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

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.

Figure 1

Electropherograms of sequences in the motor domain of the KIF5A gene. The affected individual from the family in which the SPG10 locus was originally identified (Reid et al. 1999, 2001) has both A (wild-type) and G (mutant) at nucleotide 767. The mutation changes the invariant asparagine at position 256 to a serine in the switch II loop/helix region (see fig. 3).

Figure 2

Cosegregation of the A767G mutation with the spastic paraplegia phenotype in the family in which the SPG10 locus was originally identified (Reid et al. 1999, 2001). Standard pedigree symbols are used. Genotypes at the mutation are listed as either wild-type A/A or heterozygous mutant A/G.

Figure 3

Kinesin protein homologies in the motor region. Multiple alignment showing conserved residues (shaded), nucleotide-binding motifs Switch I (Sw I) and Switch II (Sw II), and the switch II loop/helix region (Sack et al. ; Song et al. 2001). Identical residues are shaded in dark gray, strongly similar residues in medium gray, and weakly similar residues in light gray. The KIF5A mutation in the family with SPG10, as well as the NCD and KAR3 mutations, are indicated by the arrow. Sequence alignments of the various kinesin proteins were performed using ClustalW (Thompson et al. ; EMBL-EBI European Bioinformatics Institute Web site).