CABC1 Gene Mutations Cause Ubiquinone Deficiency with Cerebellar Ataxia and Seizures

Abstract

Coenzyme Q(10) (CoQ(10)) plays a pivotal role in oxidative phosphorylation (OXPHOS) in that it distributes electrons between the various dehydrogenases and the cytochrome segments of the respiratory chain. Primary coenzyme Q(10) deficiency represents a clinically heterogeneous condition suggestive of genetic heterogeneity, and several disease genes have been previously identified. The CABC1 gene, also called COQ8 or ADCK3, is the human homolog of the yeast ABC1/COQ8 gene, one of the numerous genes involved in the ubiquinone biosynthesis pathway. The exact function of the Abc1/Coq8 protein is as yet unknown, but this protein is classified as a putative protein kinase. We report here CABC1 gene mutations in four ubiquinone-deficient patients in three distinct families. These patients presented a similar progressive neurological disorder with cerebellar atrophy and seizures. In all cases, enzymological studies pointed to ubiquinone deficiency. CoQ(10) deficiency was confirmed by decreased content of ubiquinone in muscle. Various missense mutations (R213W, G272V, G272D, and E551K) modifying highly conserved amino acids of the protein and a 1 bp frameshift insertion c.[1812_1813insG] were identified. The missense mutations were introduced into the yeast ABC1/COQ8 gene and expressed in a Saccharomyces cerevisiae strain in which the ABC1/COQ8 gene was deleted. All the missense mutations resulted in a respiratory phenotype with no or decreased growth on glycerol medium and a severe reduction in ubiquinone synthesis, demonstrating that these mutations alter the protein function.

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

“…The Th584del has been previously described in patients with cerebellar ataxia (LagierTourenne and Tazir 2008), but the P602R mutation is novel (Lagier-Tourenne and Tazir 2008; Mollet et al 2008;Gerards et al 2010;Horvath et al 2012). The pathogenicity of the P602R is supported by a substitution of a neutral amino acid by a basic one, conservation of Proline602 among species and prediction as disease causing by three softwares.…”

“…Only 22 patients with ADCK3-associated cerebellar ataxia have been reported since the first publications in 2008 (Lagier-Tourenne and Tazir 2008; Mollet et al 2008;Gerards et al 2010;Horvath et al 2012).…”

“…Other findings include stroke-like lesions (Mollet et al 2008), pontine atrophy (Gerards et al 2010), thin corpus callosum, and ventricular enlargement (Horvath et al 2012).…”

A mechanism implicating plastoglobules in thylakoid disassembly during senescence and nitrogen starvation

“…In bacteria, the ubiB gene homolog of ABC1 is required for the first monooxygenase step in ubiquinone synthesis (Poon et al 2000). In humans, mutation of an ABC1-like homolog leads to neuromuscular defects such as ataxia (Mollet et al 2008). Recently, two putative kinases have been characterized in Arabidopsis: AtOSA1 (Arabidopsis oxidative stress related ABC1-like protein, At5g64940) localized at the chloroplast inner envelope membrane (Jasinski et al 2008) and AtACDO1 (ABC1-like kinase related to chlorophyll degradation and oxidative stress, At4g31390) (Yang et al 2012).…”

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).…”