title: Molecular defects in the motor adaptor BICD2 cause proximal spinal muscular atrophy with autosomal-dominant inheritance.
abstract: The most common form of spinal muscular atrophy (SMA) is a recessive disorder caused by deleterious SMN1 mutations in 5q13, whereas the genetic etiologies of non-5q SMA are very heterogeneous and largely remain to be elucidated. In a Bulgarian family affected by autosomal-dominant proximal SMA, we performed genome-wide linkage analysis and whole-exome sequencing and found a heterozygous de novo c.320C>T (p.Ser107Leu) mutation in bicaudal D homolog 2 (Drosophila) (BICD2). Further analysis of BICD2 in a cohort of 119 individuals with non-5q SMA identified a second de novo BICD2 mutation, c.2321A>G (p.Glu774Gly), in a simplex case. Detailed clinical and electrophysiological investigations revealed that both families are affected by a very similar disease course, characterized by early childhood onset, predominant involvement of lower extremities, and very slow disease progression. The amino acid substitutions are located in two interaction domains of BICD2, an adaptor protein linking the dynein molecular motor with its cargo. Our immunoprecipitation and localization experiments in HeLa and SH-SY5Y cells and affected individuals' lymphoblasts demonstrated that p.Ser107Leu causes increased dynein binding and thus leads to accumulation of BICD2 at the microtubule-organizing complex and Golgi fragmentation. In addition, the altered protein had a reduced colocalization with RAB6A, a regulator of vesicle trafficking between the Golgi and the endoplasmic reticulum. The interaction between p.Glu744Gly altered BICD2 and RAB6A was impaired, which also led to their reduced colocalization. Our study identifies BICD2 mutations as a cause of non-5q linked SMA and highlights the importance of dynein-mediated motility in motor neuron function in humans.
authors.affiliation: Molecular Neurogenomics Group, Department of Molecular Genetics, VIB, Antwerp 2610, Belgium; Neurogenetics Laboratory, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium.
authors.forename: Kristien
authors.initials: K
authors.lastname: Peeters
authors.forename: Ivan
authors.initials: I
authors.lastname: Litvinenko
authors.forename: Bob
authors.initials: B
authors.lastname: Asselbergh
authors.forename: Leonardo
authors.initials: L
authors.lastname: Almeida-Souza
authors.forename: Teodora
authors.initials: T
authors.lastname: Chamova
authors.forename: Thomas
authors.initials: T
authors.lastname: Geuens
authors.forename: Elke
authors.initials: E
authors.lastname: Ydens
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zimoń
authors.forename: Joy
authors.initials: J
authors.lastname: Irobi
authors.forename: Els
authors.initials: E
authors.lastname: De Vriendt
authors.forename: Vicky
authors.initials: V
authors.lastname: De Winter
authors.forename: Tinne
authors.initials: T
authors.lastname: Ooms
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
authors.forename: Ivailo
authors.initials: I
authors.lastname: Tournev
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
mesh_terms: D000328:Adult; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D005260:Female; D005799:Genes, Dominant; D056726:Genetic Association Studies; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins; D008875:Middle Aged; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000378:metabolism; D020125:Mutation, Missense; D010375:Pedigree; D021381:Protein Transport; D017422:Sequence Analysis, DNA; D055815:Young Adult; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: C561542:BICD2 protein, human; D002352:Carrier Proteins; D008869:Microtubule-Associated Proteins; C094135:Rab6 protein; D020691:rab GTP-Binding Proteins