De Novo Mutations in the Motor Domain of KIF1A Cause Cognitive Impairment,Spastic Paraparesis,Axonal Neuropathy,and Cerebellar Atrophy |
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| Authors: | Jae‐Ran Lee Myriam Srour Doyoun Kim Fadi. F. Hamdan So‐Hee Lim Catherine Brunel‐Guitton Jean‐Claude Décarie 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 Tyynismaa Inge 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 |
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| Affiliation: | 1. Biomedical Proteomics Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea;2. CHU Sainte‐Justine Research Center, Montreal, Canada;3. Center for Synaptic Brain Dysfunctions, Institute for Basic Science (IBS), Daejeon, Korea;4. Department of Medical Imaging, CHU Sainte‐Justine, Montreal, Canada;5. Department of Pediatrics, University of Montreal, Montreal, Canada;6. Department of Neurosciences, University of Montreal, Montreal, Canada;7. Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio;8. Department of Neurology, Stanford University;9. Division of Child Neurology, Lucile Packard Children's Hospital, Stanford, California;10. Gillette Children's Specialty Healthcare, St. Paul, Minnesota;11. Department of Neurology, Maastricht University Medical Center, Maastricht, The Netherlands;12. Orbis Medical Center, Sittard, The Netherlands;13. Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada;14. Department of Clinical Genetics, Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland;15. Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland;16. Department of Neurology, University Medical Centre 17. Utrecht, Utrecht, The Netherlands;18. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands;19. Department of Clinical Genetics and School for Oncology and Developmental Biology (GROW), Maastricht University Medical Center, Maastricht, The Netherlands;20. Department of Pediatric Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands;21. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands;22. Montreal Neurological Institute, McGill University, Montreal, Canada;23. Department of Biological Sciences, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea |
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| Abstract: | 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. |
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| Keywords: | KIF1A intellectual disability spastic paraparesis axonal neuropathy de novo mutations |
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