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Publication Detail
Mutations in BICD2 cause dominant congenital spinal muscular atrophy and hereditary spastic paraplegia.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Oates EC, Rossor AM, Hafezparast M, Gonzalez M, Speziani F, MacArthur DG, Lek M, Cottenie E, Scoto M, Foley AR, Hurles M, Houlden H, Greensmith L, Auer-Grumbach M, Pieber TR, Strom TM, Schule R, Herrmann DN, Sowden JE, Acsadi G, Menezes MP, Clarke NF, Z├╝chner S, UK10K , Muntoni F, North KN, Reilly MM
  • Publication date:
    06/06/2013
  • Pagination:
    965, 973
  • Journal:
    Am J Hum Genet
  • Volume:
    92
  • Issue:
    6
  • Status:
    Published
  • Country:
    United States
  • PII:
    S0002-9297(13)00179-1
  • Language:
    eng
  • Keywords:
    Adult, Aged, Carrier Proteins, Child, Child, Preschool, Cytoplasmic Dyneins, Female, Genes, Dominant, Genetic Linkage, Genome-Wide Association Study, HEK293 Cells, Haplotypes, Humans, Male, Microtubule-Associated Proteins, Middle Aged, Muscular Atrophy, Spinal, Mutation, Missense, Paraplegia, Pedigree, Polymorphism, Single Nucleotide, Protein Binding, Young Adult
Abstract
Dominant congenital spinal muscular atrophy (DCSMA) is a disorder of developing anterior horn cells and shows lower-limb predominance and clinical overlap with hereditary spastic paraplegia (HSP), a lower-limb-predominant disorder of corticospinal motor neurons. We have identified four mutations in bicaudal D homolog 2 (Drosophila) (BICD2) in six kindreds affected by DCSMA, DCSMA with upper motor neuron features, or HSP. BICD2 encodes BICD2, a key adaptor protein that interacts with the dynein-dynactin motor complex, which facilitates trafficking of cellular cargos that are critical to motor neuron development and maintenance. We demonstrate that mutations resulting in amino acid substitutions in two binding regions of BICD2 increase its binding affinity for the cytoplasmic dynein-dynactin complex, which might result in the perturbation of BICD2-dynein-dynactin-mediated trafficking, and impair neurite outgrowth. These findings provide insight into the mechanism underlying both the static and the slowly progressive clinical features and the motor neuron pathology that characterize BICD2-associated diseases, and underscore the importance of the dynein-dynactin transport pathway in the development and survival of both lower and upper motor neurons.
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Department of Neuromuscular Diseases
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Department of Neuromuscular Diseases
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ICH Developmental Neurosciences Prog
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Department of Neuromuscular Diseases
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Department of Neuromuscular Diseases
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