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. 2008 Mar;82(3):623-30.
doi: 10.1016/j.ajhg.2007.12.022.

CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures

Julie Mollet  1 , Agnès Delahodde, Valérie Serre, Dominique Chretien, Dimitri Schlemmer, Anne Lombes, Nathalie Boddaert, Isabelle Desguerre, Pascale de Lonlay, Hélène Ogier de Baulny, Arnold Munnich, Agnès Rötig
Affiliations

CABC1 gene mutations cause ubiquinone deficiency with cerebellar ataxia and seizures

Julie Mollet et al. Am J Hum Genet. 2008 Mar.

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.

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Figures

Figure 1
Figure 1
Brain MRI of Patients 1 and 2 The sagittal T1 showed an important cerebellar atrophy in both patients. The axial T2 also revealed abnormal hyperintensities in the posterior cerebral regions. The diffusion-weighted imaging (DWI) showed a normal apparent diffusion coefficient in these posterior regions. These abnormalities were interpreted as a stroke-like episode.
Figure 2
Figure 2
Pedigree and Haplotype Analysis in a Multiplex Family: Patients 2 and 3 Haplotypes are given (top to bottom) for loci D1S439, D1S479, CDC42BPA, D1S2805, and D1S225.
Figure 3
Figure 3
Sequence analysis of the CABC1 gene in patients 1–4 (upper panel) and sequence alignment of the CABC1 proteins from human and non-human sources (lower panel). The arrows indicate the various mutations
Figure 4
Figure 4
Functional Analysis of CABC1 Mutations (A) Functional complementation of the yeast abc1/coq8 null mutant. Growth of abc1/coq8 null mutant on either glucose (WO-HAT 20 g/liter glucose) or glycerol medium was compared (YPGly, 20 g/liter glycerol). The yeast Δabc1/coq8 null mutant was transformed with the wild-type (wt), R77W, G130V, G130D, and E409K mutant ABC1/COQ8 yeast genes cloned in pFL44 plasmid. The four spots for each experiment correspond to decreasing dilutions of transformed yeasts. (B) Quinone content in transformed Δabc1/coq8 null mutants. CoQ6 content was measured by mass spectrometry and expressed as CoQ6/CoQ10. CoQ10 was used as an internal standard.
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