ADCK3, an Ancestral Kinase, Is Mutated in a Form of Recessive Ataxia Associated with Coenzyme Q10 Deficiency

Abstract

Muscle coenzyme Q(10) (CoQ(10) or ubiquinone) deficiency has been identified in more than 20 patients with presumed autosomal-recessive ataxia. However, mutations in genes required for CoQ(10) biosynthetic pathway have been identified only in patients with infantile-onset multisystemic diseases or isolated nephropathy. Our SNP-based genome-wide scan in a large consanguineous family revealed a locus for autosomal-recessive ataxia at chromosome 1q41. The causative mutation is a homozygous splice-site mutation in the aarF-domain-containing kinase 3 gene (ADCK3). Five additional mutations in ADCK3 were found in three patients with sporadic ataxia, including one known to have CoQ(10) deficiency in muscle. All of the patients have childhood-onset cerebellar ataxia with slow progression, and three of six have mildly elevated lactate levels. ADCK3 is a mitochondrial protein homologous to the yeast COQ8 and the bacterial UbiB proteins, which are required for CoQ biosynthesis. Three out of four patients tested showed a low endogenous pool of CoQ(10) in their fibroblasts or lymphoblasts, and two out of three patients showed impaired ubiquinone synthesis, strongly suggesting that ADCK3 is also involved in CoQ(10) biosynthesis. The deleterious nature of the three identified missense changes was confirmed by the introduction of them at the corresponding positions of the yeast COQ8 gene. Finally, a phylogenetic analysis shows that ADCK3 belongs to the family of atypical kinases, which includes phosphoinositide and choline kinases, suggesting that ADCK3 plays an indirect regulatory role in ubiquinone biosynthesis possibly as part of a feedback loop that regulates ATP production.

Heterozygous Mutations in the ADCK3 Gene in Siblings with Cerebellar Atrophy and Extreme Phenotypic Variability

“…There is no explanation for the phenotypic variations in the reported patients and no correlation has been found between the degree of mitochondrial dysfunction and the disease severity as demonstrated by serum lactate, mitochondrial morphology in muscle biopsy, or respiratory chain activity in muscle, fibroblasts, and lymphocytes (Aure and Benoist 2004;Lagier-Tourenne and Tazir 2008;Mollet et al 2008;Horvath et al 2012). There must be other factors, either genetic or environmental, that influence the phenotypic expression.…”

Coenzyme Q protects Caenorhabditis elegans GABA neurons from calcium-dependent degeneration

“…CoQ also limits the production of reactive oxygen species that can damage cellular processes. Human patients with CoQ deficiency exhibit diverse symptoms ranging in severity from infantile multiorgan disease (13,14) to discrete late onset cerebellar ataxia (15,16). Although the essential role of CoQ in mitochondrial energy production and cell survival are likely to account for these deficits, the molecular basis for this heterogeneity is unclear, as are the specific cellular pathologies arising from CoQ deficiency (17).…”

How Can We Treat Mitochondrial Encephalomyopathies? Approaches to Therapy

“…59 Because there is no known effective therapy in these neurodegenerative disorders and no documented side ef-fects up to 3000 mg/day CoQ10, a trial of high-dose CoQ10 supplementation might be useful in clinical practice. 60 Pathogenic mutations in the aprataxin gene (APTX) 61 and very recently in the CABC1 gene (alias ADCK3) 62 were reported in patients with CoQ10 responsive ataxia. In these patients, muscle CoQ10 is mildly decreased, but the RC enzymes usually show normal activities and muscle biopsy does not provide histological evidence of a mitochondrial involvement.…”