Disease relevance of KIF5A

• A kinesin heavy chain (KIF5A) mutation in hereditary spastic paraplegia (SPG10) [1].
• BACKGROUND: To our knowledge, up to now, only 2 mutations in the KIF5A gene, a member of the kinesin superfamily, have been identified as the molecular cause of early-onset autosomal dominant hereditary spastic paraparesis (ADHSP) [2].

High impact information on KIF5A

• 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 [1].
• Analysis of markers on chromosome 12q gave a peak pairwise LOD score of 3.61 at D12S1691, allowing us to assign a new locus for ADPHSP (a locus that we have designated "SPG10") to this region [3].
• Haplotype construction and analysis of recombination events narrowed the SPG10 locus to a 9.2-cM region between markers D12S368 and D12S83 [3].
• KIF5C was also a neuronal KIF5 like KIF5A but was highly expressed in lower motor neurons in 2-week-old or older mice, suggesting its important roles in the maintenance of motor neurons rather than in their formation, such as axonal elongation [4].
• Because three KIF5s showed high similarity in the amino acid sequence, could rescue the KIF5B mutant cells, and could form heterodimers, we think that there are functional redundancy among the three KIF5s and that KIF5A and KIF5B prevented the KIF5C null mice from the severe phenotype [4].

Biological context of KIF5A

• We report a four-generation pedigree segregating an autosomal dominant phenotype for HSP and showing a linkage to the SPG10 locus, coding for Kinesin family member 5A [5].
• CONCLUSIONS: This finding enlarges the phenotypic spectrum of ADHSP linked to KIF5A and enhances the role of that gene in the epidemiology of this disease [2].

Associations of KIF5A with chemical compounds

• We were able to establish a definitive linkage to the SPG10 locus, and sequencing of the KIF5A gene revealed a heterozygous missense mutation 1,035 A>G in exon 10, resulting in tyrosine-to-cysteine substitution [6].

Other interactions of KIF5A

• The C-terminal domains of KIF5B and KIF5C, but not KIF5A, associate directly with importin-beta in a RanGTPase-dependent fashion in vivo and in vitro, indicating importin-beta is an endogenous cargo for a subset of KIF5s in retinal neurons [7].
• We propose that the KIF5A gene should be routinely analyzed in patients with hereditary spastic paraplegia negative for spastin and atlastin mutations [2].
• In conclusion, these data confirm the presence of SPG10 (chromosome 12), potentially reduce the minimum candidate region for SPG12 (chromosome 19q), and suggest there is at least one additional autosomal dominant SPG locus [8].

References