Mutant dynactin in motor neuron disease.
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.
Puls
Imke
I
Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA. pulsi@ninds.nih.gov
Jonnakuty
Catherine
C
LaMonte
Bernadette H
BH
Holzbaur
Erika L F
EL
Tokito
Mariko
M
Mann
Eric
E
Floeter
Mary Kay
MK
Bidus
Kimberly
K
Drayna
Dennis
D
Oh
Shin J
SJ
Brown
Robert H
RH
Ludlow
Christy L
CL
Fischbeck
Kenneth H
KH
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
D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins