title: Dominant transmission of de novo KIF1A motor domain variant underlying pure spastic paraplegia.
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.
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
authors.forename: Emil
authors.initials: E
authors.lastname: Ylikallio
authors.affiliation: Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, Korea.
authors.forename: Doyoun
authors.initials: D
authors.lastname: Kim
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.|Department of Child Neurology, Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Pirjo
authors.initials: P
authors.lastname: Isohanni
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.|Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Mari
authors.initials: M
authors.lastname: Auranen
authors.affiliation: Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, Korea.|Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
authors.forename: Eunjoon
authors.initials: E
authors.lastname: Kim
authors.affiliation: Department of Child Neurology, Children's Hospital, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Tuula
authors.initials: T
authors.lastname: Lönnqvist
authors.affiliation: Research Programs Unit, Molecular Neurology, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.|Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Henna
authors.initials: H
authors.lastname: Tyynismaa
mesh_terms: D002648:Child; D014644:Genetic Variation / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D016547:Kinesins / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense / Q000235:genetics; D010264:Paraplegia / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*
chemical_list: C094065:KIF1A protein, human; D016547:Kinesins