Abstract
Variants in family 1 kinesin (KIF1A), which encodes a kinesin axonal motor protein, have been described to cause variable neurological manifestations. Recessive missense variants have led to spastic paraplegia, and recessive truncations to sensory and autonomic neuropathy. De novo missense variants cause developmental delay or intellectual disability, cerebellar atrophy and variable spasticity. We describe a family with father-to-son transmission of de novo variant in the KIF1A motor domain, in a phenotype of pure spastic paraplegia. Structural modeling of the predicted p.(Ser69Leu) amino acid change suggested that it impairs the stable binding of ATP to the KIF1A protein. Our study reports the first dominantly inherited KIF1A variant and expands the spectrum of phenotypes caused by heterozygous KIF1A motor domain variants to include pure spastic paraplegia. We conclude that KIF1A should be considered a candidate gene for hereditary paraplegias regardless of inheritance pattern.
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Acknowledgements
We would like to thank the family for participation in the study. Riitta Lehtinen is thanked for her technical help. We also acknowledge the target enrichment, sequencing and variant calling pipeline analyses performed by the Institute for Molecular Medicine Finland. We wish to thank the following funding sources for support: Sigrid Jusélius Foundation (for HT), the Finnish Neuromuscular Disorders Association (for MA), University of Helsinki (for HT), the Academy of Finland (for HT and EY), Svenska kulturfonden (for EY), Arvid and Greta Olin’s Foundation (for EY), Finska Läkaresällskapet (for EY) and the Institute for Basic Science (for EK).
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Ylikallio, E., Kim, D., Isohanni, P. et al. Dominant transmission of de novo KIF1A motor domain variant underlying pure spastic paraplegia. Eur J Hum Genet 23, 1427–1430 (2015). https://doi.org/10.1038/ejhg.2014.297
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DOI: https://doi.org/10.1038/ejhg.2014.297
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