A dystonia-like movement disorder with brain and spinal neuronal defects is caused by mutation of the mouse laminin β1 subunit, Lamb1

  1. Yi Bessie Liu
  2. Ambika Tewari
  3. Johnny Salameh
  4. Elena Arystarkhova
  5. Thomas G Hampton
  6. Allison Brashear
  7. Laurie J Ozelius
  8. Kamran Khodakhah
  9. Kathleen J Sweadner  Is a corresponding author
  1. Harvard Medical School, United States
  2. Albert Einstein College of Medicine, United States
  3. University of Massachusetts Medical School, United States
  4. Mouse Specifics Inc., United States
  5. Wake Forest University School of Medicine, United States

Abstract

A new mutant mouse (lamb1t) exhibits intermittent dystonic hindlimb movements and postures when awake, and hyperextension when asleep. Experiments showed co-contraction of opposing muscle groups, and indicated that symptoms depended on the interaction of brain and spinal cord. SNP mapping and exome sequencing identified the dominant causative mutation in the Lamb1 gene. Laminins are extracellular matrix proteins, widely expressed but also known to be important in synapse structure and plasticity. In accordance, awake recording in the cerebellum detected abnormal output from a circuit of two Lamb1-expressing neurons, Purkinje cells and their deep cerebellar nucleus targets, during abnormal postures. We propose that dystonia-like symptoms result from lapses in descending inhibition, exposing excess activity in intrinsic spinal circuits that coordinate muscles. The mouse is a new model for testing how dysfunction in the CNS causes specific abnormal movements and postures.

Article and author information

Author details

  1. Yi Bessie Liu

    Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  2. Ambika Tewari

    Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  3. Johnny Salameh

    Department of Neurology, University of Massachusetts Medical School, Worcester, United States
    Competing interests
    No competing interests declared.
  4. Elena Arystarkhova

    Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  5. Thomas G Hampton

    Neuroscience Discovery Core, Mouse Specifics Inc., Framingham, United States
    Competing interests
    Thomas G Hampton, owner of the company that has commercialized the gait analysis instrumentation described.
  6. Allison Brashear

    Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, United States
    Competing interests
    Allison Brashear, performs research at Wake Forest with grants from Allergan, Ipsen, and Merz, and has consulting relationships with Allergan and Concerta. Her conflict of interest is managed by Wake Forest School of Medicine.
  7. Laurie J Ozelius

    Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States
    Competing interests
    No competing interests declared.
  8. Kamran Khodakhah

    Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States
    Competing interests
    No competing interests declared.
  9. Kathleen J Sweadner

    Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States
    For correspondence
    sweadner@helix.mgh.harvard.edu
    Competing interests
    No competing interests declared.

Ethics

Animal experimentation: All animal research followed the NRC Guide for the Care and Use of Laboratory Animals and the policies of the Massachusetts General Hospital or Albert Einstein College of Medicine: MGH IACUC approved protocol 2011N000108, and Albert Einstein approved protocol 20130801.

Reviewing Editor

  1. Louis Ptáček, University of California, San Francisco, United States

Publication history

  1. Received: August 25, 2015
  2. Accepted: December 15, 2015
  3. Accepted Manuscript published: December 24, 2015 (version 1)
  4. Version of Record published: January 28, 2016 (version 2)

Copyright

© 2015, Liu et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Yi Bessie Liu
  2. Ambika Tewari
  3. Johnny Salameh
  4. Elena Arystarkhova
  5. Thomas G Hampton
  6. Allison Brashear
  7. Laurie J Ozelius
  8. Kamran Khodakhah
  9. Kathleen J Sweadner
(2015)
A dystonia-like movement disorder with brain and spinal neuronal defects is caused by mutation of the mouse laminin β1 subunit, Lamb1
eLife 4:e11102.
https://doi.org/10.7554/eLife.11102

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