Limits...
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

Effects of oral administration of 2,4-dihydroxybenzoic acid (2,4-diHB) in Coq9+/+, Coq9Q95X and Coq9R239X mice and COQ9R244X patient fibroblastsA, B Kidney CoQ9 levels in Coq9+/+, Coq9Q95X and Coq9R239X mice treated with 2,4-diHB (+2,4-diHB) compared with the non-treated littermate (vehicle). Statistical analysis was performed on +2,4-diHB Coq9+/+, Coq9Q95X and Coq9R239X mice versus vehicle Coq9+/+, Coq9Q95X and Coq9R239X mice, respectively (n = 3 for each group).C, D CoQ10 levels in COQ9R244X skin fibroblasts treated with 2,4-DiHB (+2,4-diHB) compared with the non-treated controls (vehicle). Statistical analysis was performed on +2,4-diHB COQ9R244X versus vehicle COQ9R244X (n = 4 for each group).Data information: Data are expressed as mean ± SD. Student' t-test. +P < 0.05; ++P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4492823&req=5

fig10: Effects of oral administration of 2,4-dihydroxybenzoic acid (2,4-diHB) in Coq9+/+, Coq9Q95X and Coq9R239X mice and COQ9R244X patient fibroblastsA, B Kidney CoQ9 levels in Coq9+/+, Coq9Q95X and Coq9R239X mice treated with 2,4-diHB (+2,4-diHB) compared with the non-treated littermate (vehicle). Statistical analysis was performed on +2,4-diHB Coq9+/+, Coq9Q95X and Coq9R239X mice versus vehicle Coq9+/+, Coq9Q95X and Coq9R239X mice, respectively (n = 3 for each group).C, D CoQ10 levels in COQ9R244X skin fibroblasts treated with 2,4-DiHB (+2,4-diHB) compared with the non-treated controls (vehicle). Statistical analysis was performed on +2,4-diHB COQ9R244X versus vehicle COQ9R244X (n = 4 for each group).Data information: Data are expressed as mean ± SD. Student' t-test. +P < 0.05; ++P < 0.01.

Mentions: As a proof of concept, we also evaluated whether the stability of the CoQ multiprotein complex would affect a possible bypass therapy. For that purpose, we treated Coq9+/+, Coq9Q95X and Coq9R239X mice with oral 2,4-dihydroxybenzoic acid (2,4-diHB), which has been previously tested as a bypass therapy for Δcoq7 Saccharomyces cerevisiae strains (Xie et al, 2012; Doimo et al, 2014). After 1 month of treatment, Coq9Q95X and Coq9+/+ mice showed a reduction of kidney CoQ9 levels compared with the non-treated littermate (Fig10A and B and Supplementary Fig S12A–D). On the contrary, Coq9R239X mice treated with 2,4-diHB exhibited significantly higher levels of CoQ9 (184 ± 9.3%) compared with untreated Coq9R239X mice (Fig10A and B and Supplementary Fig S12E and F). Interestingly, this increase in CoQ9 levels in Coq9R239X mice was also observed in the skin fibroblasts from the patient with the homolog COQ9R244X molecular defect treated with 2,4-diHB (175.8 ± 5.6%), while on control fibroblasts, CoQ10 biosynthesis was inhibited by 2,4-diHB supplementation (Fig10C and D and Supplementary Fig S12G and H).


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)

Effects of oral administration of 2,4-dihydroxybenzoic acid (2,4-diHB) in Coq9+/+, Coq9Q95X and Coq9R239X mice and COQ9R244X patient fibroblastsA, B Kidney CoQ9 levels in Coq9+/+, Coq9Q95X and Coq9R239X mice treated with 2,4-diHB (+2,4-diHB) compared with the non-treated littermate (vehicle). Statistical analysis was performed on +2,4-diHB Coq9+/+, Coq9Q95X and Coq9R239X mice versus vehicle Coq9+/+, Coq9Q95X and Coq9R239X mice, respectively (n = 3 for each group).C, D CoQ10 levels in COQ9R244X skin fibroblasts treated with 2,4-DiHB (+2,4-diHB) compared with the non-treated controls (vehicle). Statistical analysis was performed on +2,4-diHB COQ9R244X versus vehicle COQ9R244X (n = 4 for each group).Data information: Data are expressed as mean ± SD. Student' t-test. +P < 0.05; ++P < 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492823&req=5

fig10: Effects of oral administration of 2,4-dihydroxybenzoic acid (2,4-diHB) in Coq9+/+, Coq9Q95X and Coq9R239X mice and COQ9R244X patient fibroblastsA, B Kidney CoQ9 levels in Coq9+/+, Coq9Q95X and Coq9R239X mice treated with 2,4-diHB (+2,4-diHB) compared with the non-treated littermate (vehicle). Statistical analysis was performed on +2,4-diHB Coq9+/+, Coq9Q95X and Coq9R239X mice versus vehicle Coq9+/+, Coq9Q95X and Coq9R239X mice, respectively (n = 3 for each group).C, D CoQ10 levels in COQ9R244X skin fibroblasts treated with 2,4-DiHB (+2,4-diHB) compared with the non-treated controls (vehicle). Statistical analysis was performed on +2,4-diHB COQ9R244X versus vehicle COQ9R244X (n = 4 for each group).Data information: Data are expressed as mean ± SD. Student' t-test. +P < 0.05; ++P < 0.01.
Mentions: As a proof of concept, we also evaluated whether the stability of the CoQ multiprotein complex would affect a possible bypass therapy. For that purpose, we treated Coq9+/+, Coq9Q95X and Coq9R239X mice with oral 2,4-dihydroxybenzoic acid (2,4-diHB), which has been previously tested as a bypass therapy for Δcoq7 Saccharomyces cerevisiae strains (Xie et al, 2012; Doimo et al, 2014). After 1 month of treatment, Coq9Q95X and Coq9+/+ mice showed a reduction of kidney CoQ9 levels compared with the non-treated littermate (Fig10A and B and Supplementary Fig S12A–D). On the contrary, Coq9R239X mice treated with 2,4-diHB exhibited significantly higher levels of CoQ9 (184 ± 9.3%) compared with untreated Coq9R239X mice (Fig10A and B and Supplementary Fig S12E and F). Interestingly, this increase in CoQ9 levels in Coq9R239X mice was also observed in the skin fibroblasts from the patient with the homolog COQ9R244X molecular defect treated with 2,4-diHB (175.8 ± 5.6%), while on control fibroblasts, CoQ10 biosynthesis was inhibited by 2,4-diHB supplementation (Fig10C and D and Supplementary Fig S12G and H).

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