TY - JOUR
T1 - Nonsense mutations in CABC1/ADCK3 cause progressive cerebellar ataxia and atrophy
AU - Gerards, Mike
AU - van den Bosch, Bianca
AU - Calis, Chantal
AU - Schoonderwoerd, Kees
AU - van Engelen, Klaartje
AU - Tijssen, Marina
AU - de Coo, René
AU - van der Kooi, Anneke
AU - Smeets, Hubert
N1 - Funding Information: This work was supported by a EU grant to the MitoCircle Project (Sixth Framework Program, contr. No. 005260). Copyright: Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2010/8
Y1 - 2010/8
N2 - 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.
AB - 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.
KW - Ataxia
KW - Atrophy
KW - CABC1
KW - CoQ10
KW - Mutation
KW - NMD
UR - http://www.scopus.com/inward/record.url?scp=77955424107&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.mito.2010.05.008
DO - https://doi.org/10.1016/j.mito.2010.05.008
M3 - Article
C2 - 20580948
SN - 1567-7249
VL - 10
SP - 510
EP - 515
JO - Mitochondrion
JF - Mitochondrion
IS - 5
ER -