title: Mutations in BICD2 cause dominant congenital spinal muscular atrophy and hereditary spastic paraplegia.
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.
authors.affiliation: Institute for Neuroscience and Muscle Research, Children's Hospital at Westmead, Westmead, Sydney, NSW 2145, Australia; Discipline of Paediatrics and Child Health, Faculty of Medicine, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Emily C
authors.initials: EC
authors.lastname: Oates
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Rossor
authors.forename: Majid
authors.initials: M
authors.lastname: Hafezparast
authors.forename: Michael
authors.initials: M
authors.lastname: Gonzalez
authors.forename: Fiorella
authors.initials: F
authors.lastname: Speziani
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.forename: Monkol
authors.initials: M
authors.lastname: Lek
authors.forename: Ellen
authors.initials: E
authors.lastname: Cottenie
authors.forename: Mariacristina
authors.initials: M
authors.lastname: Scoto
authors.forename: A Reghan
authors.initials: AR
authors.lastname: Foley
authors.forename: Matthew
authors.initials: M
authors.lastname: Hurles
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
authors.forename: Linda
authors.initials: L
authors.lastname: Greensmith
authors.forename: Michaela
authors.initials: M
authors.lastname: Auer-Grumbach
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Pieber
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Rebecca
authors.initials: R
authors.lastname: Schule
authors.forename: David N
authors.initials: DN
authors.lastname: Herrmann
authors.forename: Janet E
authors.initials: JE
authors.lastname: Sowden
authors.forename: Gyula
authors.initials: G
authors.lastname: Acsadi
authors.forename: Manoj P
authors.initials: MP
authors.lastname: Menezes
authors.forename: Nigel F
authors.initials: NF
authors.lastname: Clarke
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
authors.forename: Mary M
authors.initials: MM
authors.lastname: Reilly
mesh_terms: D000328:Adult; D000368:Aged; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D056445:Cytoplasmic Dyneins / Q000378:metabolism; D005260:Female; D005799:Genes, Dominant; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D057809:HEK293 Cells; D006239:Haplotypes; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins; D008875:Middle Aged; D009134:Muscular Atrophy, Spinal / Q000151:congenital / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D010264:Paraplegia / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011485:Protein Binding; D055815:Young Adult
chemical_list: C561542:BICD2 protein, human; D002352:Carrier Proteins; D008869:Microtubule-Associated Proteins; D056445:Cytoplasmic Dyneins