Pathogenicity of two COQ7 mutations and responses to 2,4‐dihydroxybenzoate bypass treatment

Abstract

Primary ubiquinone (co‐enzyme Q) deficiency results in a wide range of clinical features due to mitochondrial dysfunction. Here, we analyse and characterize two mutations in the ubiquinone biosynthetic gene COQ7. One mutation from the only previously identified patient (V141E), and one (L111P) from a 6‐year‐old girl who presents with spasticity and bilateral sensorineural hearing loss. We used patient fibroblast cell lines and a heterologous expression system to show that both mutations lead to loss of protein stability and decreased levels of ubiquinone that correlate with the severity of mitochondrial dysfunction. The severity of L111P is enhanced by the particular COQ7 polymorphism (T103M) that the patient carries, but not by a mitochondrial DNA mutation (A1555G) that is also present in the patient and that has been linked to aminoglycoside‐dependent hearing loss. We analysed treatment with the unnatural biosynthesis precursor 2,4‐dihydroxybenzoate (DHB), which can restore ubiquinone synthesis in cells completely lacking the enzymatic activity of COQ7. We find that the treatment is not beneficial for every COQ7 mutation and its outcome depends on the extent of enzyme activity loss.

β‐ RA reduces DMQ /CoQ ratio and rescues the encephalopathic phenotype in Coq9 R239X mice

“…In either case, our data on the Coq9 R239X mouse model together with those obtained in the Coq7 conditional KO model indicate that it is possible to influence the CoQ biosynthesis in vivo with the use of the appropriated 4-HB analog(s). These results partially corroborate previous data in vitro using mutant yeasts and human skin fibroblasts derived from patients with primary CoQ deficiency (Ozeir et al, 2011;Xie et al, 2012;Doimo et al, 2014;Freyer et al, 2015;Luna-Sanchez et al, 2015;Herebian et al, 2017b,c;Pierrel, 2017;Wang et al, 2017).…”

“…Consistent with those results, 4‐HB or vanillic acid induced an increase of the CoQ biosynthetic protein in vitro (Herebian et al , ,c). Moreover, we must also consider that the β‐RA administration was able to increase the levels of CoQ 9 in renal and cardiac mitochondria, as well as in muscle tissue in a conditional Coq7 KO model, which lacks COQ7 protein (Wang et al , , ). Nevertheless, the cerebral CoQ 9 levels after β‐RA supplementation were not determined in the conditional Coq7 KO mice (Wang et al , , ).…”

“…Those differences may reflect the diverse structure and functionality of the mitochondria in different organisms, tissues, and cell types (Vafai & Mootha, 2012). Thus, our study points out the importance of the DMQ 9 /CoQ 9 ratio in the disease phenotype, a fact that is further supported by several evidences: (i) The Coq9 Q95X mouse model has low levels of DMQ 9 and higher levels of CoQ biosynthetic proteins (compared to the Coq9 R239X muse model), and the lifespan is not compromised; (ii) the treatment with ubiquinol-10 in Coq9 R239X mice does not change the DMQ 9 levels and its therapeutic effects are significantly lower than those after b-RA treatment; (iii) the reduction in the DMQ 9 levels in the Coq7 conditional KO mice after b-RA therapy may also contribute to the increased survival observed in this mouse model, although the phenotype of this mouse model is not clear (Wang et al, 2015); and (iv) patients with high levels of DMQ 10 in the samples used for the diagnostic (muscle and/or skin fibroblasts) are associated to severe clinical presentations (Duncan et al, 2009;Freyer et al, 2015;Danhauser et al, 2016;Wang et al, 2017;Smith et al, 2018).…”

“…The therapeutic results are greater than those obtained by the classical oral CoQ supplementation because of the decrease of the DMQ/CoQ ratio. Therefore, b-RA should be preferentially considered for the treatment of human CoQ 10 deficiency with accumulation of DMQ 10 , as it has been reported in patients with mutations in COQ9, COQ7, or COQ4 (Duncan et al, 2009;Freyer et al, 2015;Danhauser et al, 2016;Herebian et al, 2017b;Wang et al, 2017;Smith et al, 2018) but also in cells under siRNA knockdown of COQ3, COQ5 and COQ6 (Herebian et al, 2017b). Similar principles could be applied for 3,4-hydroxybenzoic acid, vanillic acid, 2-methyl-4-hydroxybenzoic acid, or 2,3-dimethoxy-4hydroxybenzoic acid in the cases of mutations in COQ6, COQ5, or COQ3 (Heeringa et al, 2011;Yoo et al, 2012;Ribas et al, 2014;Gigante et al, 2017;Herebian et al, 2017a;Pierrel, 2017), respectively.…”

Hereditary spastic paraplegia: from diagnosis to emerging therapeutic approaches

“…These include adrenoleukodystophy (ABCD1), 57 arginase deficiency (ARG1), 58 cerebrotendinous xanthomatosis (CYP27A1), 59 dopa-responsive dystonia (GCH1, TH, and other genes), 60 phenylketonuria (PAH), 61 biotinidase deficiency (BTD), 62 cobalamin-related remethylation disorders, 63 methylenetetrahydrofolate reductase deficiency (MTHFR), 64 and primary coenzyme Q10 deficiencies. 65…”