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

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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.

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Yi Bessie Liu

Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States

Competing interests
No competing interests declared.
Ambika Tewari

Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States

Competing interests
No competing interests declared.
Johnny Salameh

Department of Neurology, University of Massachusetts Medical School, Worcester, United States

Competing interests
No competing interests declared.
Elena Arystarkhova

Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States

Competing interests
No competing interests declared.
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.
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.
Laurie J Ozelius

Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States

Competing interests
No competing interests declared.
Kamran Khodakhah

Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States

Competing interests
No competing interests declared.
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.

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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.