Nonsense mutations in CABC1/ADCK3 cause progressive cerebellar ataxia and atrophy

Mike Gerards, Bianca van den Bosch, Chantal Calis, Kees Schoonderwoerd, Klaartje van Engelen, Marina Tijssen, René de Coo, Anneke van der Kooi, Hubert Smeets*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)510-515
Number of pages6
JournalMitochondrion
Volume10
Issue number5
DOIs
Publication statusPublished - Aug 2010

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