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Neuron. 2014 Apr 16;82(2):334-49. doi: 10.1016/j.neuron.2014.02.038. Epub 2014 Mar 20.

Human CFEOM1 mutations attenuate KIF21A autoinhibition and cause oculomotor axon stalling.

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  • 1Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Program in Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
  • 2Program in Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
  • 3Department of Biology, University of Iowa, College of Liberal Arts and Sciences, Iowa City, IA, 52242, USA.
  • 4Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
  • 5Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
  • 6Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA.
  • 7Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA.
  • 8Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Program in Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
  • 9Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Program in Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815, USA.
  • 10Max F. Perutz Laboratories, University of Vienna, Department of Biochemistry and Cell Biology, Dr. Bohrgasse 9, A-1030 Vienna, Austria.
  • 11Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA; Program in Genomics, Boston Children's Hospital, Boston, MA 02115, USA; Department of Medicine (Genetics), Boston Children's Hospital, Boston, MA 02115, USA; Department of Ophthalmology, Boston Children's Hospital, Boston, MA 02115, USA; Manton Center for Orphan Disease Research, Boston Children's Hospital, Boston, MA 02115, USA; Department of Neurology, Harvard Medical School, Boston, MA 02115, USA; Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA; Department of Ophthalmology, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815, USA; The Broad Institute of Harvard and MIT, 301 Binney Street, Cambridge, MA 02142, USA. Electronic address: elizabeth.engle@childrens.harvard.edu.

Abstract

The ocular motility disorder "Congenital fibrosis of the extraocular muscles type 1" (CFEOM1) results from heterozygous mutations altering the motor and third coiled-coil stalk of the anterograde kinesin, KIF21A. We demonstrate that Kif21a knockin mice harboring the most common human mutation develop CFEOM. The developing axons of the oculomotor nerve's superior division stall in the proximal nerve; the growth cones enlarge, extend excessive filopodia, and assume random trajectories. Inferior division axons reach the orbit but branch ectopically. We establish a gain-of-function mechanism and find that human motor or stalk mutations attenuate Kif21a autoinhibition, providing in vivo evidence for mammalian kinesin autoregulation. We identify Map1b as a Kif21a-interacting protein and report that Map1b⁻/⁻ mice develop CFEOM. The interaction between Kif21a and Map1b is likely to play a critical role in the pathogenesis of CFEOM1 and highlights a selective vulnerability of the developing oculomotor nerve to perturbations of the axon cytoskeleton.

Copyright © 2014 Elsevier Inc. All rights reserved.

PMID:
24656932
[PubMed - indexed for MEDLINE]
PMCID:
PMC4002761
Free PMC Article

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