Abstract
Autosomal dominant hereditary spastic paraplegia (AD HSP) linked to chromosome 12q (SPG10) is caused by mutations in the neuronal kinesin heavy-chain KIF5A gene. This is a rare cause of AD HSP, and only two disease-causing mutations have been reported thus far. In both instances, affected individuals harboring mutations in the KIF5A gene displayed symptom onset at a very early age. Here we present the results of clinical and genetic analyses of a large kindred with uncomplicated AD HSP. 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. This mutation is located in a highly conserved kinesin motor domain of the neuronal kinesin heavy-chain protein, but in contrast to two previously reported missense mutations, the age of symptom onset in our family was much later, with an average age of 36.1±4 years. Our results demonstrate that mutations in the KIF5A gene can also be associated with an adult age of onset of AD HSP.
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Acknowledgements
We thank the members of the family described here, whose help and participation made this work possible. This work was supported by the National Institutes of Health (grant K08NS42743) and the Spastic Paraplegia Foundation (P.H.), and in part by GCRC grant RR00095 to the VUMC General Clinical Research Center. The authors thank Yuki Bradford for assistance with genetic linkage analysis.
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Blair, M.A., Ma, S. & Hedera, P. Mutation in KIF5A can also cause adult-onset hereditary spastic paraplegia. Neurogenetics 7, 47–50 (2006). https://doi.org/10.1007/s10048-005-0027-8
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DOI: https://doi.org/10.1007/s10048-005-0027-8