title: Mutant dynactin in motor neuron disease.
abstract: Impaired axonal transport in motor neurons has been proposed as a mechanism for neuronal degeneration in motor neuron disease. Here we show linkage of a lower motor neuron disease to a region of 4 Mb at chromosome 2p13. Mutation analysis of a gene in this interval that encodes the largest subunit of the axonal transport protein dynactin showed a single base-pair change resulting in an amino-acid substitution that is predicted to distort the folding of dynactin's microtubule-binding domain. Binding assays show decreased binding of the mutant protein to microtubules. Our results show that dysfunction of dynactin-mediated transport can lead to human motor neuron disease.
authors.affiliation: Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA. pulsi@ninds.nih.gov
authors.forename: Imke
authors.initials: I
authors.lastname: Puls
authors.forename: Catherine
authors.initials: C
authors.lastname: Jonnakuty
authors.forename: Bernadette H
authors.initials: BH
authors.lastname: LaMonte
authors.forename: Erika L F
authors.initials: EL
authors.lastname: Holzbaur
authors.forename: Mariko
authors.initials: M
authors.lastname: Tokito
authors.forename: Eric
authors.initials: E
authors.lastname: Mann
authors.forename: Mary Kay
authors.initials: MK
authors.lastname: Floeter
authors.forename: Kimberly
authors.initials: K
authors.lastname: Bidus
authors.forename: Dennis
authors.initials: D
authors.lastname: Drayna
authors.forename: Shin J
authors.initials: SJ
authors.lastname: Oh
authors.forename: Robert H
authors.initials: RH
authors.lastname: Brown
authors.forename: Christy L
authors.initials: CL
authors.lastname: Ludlow
authors.forename: Kenneth H
authors.initials: KH
authors.lastname: Fischbeck
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D001692:Biological Transport; D002503:Centromere / Q000378:metabolism; D002889:Chromosomes, Human, Pair 2; D003001:Cloning, Molecular; D004330:Drosophila; D000072159:Dynactin Complex; D008040:Genetic Linkage; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D008870:Microtubules / Q000378:metabolism; D008957:Models, Genetic; D008958:Models, Molecular; D016472:Motor Neuron Disease / Q000235:genetics*; D009154:Mutation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D011995:Recombination, Genetic
chemical_list: D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins