Copyright © 2002 The American Society of Human Genetics. All rights reserved.
The American Journal of Human Genetics, Volume 71, Issue 5, 1189-1194, 1 November 2002
doi:10.1086/344210
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A Kinesin Heavy Chain (KIF5A) Mutation in Hereditary Spastic Paraplegia (SPG10)
Evan Reid1, 
, 
, Mark Kloos3, Allison Ashley-Koch4, Lori Hughes3, Simon Bevan1, Ingrid K. Svenson3, Felicia Lennon Graham4, Perry C. Gaskell4, Andrew Dearlove2, Margaret A. Pericak-Vance4, David C. Rubinsztein1 and Douglas A. Marchuk3, ,
1 Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, United Kingdom
2 Medical Research Council U.K. Human Genome Mapping Project Resource Centre, Babraham Bioincubator, Cambridge, United Kingdom
3 Department of Molecular Genetics, Duke University Medical Center, Durham, NC Microbiology and
4 Center for Human Genetics, Duke University Medical Center, Durham, NC
Address for correspondence and reprints: Dr. Douglas A. Marchuk, Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710,; or Dr. Evan Reid, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 2XY, United Kingdom,Abstract
We have identified a missense mutation in the motor domain of the neuronal kinesin heavy chain gene KIF5A, in a family with hereditary spastic paraplegia. The mutation occurs in the family in which the SPG10 locus was originally identified, at an invariant asparagine residue that, when mutated in orthologous kinesin heavy chain motor proteins, prevents stimulation of the motor ATPase by microtubule-binding. Mutation of kinesin orthologues in various species leads to phenotypes resembling hereditary spastic paraplegia. The conventional kinesin motor powers intracellular movement of membranous organelles and other macromolecular cargo from the neuronal cell body to the distal tip of the axon. This finding suggests that the underlying pathology of SPG10 and possibly of other forms of hereditary spastic paraplegia may involve perturbation of neuronal anterograde (or retrograde) axoplasmic flow, leading to axonal degeneration, especially in the longest axons of the central nervous system.
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