Mutant dynactin in motor neuron disease

Nat Genet. 2003 Apr;33(4):455-6. doi: 10.1038/ng1123.

Imke Puls ¹, Catherine Jonnakuty, Bernadette H LaMonte, Erika L F Holzbaur, Mariko Tokito, Eric Mann, Mary Kay Floeter, Kimberly Bidus, Dennis Drayna, Shin J Oh, Robert H Brown Jr, Christy L Ludlow, Kenneth H Fischbeck

Affiliations

Affiliation

1 Neurogenetics Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892, USA. pulsi@ninds.nih.gov

PMID: 12627231 DOI: 10.1038/ng1123

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.

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