title: Familial amyotrophic lateral sclerosis is associated with a mutation in D-amino acid oxidase.
abstract: We report a unique mutation in the D-amino acid oxidase gene (R199W DAO) associated with classical adult onset familial amyotrophic lateral sclerosis (FALS) in a three generational FALS kindred, after candidate gene screening in a 14.52 cM region on chromosome 12q22-23 linked to disease. Neuronal cell lines expressing R199W DAO showed decreased viability and increased ubiquitinated aggregates compared with cells expressing the wild-type protein. Similarly, lentiviral-mediated expression of R199W DAO in primary motor neuron cultures caused increased TUNEL labeling. This effect was also observed when motor neurons were cocultured on transduced astrocytes expressing R199W, indicating that the motor neuron cell death induced by this mutation is mediated by both cell autonomous and noncell autonomous processes. DAO controls the level of D-serine, which accumulates in the spinal cord in cases of sporadic ALS and in a mouse model of ALS, indicating that this abnormality may represent a fundamental component of ALS pathogenesis.
authors.affiliation: Department of Cellular and Molecular Neuroscience, Division of Neuroscience and Mental Health, Faculty of Medicine, Imperial College London, Hammersmith Hospital Campus, London W12 0NN, United Kingdom.
authors.forename: John
authors.initials: J
authors.lastname: Mitchell
authors.forename: Praveen
authors.initials: P
authors.lastname: Paul
authors.forename: Han-Jou
authors.initials: HJ
authors.lastname: Chen
authors.forename: Alex
authors.initials: A
authors.lastname: Morris
authors.forename: Miles
authors.initials: M
authors.lastname: Payling
authors.forename: Mario
authors.initials: M
authors.lastname: Falchi
authors.forename: James
authors.initials: J
authors.lastname: Habgood
authors.forename: Stefania
authors.initials: S
authors.lastname: Panoutsou
authors.forename: Sabine
authors.initials: S
authors.lastname: Winkler
authors.forename: Veronica
authors.initials: V
authors.lastname: Tisato
authors.forename: Amin
authors.initials: A
authors.lastname: Hajitou
authors.forename: Bradley
authors.initials: B
authors.lastname: Smith
authors.forename: Caroline
authors.initials: C
authors.lastname: Vance
authors.forename: Christopher
authors.initials: C
authors.lastname: Shaw
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Mazarakis
authors.forename: Jacqueline
authors.initials: J
authors.lastname: de Belleroche
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000201:enzymology* / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D003605:D-Amino-Acid Oxidase / Q000235:genetics* / Q000502:physiology*; D005260:Female; D008040:Genetic Linkage; D008297:Male; D051379:Mice; D018895:Microsatellite Repeats; D009046:Motor Neurons / Q000378:metabolism; D009154:Mutation; D019636:Neurodegenerative Diseases / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D051381:Rats
chemical_list: D003605:D-Amino-Acid Oxidase