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

Luna-Sánchez M, Díaz-Casado E, Barca E, Tejada MÁ, Montilla-García Á, Cobos EJ, Escames G, Acuña-Castroviejo D, Quinzii CM, López LC - EMBO Mol Med (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

No MeSH data available.


Related in: MedlinePlus

CoQ biosynthetic gene expressionA–E mRNA expression levels of Coq9 (A), Coq7 (B), Adck3 (C), Coq5 (D) and Coq6 (E) on cerebrum of Coq9+/+, Coq9Q95X and Coq9Q95X mice at 3 months of age. **P < 0.01; ***P < 0.001; Coq9Q95X and Coq9R239X mice versus Coq9+/+ mice. ###P < 0.001; Coq9Q95X versus Coq9R239X mice.F–J mRNA expression levels of Coq9 (F), Coq7 (G), Adck3 (H), Coq5 (I) and Coq6 (J) on kidney of Coq9+/+, Coq9Q95X and Coq9Q95X mice at 3 months of age. ***P < 0.001; Coq9Q95X and Coq9R239X mice versus Coq9+/+ mice. #P < 0.05; ###P < 0.001; Coq9Q95X versus Coq9R239X mice.K–O mRNA expression levels of Coq9 (K), Coq7 (L), Adck3 (M), Coq5 (N) and Coq6 (O) on triceps surae of Coq9+/+, Coq9Q95X and Coq9Q95X mice at 3 months of age. *P < 0.05; ***P < 0.001; Coq9Q95X and Coq9R239X mice versus Coq9+/+ mice. #P < 0.05; Coq9Q95X versus Coq9R239X mice.Data information: All values are presented as mean ± SD. One-way ANOVA with a Tukey's post hoc test. Numbers above columns indicate P-values of the one-way ANOVA test (n = 5 for each group).
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fig04: CoQ biosynthetic gene expressionA–E mRNA expression levels of Coq9 (A), Coq7 (B), Adck3 (C), Coq5 (D) and Coq6 (E) on cerebrum of Coq9+/+, Coq9Q95X and Coq9Q95X mice at 3 months of age. **P < 0.01; ***P < 0.001; Coq9Q95X and Coq9R239X mice versus Coq9+/+ mice. ###P < 0.001; Coq9Q95X versus Coq9R239X mice.F–J mRNA expression levels of Coq9 (F), Coq7 (G), Adck3 (H), Coq5 (I) and Coq6 (J) on kidney of Coq9+/+, Coq9Q95X and Coq9Q95X mice at 3 months of age. ***P < 0.001; Coq9Q95X and Coq9R239X mice versus Coq9+/+ mice. #P < 0.05; ###P < 0.001; Coq9Q95X versus Coq9R239X mice.K–O mRNA expression levels of Coq9 (K), Coq7 (L), Adck3 (M), Coq5 (N) and Coq6 (O) on triceps surae of Coq9+/+, Coq9Q95X and Coq9Q95X mice at 3 months of age. *P < 0.05; ***P < 0.001; Coq9Q95X and Coq9R239X mice versus Coq9+/+ mice. #P < 0.05; Coq9Q95X versus Coq9R239X mice.Data information: All values are presented as mean ± SD. One-way ANOVA with a Tukey's post hoc test. Numbers above columns indicate P-values of the one-way ANOVA test (n = 5 for each group).

Mentions: In cerebrum and kidney, Coq9 mRNA levels were nearly undetectable in Coq9Q95X compared with Coq9+/+ mice (1 ± 0.38 and 1 ± 0.90%, respectively) and significantly decreased in Coq9R239X compared with Coq9+/+ mice (18 ± 0.38 and 10 ± 0.21%, respectively) (Fig4A and F). Similar levels of Coq7 and Coq5 mRNA expression were detected in cerebrum and kidney of Coq9Q95X, Coq9R239X and Coq9+/+ mice (Fig4B, D, G and I), while Coq6 was significantly decreased (72.1 ± 4.35%) only in cerebrum of Coq9Q95X compared with Coq9+/+ mice (Fig4D); Adck3 was slightly increased in kidney of Coq9R239X compared to Coq9Q95X (116 ± 7.9 versus 85.1 ± 20.6%) (Fig4H). In muscle, Coq9 mRNA levels were similarly decreased in both Coq9Q95X and Coq9R239X (3 ± 0.9 and 0.5 ± 0.2%) compared to Coq9+/+ mice (Fig4K). Moreover, Adck3 and Coq5 mRNA levels were significantly decreased in Coq9Q95X mice compared to Coq9+/+ mice (65.3 ± 11.1% for Adck3 and 77.6 ± 8.9% for Coq5) (Fig4M and N). Comparing the two mutant mice, it is remarkable that Coq9 mRNA expression levels in cerebrum and kidney of Coq9R239X mice were significantly higher compared to Coq9Q95X (18.3 ± 1.6 versus 1.3 ± 0.4% in cerebrum and 10.6 ± 2.2 versus 1.3 ± 0.9% in kidney) (Fig4A and F). In contrast, in muscle, there were no differences in Coq9 mRNA levels between the two mutant models (Fig4K). The degradation of the mutant Coq9 mRNA in both mouse models (Coq9Q95X and Coq9R239X) is due to nonsense-mediated mRNA decay (NMD) since the treatment of mutant MEFs with cyclohexamide, an inhibitor of NMD (Rio Frio et al, 2008), increased the levels of Coq9 mRNA in Coq9Q95X (fold increase 5.5 ± 1.1, treated/untreated) and Coq9R239X (fold increase 21.4 ± 6.8, treated/untreated) compared to the mild effect in Coq9+/+ (fold increase 1.5 ± 0.1, treated/untreated) cells (Table1).


