De Novo Mutations in the Motor Domain of KIF1A Cause Cognitive Impairment, Spastic Paraparesis, Axonal Neuropathy, and Cerebellar Atrophy

Jae-Ran Lee, Myriam Srour, Doyoun Kim, Fadi. F. Hamdan, So-Hee Lim, Catherine Brunel-Guitton, Jean-Claude Decarie, Elsa Rossignol, Grant A. Mitchell, Allison Schreiber, Rocio Moran, Keith Van Haren, Randal Richardson, Joost Nicolai, Karin M. E. J. Oberndorff, Justin D. Wagner, Kym M. Boycott, Elisa Rahikkala, Nella Junna, Henna TyynismaaInge Cuppen, Nienke E. Verbeek, Connie T. R. M. Stumpel, Michel A. Willemsen, Sonja A. de Munnik, Guy A. Rouleau, Eunjoon Kim, Erik-Jan Kamsteeg, Tjitske Kleefstra, Jacques L. Michaud*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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KIF1A is a neuron-specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type-2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.
Original languageEnglish
Pages (from-to)69-78
JournalHuman Mutation
Issue number1
Publication statusPublished - Jan 2015


  • KIF1A
  • intellectual disability
  • spastic paraparesis
  • axonal neuropathy
  • de novo mutations

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