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.