title: Nonsense mutations in CABC1/ADCK3 cause progressive cerebellar ataxia and atrophy.
abstract: Hereditary ataxias are genetic disorders characterized by uncoordinated gait and often poor coordination of hands, speech, and eye movements. Frequently, atrophy of the cerebellum occurs. Many ataxias are autosomal dominant, but autosomal recessive (AR) disease occurs as well. Homozygosity mapping in a consanguineous family with three affected children with progressive cerebellar ataxia and atrophy revealed a candidate locus on chromosome 1, containing the CABC1/ADCK3 (the chaperone, ABC1 activity of bc1 complex homologue) gene. CABC1/ADCK3 is the homologue of the yeast Coq8 gene, which is involved in the ubiquinone biosynthesis pathway. Mutation analysis of this gene showed a homozygous nonsense mutation (c.1042C>T, p.R348X). Eight additional patients with AR cerebellar ataxia and atrophy were screened for mutations in the CABC1/ADCK3 gene. One patient was compound heterozygous for the same c.1042C>T mutation and a second nonsense mutation (c.1136T>A, p.L379X). Both mutations created a premature stop codon, triggering nonsense mediated mRNA decay as the pathogenic mechanism. We found no evidence of a Dutch founder for the c.1042C>T mutation in AR ataxia. We report here the first nonsense mutations in CABC1 that most likely lead to complete absence of a functional CABC1 protein. Our results indicate that CABC1 is an important candidate for mutation analysis in progressive cerebellar ataxia and atrophy on MRI to identify those patients, who may benefit from CoQ10 treatment.
authors.affiliation: Department of Genetics and Cell Biology, Unit Clinical Genomics Maastricht University, Maastricht, The Netherlands.
authors.forename: Mike
authors.initials: M
authors.lastname: Gerards
authors.forename: Bianca
authors.initials: B
authors.lastname: van den Bosch
authors.forename: Chantal
authors.initials: C
authors.lastname: Calis
authors.forename: Kees
authors.initials: K
authors.lastname: Schoonderwoerd
authors.forename: Klaartje
authors.initials: K
authors.lastname: van Engelen
authors.forename: Marina
authors.initials: M
authors.lastname: Tijssen
authors.forename: René
authors.initials: R
authors.lastname: de Coo
authors.forename: Anneke
authors.initials: A
authors.lastname: van der Kooi
authors.forename: Hubert
authors.initials: H
authors.lastname: Smeets
mesh_terms: D001284:Atrophy; D002524:Cerebellar Ataxia; D002531:Cerebellum / Q000473:pathology*; D018389:Codon, Nonsense / Q000235:genetics; D005260:Female; D006801:Humans; D008297:Male; D024101:Mitochondrial Proteins / Q000172:deficiency*; D020871:RNA Stability
chemical_list: C553453:COQ8A protein, human; D018389:Codon, Nonsense; D024101:Mitochondrial Proteins