title: A novel mutation of aprataxin associated with ataxia ocular apraxia type 1: phenotypical and genotypical characterization.
abstract: Ataxia oculomotor apraxia type 1 (AOA1) is the most common form of autosomal recessive ataxia in Japan, and the second in Portugal after Friedreich ataxia. AOA1 is typically characterized by early-onset cerebellar ataxia, oculomotor apraxia, hypoalbuminemia, hypercholesterolemia and late axonal sensori-motor neuropathy. AOA1 is associated with the aprataxin gene (APTX) encoding a protein involved in DNA repair. We characterized a novel homozygous missense mutation of APTX in a 34 year-old female patient born from consanguineous parents. The mutation, a Val230Gly caused by a c.689 T>G substitution, involved the histidine-triad (HIT) domain of the protein, affected a phylogenetically conserved amino acid and was absent in the control population. We described the clinical and neurophysiological features, the findings at structural and functional brain imaging, and the pathological picture of the sural nerve biopsy. The report emphasized the genetical and phenotypical heterogeneity of AOA1 by demonstrating atypical features such as absence of oculomotor apraxia and signs of pyramidal involvement. Expression studies by Western blotting on fibroblasts demonstrated that the homozygous Val230Gly mutation was associated with decreased levels of APTX indicating a loss-of-function mechanism.
authors.affiliation: Section of Clinical Neurology, Department of Neurological and Visual Sciences, University of Verona, Italy.
authors.forename: Moreno
authors.initials: M
authors.lastname: Ferrarini
authors.forename: Giovanna
authors.initials: G
authors.lastname: Squintani
authors.forename: Tiziana
authors.initials: T
authors.lastname: Cavallaro
authors.forename: Sergio
authors.initials: S
authors.lastname: Ferrari
authors.forename: Nicolo'
authors.initials: N
authors.lastname: Rizzuto
authors.forename: Gian Maria
authors.initials: GM
authors.lastname: Fabrizi
mesh_terms: D000328:Adult; D020269:Alcoholic Neuropathy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D019943:Amino Acid Substitution; D001072:Apraxias / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D001284:Atrophy / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D002531:Cerebellum / Q000473:pathology / Q000503:physiopathology; D003241:Consanguinity; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics*; D004569:Electroencephalography; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008279:Magnetic Resonance Imaging; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D015835:Ocular Motility Disorders / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D010375:Pedigree; D010641:Phenotype; D049268:Positron-Emission Tomography
chemical_list: C438188:APTX protein, human; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins