title: Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy.
abstract: Homozygous deletion of the survival motor neuron 1 gene (SMN1) causes spinal muscular atrophy (SMA), the most frequent genetic cause of early childhood lethality. In rare instances, however, individuals are asymptomatic despite carrying the same SMN1 mutations as their affected siblings, thereby suggesting the influence of modifier genes. We discovered that unaffected SMN1-deleted females exhibit significantly higher expression of plastin 3 (PLS3) than their SMA-affected counterparts. We demonstrated that PLS3 is important for axonogenesis through increasing the F-actin level. Overexpression of PLS3 rescued the axon length and outgrowth defects associated with SMN down-regulation in motor neurons of SMA mouse embryos and in zebrafish. Our study suggests that defects in axonogenesis are the major cause of SMA, thereby opening new therapeutic options for SMA and similar neuromuscular diseases.
authors.affiliation: Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany.
authors.forename: Gabriela E
authors.initials: GE
authors.lastname: Oprea
authors.forename: Sandra
authors.initials: S
authors.lastname: Kröber
authors.forename: Michelle L
authors.initials: ML
authors.lastname: McWhorter
authors.forename: Wilfried
authors.initials: W
authors.lastname: Rossoll
authors.forename: Stefan
authors.initials: S
authors.lastname: Müller
authors.forename: Michael
authors.initials: M
authors.lastname: Krawczak
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Bassell
authors.forename: Christine E
authors.initials: CE
authors.lastname: Beattie
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Wirth
mesh_terms: D000199:Actins / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism / Q000502:physiology* / Q000648:ultrastructure; D002454:Cell Differentiation; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D020439:Growth Cones / Q000378:metabolism / Q000648:ultrastructure; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins; D051379:Mice; D008840:Microfilament Proteins; D009134:Muscular Atrophy, Spinal / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D010750:Phosphoproteins / Q000097:blood / Q000235:genetics* / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D055532:SMN Complex Proteins; D013116:Spinal Cord / Q000378:metabolism; D055533:Survival of Motor Neuron 1 Protein; D014158:Transcription, Genetic; D015027:Zebrafish / Q000196:embryology / Q000235:genetics
chemical_list: D000199:Actins; D017362:Cyclic AMP Response Element-Binding Protein; D008562:Membrane Glycoproteins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; C026742:plastin; C526474:smn1 protein, zebrafish