title: A dystonia-like movement disorder with brain and spinal neuronal defects is caused by mutation of the mouse laminin β1 subunit, Lamb1.
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.
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
authors.forename: Yi Bessie
authors.initials: YB
authors.lastname: Liu
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States.
authors.forename: Ambika
authors.initials: A
authors.lastname: Tewari
authors.affiliation: Department of Neurology, University of Massachusetts Medical School, Worcester, United States.
authors.forename: Johnny
authors.initials: J
authors.lastname: Salameh
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
authors.forename: Elena
authors.initials: E
authors.lastname: Arystarkhova
authors.affiliation: Neuroscience Discovery Core, Mouse Specifics Inc., Framingham, United States.
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Hampton
authors.affiliation: Department of Neurology, Wake Forest University School of Medicine, Winston-Salem, United States.
authors.forename: Allison
authors.initials: A
authors.lastname: Brashear
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
authors.forename: Laurie J
authors.initials: LJ
authors.lastname: Ozelius
authors.affiliation: Dominick P. Purpura Department of Neuroscience, Albert Einstein College of Medicine, New York, United States.
authors.forename: Kamran
authors.identifier: http://orcid.org/0000-0001-7905-5335
authors.initials: K
authors.lastname: Khodakhah
authors.affiliation: Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, United States.
authors.forename: Kathleen J
authors.identifier: http://orcid.org/0000-0002-2817-5262
authors.initials: KJ
authors.lastname: Sweadner
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology*; D004421:Dystonia / Q000473:pathology; D007797:Laminin / Q000235:genetics* / Q000378:metabolism*; D008124:Locomotion; D051379:Mice; D009069:Movement Disorders / Q000473:pathology*; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009434:Neural Pathways / Q000473:pathology; D011187:Posture; D013131:Spine / Q000473:pathology*
chemical_list: C513277:Lamb1 protein, mouse; D007797:Laminin; D050505:Mutant Proteins
keywords: exome sequencing; extracellular matrix; laminin; mouse; movement disorder; neuroscience; spinal cord circuits; synapse