title: Human CFEOM1 mutations attenuate KIF21A autoinhibition and cause oculomotor axon stalling.
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.
authors.affiliation: Department 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.
authors.forename: Long
authors.initials: L
authors.lastname: Cheng
authors.affiliation: Department 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.
authors.forename: Jigar
authors.initials: J
authors.lastname: Desai
authors.affiliation: Program in Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Carlos J
authors.initials: CJ
authors.lastname: Miranda
authors.affiliation: Department of Biology, University of Iowa, College of Liberal Arts and Sciences, Iowa City, IA, 52242, USA.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: Duncan
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Weihong
authors.initials: W
authors.lastname: Qiu
authors.affiliation: Department 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.
authors.forename: Alicia A
authors.initials: AA
authors.lastname: Nugent
authors.affiliation: Department 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.
authors.forename: Adrianne L
authors.initials: AL
authors.lastname: Kolpak
authors.affiliation: Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Carrie C
authors.initials: CC
authors.lastname: Wu
authors.affiliation: Program in Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Drokhlyansky
authors.affiliation: Department 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.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Delisle
authors.affiliation: Department 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.
authors.forename: Wai-Man
authors.initials: WM
authors.lastname: Chan
authors.affiliation: Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wei
authors.affiliation: Max F. Perutz Laboratories, University of Vienna, Department of Biochemistry and Cell Biology, Dr. Bohrgasse 9, A-1030 Vienna, Austria.
authors.forename: Friedrich
authors.initials: F
authors.lastname: Propst
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Samara L
authors.initials: SL
authors.lastname: Reck-Peterson
authors.affiliation: Department of Biology, University of Iowa, College of Liberal Arts and Sciences, Iowa City, IA, 52242, USA.
authors.forename: Bernd
authors.initials: B
authors.lastname: Fritzsch
authors.affiliation: Department 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.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Engle
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001369:Axons / Q000473:pathology* / Q000648:ultrastructure; D002452:Cell Count; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D015785:Eye Diseases, Hereditary / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005133:Eye Movements / Q000235:genetics / Q000502:physiology; D005355:Fibrosis / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation / Q000235:genetics; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D016547:Kinesins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000502:physiology; D009154:Mutation / Q000235:genetics*; D009434:Neural Pathways / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D015835:Ocular Motility Disorders / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009802:Oculomotor Nerve / Q000473:pathology* / Q000648:ultrastructure
chemical_list: C119023:KIF21A protein, human; D008869:Microtubule-Associated Proteins; C085284:microtubule-associated protein 1B; D049452:Green Fluorescent Proteins; D016547:Kinesins