¹The Wellcome Trust Centre For Human Genetics, University of Oxford, UK

²Neurologische Klinik, Ludwig-Maximilians-Universität, Munich, Germany

³DIBIT, HSR Scientific Park, Human Molecular Genetics Unit 2A3, Milan, Italy

⁴St George's and Atkinson Morley's Hospitals, London, UK

⁵Department of Molecular Pathogenesis, Institute of Neurology, London, UK

⁶Department of Neurosciences, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

⁷Neurometabolic Unit, Institute of Neurological Sciences, University of Siena, Italy

⁸Department of Neurology, Gunma University School of Medicine, Maebashi, Japan

⁹Mount Sinai School of Medicine, New York, NY and Allergan, Inc, Irvine, CA, USA

¹⁰National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, USA

¹¹Inherited Cardiac Disease Section, Cardiovascular Branch, National Heart Lung and Blood Institute, Bethesda, USA

¹²Department of Neurology, University of Ulm, Ulm, Germany

¹³Department of Clinical Genetics, Royal Liverpool Children's Hospital (Alder Hey), Liverpool, UK

¹⁴Department of Neurology, Pinderfields Hospital, Wakefield, UK

¹⁵Federation of Clinical Neurosciences, Hôpital Pellegrin, Bordeaux, France

¹⁶Federal University of Santa Catarina, Brazil

¹⁷Department of Neurology, University of Miami School of Medicine, Miami, USA

¹⁸Sección de Neurología, Hospital de Conxo, Complexo Hospitalario Universitario, Santiago de Compostela, Spain

¹⁹Department of Neurology, University Hospital, Trondheim, Norway

²⁰Klinik und Poliklinik für Neurologie, Charité, Humboldt-Universität, Berlin, Germany

²¹Department of Neurology, Medical School Hannover, Germany

²²Psychiatrische Klinik Oberwil, Oberwil, Switzerland

²³Istituto Nazionale Neurologico "C. Besta", Milan, Italy

²⁴Department of Human Genetics, Hadassah University Hospital, Jerusalem, Israel

²⁵Department of Neurology, Hadassah University Hospital, Jerusalem, Israel

²⁶Akershus Universitetssykehus, Nordbyhagen, Norway

²⁷Facultad de Medicina, Universidad de Buenos Aires, Argentina

²⁸Faculty of Sciences of the Movement, University of Naples "Parthenope", Naples, Italy

²⁹Center for Research in Neurosciences, McGill University and the McGill University Health Center Research Institute, Montreal, Canada

³⁰Neurologische Klinik, Christian-Albrechts-Universität zu Kiel, Kiel, Germany

³¹Servicio de Neurología, Hospital Universitario, La Paz, Madrid, Spain

³²Reta Lila Weston Institute for Neurological Studies, Royal free and UCL School of Medicine, Windeyer Medical Institute, London, UK

³³Department of Neurology, CHU Rangueil, Toulouse, France

³⁴Unité des Troubles du Mouvement André-Barbeau, CHUM Hotel-Dieu, Montréal, Canada

³⁵Department of Clinical Genetics, Churchill Hospital, Oxford, UK

Correspondence to: A P Monaco, The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Headington, Oxford, OX3 7BN, UK. Tel: +44 1865 287502; Fax: +44 1865 287650; E-mail; anthony.monaco@well.ox.ac.uk

Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder whose characteristic features include hyperkinetic movements and abnormal red blood cell morphology. Mutations in the CHAC gene on 9q21 were recently found to cause chorea-acanthocytosis. CHAC encodes a large, novel protein with a yeast homologue implicated in protein sorting. In this study, all 73 exons plus flanking intronic sequence in CHAC were screened for mutations by denaturing high-performance liquid chromatography in 43 probands with ChAc. We identified 57 different mutations, 54 of which have not previously been reported, in 39 probands. The novel mutations comprise 15 nonsense, 22 insertion/deletion, 15 splice-site and two missense mutations and are distributed throughout the CHAC gene. Three mutations were found in multiple families within this or our previous study. The preponderance of mutations that are predicted to cause absence of gene product is consistent with the recessive inheritance of this disease. The high proportion of splice-site mutations found is probably a reflection of the large number of exons that comprise the CHAC gene. The CHAC protein product, chorein, appears to have a certain tolerance to amino-acid substitutions since only two out of nine substitutions described here appear to be pathogenic.

European Journal of Human Genetics (2002) 10, 773-781. doi:10.1038/sj.ejhg.5200866

choreoacanthocytosis; neuroacanthocytosis; mutational spectrum; CHAC; chorein