title: Mutations in BICD2, which encodes a golgin and important motor adaptor, cause congenital autosomal-dominant spinal muscular atrophy.
abstract: Spinal muscular atrophy (SMA) is a heterogeneous group of neuromuscular disorders caused by degeneration of lower motor neurons. Although functional loss of SMN1 is associated with autosomal-recessive childhood SMA, the genetic cause for most families affected by dominantly inherited SMA is unknown. Here, we identified pathogenic variants in bicaudal D homolog 2 (Drosophila) (BICD2) in three families afflicted with autosomal-dominant SMA. Affected individuals displayed congenital slowly progressive muscle weakness mainly of the lower limbs and congenital contractures. In a large Dutch family, linkage analysis identified a 9q22.3 locus in which exome sequencing uncovered c.320C>T (p.Ser107Leu) in BICD2. Sequencing of 23 additional families affected by dominant SMA led to the identification of pathogenic variants in one family from Canada (c.2108C>T [p.Thr703Met]) and one from the Netherlands (c.563A>C [p.Asn188Thr]). BICD2 is a golgin and motor-adaptor protein involved in Golgi dynamics and vesicular and mRNA transport. Transient transfection of HeLa cells with all three mutant BICD2 cDNAs caused massive Golgi fragmentation. This observation was even more prominent in primary fibroblasts from an individual harboring c.2108C>T (p.Thr703Met) (affecting the C-terminal coiled-coil domain) and slightly less evident in individuals with c.563A>C (p.Asn188Thr) (affecting the N-terminal coiled-coil domain). Furthermore, BICD2 levels were reduced in affected individuals and trapped within the fragmented Golgi. Previous studies have shown that Drosophila mutant BicD causes reduced larvae locomotion by impaired clathrin-mediated synaptic endocytosis in neuromuscular junctions. These data emphasize the relevance of BICD2 in synaptic-vesicle recycling and support the conclusion that BICD2 mutations cause congenital slowly progressive dominant SMA.
authors.affiliation: Department of Human Genetics, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands; Institute for Genetic and Metabolic Disease, Radboud University Medical Centre, 6525 GA Nijmegen, the Netherlands.
authors.forename: Kornelia
authors.initials: K
authors.lastname: Neveling
authors.forename: Lilian A
authors.initials: LA
authors.lastname: Martinez-Carrera
authors.forename: Irmgard
authors.initials: I
authors.lastname: Hölker
authors.forename: Angelien
authors.initials: A
authors.lastname: Heister
authors.forename: Aad
authors.initials: A
authors.lastname: Verrips
authors.forename: Seyyed Mohsen
authors.initials: SM
authors.lastname: Hosseini-Barkooie
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Sascha
authors.initials: S
authors.lastname: Vermeer
authors.forename: Maartje
authors.initials: M
authors.lastname: Pennings
authors.forename: Rowdy
authors.initials: R
authors.lastname: Meijer
authors.forename: Margot
authors.initials: M
authors.lastname: te Riele
authors.forename: Catharina J M
authors.initials: CJ
authors.lastname: Frijns
authors.forename: Oksana
authors.initials: O
authors.lastname: Suchowersky
authors.forename: Linda
authors.initials: L
authors.lastname: MacLaren
authors.forename: Sabine
authors.initials: S
authors.lastname: Rudnik-Schöneborn
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Sinke
authors.forename: Klaus
authors.initials: K
authors.lastname: Zerres
authors.forename: R Brian
authors.initials: RB
authors.lastname: Lowry
authors.forename: Henny H
authors.initials: HH
authors.lastname: Lemmink
authors.forename: Lutz
authors.initials: L
authors.lastname: Garbes
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.forename: Helenius J
authors.initials: HJ
authors.lastname: Schelhaas
authors.forename: Hans
authors.initials: H
authors.lastname: Scheffer
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Wirth
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002675:Child, Preschool; D017124:Conserved Sequence; D005260:Female; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D005799:Genes, Dominant; D056726:Genetic Association Studies; D008040:Genetic Linkage; D006056:Golgi Apparatus / Q000378:metabolism / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D008297:Male; D008869:Microtubule-Associated Proteins; D009134:Muscular Atrophy, Spinal / Q000151:congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D020125:Mutation, Missense; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: C561542:BICD2 protein, human; D002352:Carrier Proteins; D008869:Microtubule-Associated Proteins