title: A novel human-specific splice isoform alters the critical C-terminus of Survival Motor Neuron protein.
abstract: Spinal muscular atrophy (SMA), a leading genetic disease of children and infants, is caused by mutations or deletions of Survival Motor Neuron 1 (SMN1) gene. SMN2, a nearly identical copy of SMN1, fails to compensate for the loss of SMN1 due to skipping of exon 7. SMN2 predominantly produces SMNΔ7, an unstable protein. Here we report exon 6B, a novel exon, generated by exonization of an intronic Alu-like sequence of SMN. We validate the expression of exon 6B-containing transcripts SMN6B and SMN6BΔ7 in human tissues and cell lines. We confirm generation of SMN6B transcripts from both SMN1 and SMN2. We detect expression of SMN6B protein using antibodies raised against a unique polypeptide encoded by exon 6B. We analyze RNA-Seq data to show that hnRNP C is a potential regulator of SMN6B expression and demonstrate that SMN6B is a substrate of nonsense-mediated decay. We show interaction of SMN6B with Gemin2, a critical SMN-interacting protein. We demonstrate that SMN6B is more stable than SMNΔ7 and localizes to both the nucleus and the cytoplasm. Our finding expands the diversity of transcripts generated from human SMN genes and reveals a novel protein isoform predicted to be stably expressed during conditions of stress.
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Joonbae
authors.initials: J
authors.lastname: Seo
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Natalia N
authors.initials: NN
authors.lastname: Singh
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Ottesen
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.|Center for Advanced Host Defenses, Immunobiotics &Translational Comparative Medicine (CAHDIT), Iowa State University, Ames, IA 50011, USA.
authors.forename: Brian M
authors.initials: BM
authors.lastname: Lee
authors.affiliation: Department of Biomedical Sciences, Iowa State University, Ames, Iowa 50011, USA.
authors.forename: Ravindra N
authors.initials: RN
authors.lastname: Singh
mesh_terms: D017398:Alternative Splicing; D000818:Animals; D002460:Cell Line; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D005091:Exons; D006367:HeLa Cells; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C / Q000378:metabolism; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D009419:Nerve Tissue Proteins / Q000378:metabolism; D059365:Nonsense Mediated mRNA Decay; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D055550:Protein Stability; D016601:RNA-Binding Proteins / Q000378:metabolism; D017423:Sequence Analysis, RNA / Q000379:methods*; D055533:Survival of Motor Neuron 1 Protein / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D055540:Survival of Motor Neuron 2 Protein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: C108381:GEMIN2 protein, human; C503635:HNRNPC protein, human; D034482:Heterogeneous-Nuclear Ribonucleoprotein Group C; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein