|
|||||
|
|
ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency |
|
| Authors: | Lagier-Tourenne Clotilde Tazir Meriem López Luis Carlos Quinzii Catarina M Assoum Mirna Drouot Nathalie Busso Cleverson Makri Samira Ali-Pacha Lamia Benhassine Traki Anheim Mathieu Lynch David R Thibault Christelle Plewniak Frédéric Bianchetti Laurent Tranchant Christine Poch Olivier DiMauro Salvatore Mandel Jean-Louis Barros Mario H Hirano Michio Koenig Michel |
| Affiliation: | 1 Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, et Collège de France, Chaire de génétique humaine, 67404 Illkirch, France; Hôpitaux Universitaires de Strasbourg, Strasbourg, F-67000 France 2 Service de Neurologie, Centre Hospitalo-Universitaire Mustapha, Algiers 16000, Algeria 3 Department of Neurology, Columbia University Medical Center, New York, NY 10032 USA 4 Departamento de Microbiologia - ICB-II - Universidade de São Paulo, 05508-900, São Paulo, SP, Brasil 5 Service de Neurologie, Hôpital Ait Idir, Algiers, Algeria 6 Institut Pasteur d'Alger, El Hamma, Algiers, Algeria 7 Service de Neurologie, Hôpitaux Universitaires de Strasbourg, 67091 Strasbourg, France 8 Department of Neurology, University of Pennsylvania School of Medicine and Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA |
| Abstract: | Muscle coenzyme Q(10) (CoQ(10) or ubiquinone) deficiency has been identified in more than 20 patients with presumed autosomal-recessive ataxia. However, mutations in genes required for CoQ(10) biosynthetic pathway have been identified only in patients with infantile-onset multisystemic diseases or isolated nephropathy. Our SNP-based genome-wide scan in a large consanguineous family revealed a locus for autosomal-recessive ataxia at chromosome 1q41. The causative mutation is a homozygous splice-site mutation in the aarF-domain-containing kinase 3 gene (ADCK3). Five additional mutations in ADCK3 were found in three patients with sporadic ataxia, including one known to have CoQ(10) deficiency in muscle. All of the patients have childhood-onset cerebellar ataxia with slow progression, and three of six have mildly elevated lactate levels. ADCK3 is a mitochondrial protein homologous to the yeast COQ8 and the bacterial UbiB proteins, which are required for CoQ biosynthesis. Three out of four patients tested showed a low endogenous pool of CoQ(10) in their fibroblasts or lymphoblasts, and two out of three patients showed impaired ubiquinone synthesis, strongly suggesting that ADCK3 is also involved in CoQ(10) biosynthesis. The deleterious nature of the three identified missense changes was confirmed by the introduction of them at the corresponding positions of the yeast COQ8 gene. Finally, a phylogenetic analysis shows that ADCK3 belongs to the family of atypical kinases, which includes phosphoinositide and choline kinases, suggesting that ADCK3 plays an indirect regulatory role in ubiquinone biosynthesis possibly as part of a feedback loop that regulates ATP production. |
| Keywords: | |
| 本文献已被 ScienceDirect PubMed 等数据库收录！ | |
