Human CFEOM1 mutations attenuate KIF21A autoinhibition and cause oculomotor axon stalling

Long Cheng; Jigar Desai; Carlos J Miranda; Jeremy S Duncan; Weihong Qiu; Alicia A Nugent; Adrianne L Kolpak; Carrie C Wu; Eugene Drokhlyansky; Michelle M Delisle; Wai-Man Chan; Yan Wei; Friedrich Propst; Samara L Reck-Peterson; Bernd Fritzsch; Elizabeth C Engle

doi:10.1016/j.neuron.2014.02.038

Human CFEOM1 mutations attenuate KIF21A autoinhibition and cause oculomotor axon stalling

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

Authors

Long Cheng¹, Jigar Desai¹, Carlos J Miranda², Jeremy S Duncan³, Weihong Qiu⁴, Alicia A Nugent⁵, Adrianne L Kolpak⁶, Carrie C Wu⁷, Eugene Drokhlyansky², Michelle M Delisle⁸, Wai-Man Chan⁹, Yan Wei⁷, Friedrich Propst¹⁰, Samara L Reck-Peterson⁴, Bernd Fritzsch³, Elizabeth C Engle¹¹

Affiliations

¹ 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.
² Program in Genomics, Boston Children's Hospital, Boston, MA 02115, USA.
³ Department of Biology, University of Iowa, College of Liberal Arts and Sciences, Iowa City, IA, 52242, USA.
⁴ Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
⁵ 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.
⁶ 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.
⁷ Department of Neurology, Boston Children's Hospital, Boston, MA 02115, USA; FM Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA 02115, USA.
⁸ 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.
⁹ 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.
¹⁰ Max F. Perutz Laboratories, University of Vienna, Department of Biochemistry and Cell Biology, Dr. Bohrgasse 9, A-1030 Vienna, Austria.
¹¹ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Video-Audio Media

MeSH terms

Age Factors
Animals
Animals, Newborn
Axons / pathology*
Axons / ultrastructure
Cell Count
Disease Models, Animal
Embryo, Mammalian
Eye Diseases, Hereditary / genetics*
Eye Diseases, Hereditary / pathology
Eye Diseases, Hereditary / physiopathology
Eye Movements / genetics
Eye Movements / physiology
Fibrosis / genetics*
Fibrosis / pathology
Fibrosis / physiopathology
Gene Expression Regulation / genetics
Green Fluorescent Proteins / genetics
Green Fluorescent Proteins / metabolism
HEK293 Cells
Humans
Kinesins / genetics*
Kinesins / metabolism*
Mice
Mice, Transgenic
Microtubule-Associated Proteins / genetics
Microtubule-Associated Proteins / physiology
Mutation / genetics*
Neural Pathways / metabolism
Neural Pathways / pathology
Neural Pathways / ultrastructure
Ocular Motility Disorders / genetics*
Ocular Motility Disorders / pathology
Ocular Motility Disorders / physiopathology
Oculomotor Nerve / pathology*
Oculomotor Nerve / ultrastructure

Substances

KIF21A protein, human
Microtubule-Associated Proteins
microtubule-associated protein 1B
Green Fluorescent Proteins
Kinesins

Supplementary concepts

Fibrosis of Extraocular Muscles, Congenital, 3B

Abstract

Publication types

MeSH terms

Substances

Supplementary concepts

Grants and funding