Defective kinesin binding of TUBB2A causes progressive spastic ataxia syndrome resembling sacsinopathy

A. Sferra, F. Fattori, T. Rizza, E. Flex, E. Bellacchio, A. Bruselles, S. Petrini, S. Cecchetti, M. Teson, F. Restaldi, A. Ciolfi, F.M. Santorelli, G. Zanni, S. Barresi, C. Castiglioni, M. Tartaglia, E. Bertini

Research output: Contribution to journalArticlepeer-review


Microtubules participate in fundamental cellular processes, including chromosomal segregation and cell division, migration and intracellular trafficking. Their proper function is required for correct central nervous system development and operative preservation, and mutations in genes coding tubulins, the constituting units of microtubules, underlie a family of neurodevelopmental and neurodegenerative diseases, collectively known as 'tubulinopathies', characterized by a wide range of neuronal defects resulting from defective proliferation, migration and function. Here, we causally link a previously unreported missense mutation in TUBB2A (c.1249G > A, p.D417N), encoding one of the neuron-specific b-tubulin isotype II, to a disorder characterized by progressive spastic paraplegia, peripheral sensory-motor polyneuropathy and ataxia. Asp417 is a highly conserved solvent-exposed residue at the site mediating binding of kinesin superfamily motors. Impaired binding to KIF1A, a neuron-specific kinesin required for transport of synaptic vesicle precursors of the disease-associated TUBB2A mutant, was predicted by structural analyses and confirmed experimentally in vitro.We show that overexpression of TUBB2AD417N disrupts the mitotic spindle bipolarity and morphology and affects the M phase entry and length. Differently from the TUBB2AN247K and TUBB2AA248V, two mutants previously identified to affect neurodevelopment, TUBB2AD417N retains the ability to assemble into microtubules. Consistent with the differential clinical and structural impact, TUBB2AA248V does not drastically affect TUBB2A binding to KIF1A, nor mitotic spindle bipolarity. Overall, our data demonstrate a pathogenic role of the p.D417N substitution that is different from previously reported TUBB2A mutations and expand the phenotypic spectrum associated with mutations in this gene. © The Author(s) 2018. Published by Oxford University Press. All rights reserved.
Original languageEnglish
Pages (from-to)1892-1904
Number of pages13
JournalHuman Molecular Genetics
Issue number11
Publication statusPublished - 2018


  • beta tubulin
  • kinesin
  • tubulin
  • tubulin b2a
  • unclassified drug
  • KIF1A protein, human
  • protein binding
  • TUBB2A protein, human
  • adult
  • amino acid sequence
  • Article
  • ataxia
  • case report
  • cell cycle M phase
  • cells
  • cerebellum vermis
  • clinical article
  • corpus callosum
  • electromyography
  • electroretinogram
  • fibroblast
  • follow up
  • gene overexpression
  • HEK293 cell line
  • hereditary motor sensory neuropathy
  • human
  • in vitro study
  • macular degeneration
  • male
  • medical history
  • missense mutation
  • mitosis spindle
  • motor nerve conduction
  • muscle atrophy
  • nerve conduction velocity
  • neuroimaging
  • neurologic examination
  • nuclear magnetic resonance imaging
  • optic nerve atrophy
  • optical coherence tomography
  • priority journal
  • protein stability
  • Sanger sequencing
  • somatosensory evoked potential
  • spastic paraplegia
  • spinocerebellar degeneration
  • strabismus
  • synapse vesicle
  • visual evoked potential
  • whole exome sequencing
  • young adult
  • adolescent
  • cell motion
  • cell proliferation
  • child
  • diagnostic imaging
  • female
  • genetics
  • intellectual impairment
  • metabolism
  • microtubule
  • nerve cell
  • paraplegia
  • pathology
  • pathophysiology
  • polyneuropathy
  • sensorimotor cortex
  • spasticity
  • spindle apparatus
  • Adolescent
  • Adult
  • Cell Movement
  • Cell Proliferation
  • Child
  • Female
  • Humans
  • Intellectual Disability
  • Kinesin
  • Male
  • Microtubules
  • Muscle Spasticity
  • Neurons
  • Optic Atrophy
  • Paraplegia
  • Polyneuropathies
  • Protein Binding
  • Sensorimotor Cortex
  • Spindle Apparatus
  • Spinocerebellar Ataxias
  • Spinocerebellar Degenerations
  • Tubulin


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