultad de Medicina, Universidad de Granada, Granada, Spain Centro de Investigación Biomédica, Instituto de Biotecnología, Parque Tecnológico de Ciencias de la Salud, Granada, Spain luisca@ugr.es.

Abstract

Primary coenzyme Q10 (CoQ10) deficiency is due to mutations in genes involved in CoQ biosynthesis. The disease has been associated with five major phenotypes, but a genotype-phenotype correlation is unclear. Here, we compare two mouse models with a genetic modification in Coq9 gene (Coq9(Q95X) and Coq9(R239X)), and their responses to 2,4-dihydroxybenzoic acid (2,4-diHB). Coq9(R239X) mice manifest severe widespread CoQ deficiency associated with fatal encephalomyopathy and respond to 2,4-diHB increasing CoQ levels. In contrast, Coq9(Q95X) mice exhibit mild CoQ deficiency manifesting with reduction in CI+III activity and mitochondrial respiration in skeletal muscle, and late-onset mild mitochondrial myopathy, which does not respond to 2,4-diHB. We show that these differences are due to the levels of COQ biosynthetic proteins, suggesting that the presence of a truncated version of COQ9 protein in Coq9(R239X) mice destabilizes the CoQ multiprotein complex. Our study points out the importance of the multiprotein complex for CoQ biosynthesis in mammals, which may provide new insights to understand the genotype-phenotype heterogeneity associated with human CoQ deficiency and may have a potential impact on the treatment of this mitochondrial disorder.

KEYWORDS:

CoQ multiprotein complex; Coq9; mitochondrial myopathy; mouse model; nonsense‐mediated mRNA decay

PMID:
25802402
PMCID:
PMC4492823
DOI:
10.15252/emmm.201404632
[Indexed for MEDLINE]
Free PMC Article

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