A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10)

Evan Reid, Mark Kloos, Allison Ashley-Koch, Lori Hughes, Simon Bevan, Ingrid K. Svenson, Felicia Lennon Graham, Perry C. Gaskell, Andrew Dearlove, Margaret A. Pericak-Vance, David C. Rubinsztein, Douglas A. Marchuk

Research output: Contribution to journalArticle

368 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1189-1194
Number of pages6
JournalAmerican journal of human genetics
Volume71
Issue number5
DOIs
StatePublished - 2002

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Reid, E., Kloos, M., Ashley-Koch, A., Hughes, L., Bevan, S., Svenson, I. K., Graham, F. L., Gaskell, P. C., Dearlove, A., Pericak-Vance, M. A., Rubinsztein, D. C., & Marchuk, D. A. (2002). A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10). American journal of human genetics, 71(5), 1189-1194. https://doi.org/10.1086/344210