title: SMA-causing missense mutations in survival motor neuron (Smn) display a wide range of phenotypes when modeled in Drosophila.
abstract: Mutations in the human survival motor neuron 1 (SMN) gene are the primary cause of spinal muscular atrophy (SMA), a devastating neuromuscular disorder. SMN protein has a well-characterized role in the biogenesis of small nuclear ribonucleoproteins (snRNPs), core components of the spliceosome. Additional tissue-specific and global functions have been ascribed to SMN; however, their relevance to SMA pathology is poorly understood and controversial. Using Drosophila as a model system, we created an allelic series of twelve Smn missense mutations, originally identified in human SMA patients. We show that animals expressing these SMA-causing mutations display a broad range of phenotypic severities, similar to the human disease. Furthermore, specific interactions with other proteins known to be important for SMN's role in RNP assembly are conserved. Intragenic complementation analyses revealed that the three most severe mutations, all of which map to the YG box self-oligomerization domain of SMN, display a stronger phenotype than the null allele and behave in a dominant fashion. In support of this finding, the severe YG box mutants are defective in self-interaction assays, yet maintain their ability to heterodimerize with wild-type SMN. When expressed at high levels, wild-type SMN is able to suppress the activity of the mutant protein. These results suggest that certain SMN mutants can sequester the wild-type protein into inactive complexes. Molecular modeling of the SMN YG box dimer provides a structural basis for this dominant phenotype. These data demonstrate that important structural and functional features of the SMN YG box are conserved between vertebrates and invertebrates, emphasizing the importance of self-interaction to the proper functioning of SMN.
authors.affiliation: Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Kavita
authors.initials: K
authors.lastname: Praveen
authors.affiliation: Integrative Program for Biological and Genome Sciences, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wen
authors.affiliation: Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Kelsey M
authors.initials: KM
authors.lastname: Gray
authors.affiliation: Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: John J
authors.initials: JJ
authors.lastname: Noto
authors.affiliation: Department of Biology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: Akash R
authors.initials: AR
authors.lastname: Patlolla
authors.affiliation: Department of Biochemistry & Biophysics, University of Pennsylvania, Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America.
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Van Duyne
authors.affiliation: Curriculum in Genetics and Molecular Biology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America; Integrative Program for Biological and Genome Sciences, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America; Department of Biology, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, Chapel Hill, North Carolina, United States of America.
authors.forename: A Gregory
authors.initials: AG
authors.lastname: Matera
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004330:Drosophila / Q000235:genetics*; D029721:Drosophila Proteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D009046:Motor Neurons / Q000473:pathology; D009134:Muscular Atrophy, Spinal / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D055503:Protein Multimerization / Q000235:genetics; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D017411:Ribonucleoproteins, Small Nuclear / Q000235:genetics; D055532:SMN Complex Proteins / Q000737:chemistry / Q000235:genetics*; D013329:Structure-Activity Relationship
chemical_list: D029721:Drosophila Proteins; D016601:RNA-Binding Proteins; D017411:Ribonucleoproteins, Small Nuclear; D055532:SMN Complex Proteins; C542563:Smn protein, Drosophila