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

Luna-Sánchez M, Díaz-Casado E, Barca E, Tejada MÁ, Montilla-García Á, Cobos EJ, Escames G, Acuña-Castroviejo D, Quinzii CM, López LC - EMBO Mol Med (2015)

CoQ biosynthetic gene expressionA–E mRNA expression levels of Coq9 (A), Coq7 (B), Adck3 (C), Coq5 (D) and Coq6 (E) on cerebrum of Coq9+/+, Coq9Q95X and Coq9Q95X mice at 3 months of age. **P < 0.01; ***P < 0.001; Coq9Q95X and Coq9R239X mice versus Coq9+/+ mice. ###P < 0.001; Coq9Q95X versus Coq9R239X mice.F–J mRNA expression levels of Coq9 (F), Coq7 (G), Adck3 (H), Coq5 (I) and Coq6 (J) on kidney of Coq9+/+, Coq9Q95X and Coq9Q95X mice at 3 months of age. ***P < 0.001; Coq9Q95X and Coq9R239X mice versus Coq9+/+ mice. #P < 0.05; ###P < 0.001; Coq9Q95X versus Coq9R239X mice.K–O mRNA expression levels of Coq9 (K), Coq7 (L), Adck3 (M), Coq5 (N) and Coq6 (O) on triceps surae of Coq9+/+, Coq9Q95X and Coq9Q95X mice at 3 months of age. *P < 0.05; ***P < 0.001; Coq9Q95X and Coq9R239X mice versus Coq9+/+ mice. #P < 0.05; Coq9Q95X versus Coq9R239X mice.Data information: All values are presented as mean ± SD. One-way ANOVA with a Tukey's post hoc test. Numbers above columns indicate P-values of the one-way ANOVA test (n = 5 for each group).
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fig04: CoQ biosynthetic gene expressionA–E mRNA expression levels of Coq9 (A), Coq7 (B), Adck3 (C), Coq5 (D) and Coq6 (E) on cerebrum of Coq9+/+, Coq9Q95X and Coq9Q95X mice at 3 months of age. **P < 0.01; ***P < 0.001; Coq9Q95X and Coq9R239X mice versus Coq9+/+ mice. ###P < 0.001; Coq9Q95X versus Coq9R239X mice.F–J mRNA expression levels of Coq9 (F), Coq7 (G), Adck3 (H), Coq5 (I) and Coq6 (J) on kidney of Coq9+/+, Coq9Q95X and Coq9Q95X mice at 3 months of age. ***P < 0.001; Coq9Q95X and Coq9R239X mice versus Coq9+/+ mice. #P < 0.05; ###P < 0.001; Coq9Q95X versus Coq9R239X mice.K–O mRNA expression levels of Coq9 (K), Coq7 (L), Adck3 (M), Coq5 (N) and Coq6 (O) on triceps surae of Coq9+/+, Coq9Q95X and Coq9Q95X mice at 3 months of age. *P < 0.05; ***P < 0.001; Coq9Q95X and Coq9R239X mice versus Coq9+/+ mice. #P < 0.05; Coq9Q95X versus Coq9R239X mice.Data information: All values are presented as mean ± SD. One-way ANOVA with a Tukey's post hoc test. Numbers above columns indicate P-values of the one-way ANOVA test (n = 5 for each group).
Mentions: In cerebrum and kidney, Coq9 mRNA levels were nearly undetectable in Coq9Q95X compared with Coq9+/+ mice (1 ± 0.38 and 1 ± 0.90%, respectively) and significantly decreased in Coq9R239X compared with Coq9+/+ mice (18 ± 0.38 and 10 ± 0.21%, respectively) (Fig4A and F). Similar levels of Coq7 and Coq5 mRNA expression were detected in cerebrum and kidney of Coq9Q95X, Coq9R239X and Coq9+/+ mice (Fig4B, D, G and I), while Coq6 was significantly decreased (72.1 ± 4.35%) only in cerebrum of Coq9Q95X compared with Coq9+/+ mice (Fig4D); Adck3 was slightly increased in kidney of Coq9R239X compared to Coq9Q95X (116 ± 7.9 versus 85.1 ± 20.6%) (Fig4H). In muscle, Coq9 mRNA levels were similarly decreased in both Coq9Q95X and Coq9R239X (3 ± 0.9 and 0.5 ± 0.2%) compared to Coq9+/+ mice (Fig4K). Moreover, Adck3 and Coq5 mRNA levels were significantly decreased in Coq9Q95X mice compared to Coq9+/+ mice (65.3 ± 11.1% for Adck3 and 77.6 ± 8.9% for Coq5) (Fig4M and N). Comparing the two mutant mice, it is remarkable that Coq9 mRNA expression levels in cerebrum and kidney of Coq9R239X mice were significantly higher compared to Coq9Q95X (18.3 ± 1.6 versus 1.3 ± 0.4% in cerebrum and 10.6 ± 2.2 versus 1.3 ± 0.9% in kidney) (Fig4A and F). In contrast, in muscle, there were no differences in Coq9 mRNA levels between the two mutant models (Fig4K). The degradation of the mutant Coq9 mRNA in both mouse models (Coq9Q95X and Coq9R239X) is due to nonsense-mediated mRNA decay (NMD) since the treatment of mutant MEFs with cyclohexamide, an inhibitor of NMD (Rio Frio et al, 2008), increased the levels of Coq9 mRNA in Coq9Q95X (fold increase 5.5 ± 1.1, treated/untreated) and Coq9R239X (fold increase 21.4 ± 6.8, treated/untreated) compared to the mild effect in Coq9+/+ (fold increase 1.5 ± 0.1, treated/untreated) cells (Table1).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: 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.

No MeSH data available.


Related in: MedlinePlus