Autosomal dominant congenital spinal muscular atrophy is caused by mutations in BICD2, a golgin and important motor adaptor. B. Wirth1, L. A. Martinez-Carrera1, I. Hölker1, A. Heister2, A. Verrips3, S. M. Hosseini-Barkooie1, C. Gilissen3,4,5,6, S. Vermeer3,4, M. Pennings3, R. Meijer3, M. te Riele7, C. J. M. Frijns8, O. Suchowersky9, L. MacLaren10, S. Rudnik-Schöneborn11, R. J. Sinke12, K. Zerres11, R. B. Lowry10, H. H. Lemmink12, L. Garbes1, M. Synofzik13, J. A. Veltman3,4,5, H. J. Schelhaas7, H. Scheffer3,4, K. Neveling3,4 1) Institute of Human Genetics, Institute of Genetics and Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany; 2) Dept. of Human Genetics, Radboud University Medical Centre, Nijmegen, The Netherlands; 3) Dept. of Pediatric Neurology, Canisius-Wilhelmina Hospital, Nijmegen, The Netherlands; 4) Inst. for Genetic and Metabolic Disease, Radboud University Medical Centre, Nijmegen, The Netherlands; 5) Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands; 6) Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital, Bergen, Norway; 7) Department of Neurology, Radboud University Medical Centre, Nijmegen, The Netherlands; 8) Dept. of Neurology, University Medical Centre Utrecht, Utrecht, the Netherlands; 9) Dept. of Medicine (Neurology), Medical Genetics, and Psychiatry, University of Alberta, Edmonton Alberta, Canada; 10) Dept. of Medical Genetics and Pediatrics, Alberta Childrens Hospital, University of Calgary, Calgary, Canada; 11) Institute of Human Genetics, University Aachen, Aachen, Germany; 12) Dept of Genetics, University of Groningen and University Medical Center Groningen, Groningen, The Netherlands; 13) Hertie-Institute for Clinical brain Research and Center for Neurology, Department of Neurodegenerative Diseases, University of Tübingen, Germany.

   Spinal muscular atrophy (SMA) is a heterogeneous group of neuromuscular disorders caused by degeneration of lower motor neurons. While functional loss of SMN1 is associated with autosomal recessive childhood SMA, the genetic cause for most families with a dominant inheritance of SMA is unknown. Here, we identified pathogenic variants in the bicaudal D2 (BICD2) in families with autosomal dominant SMA. Affected individuals present with congenital slowly-progressive muscle weakness mainly of lower limbs and congenital contractures. In a large Dutch family, linkage analysis identified a locus on chromosome 9q22.3, in which exome sequencing uncovered the c.320C>T (p.Ser107Leu) mutation in BICD2. In 3/24 families with dominant SMA additional pathogenic variants c.2108C>T (p.Thr703Met), c.563A>C, (p.Asn188Thr) and c.2239C>T (p747R>C) were identified. Complete sequencing of the coding region of BICD1 revealed no pathogenic variant, excluding this BICD2 paralog as a further candidate gene. BICD2 is a golgin and motor adaptor protein involved in Golgi dynamics and in 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, especially in the patient carrying the mutation p.Thr703Met localized in C-terminal coiled-coil domain. Furthermore, BICD2 was 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. In vivo studies in zebrafish overexpressing each of the BICD2 mutants or wt RNA are in progress. BICD2 is the first gene described to be involved in an autosomal dominant inherited SMA and its interacting partners are further excellent candidates for the many unsolved SMA cases.

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