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Mild SMN missense alleles are only functional in the presence of SMN2 in mammals.
Iyer, Chitra C; Corlett, Kaitlyn M; Massoni-Laporte, Aurélie; Duque, Sandra I; Madabusi, Narasimhan; Tisdale, Sarah; McGovern, Vicki L; Le, Thanh T; Zaworski, Phillip G; Arnold, W David; Pellizzoni, Livio; Burghes, Arthur H M.
Afiliación
  • Iyer CC; Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
  • Corlett KM; Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
  • Massoni-Laporte A; Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
  • Duque SI; Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
  • Madabusi N; Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
  • Tisdale S; Center for Motor Neuron Biology and Disease, Columbia University, New York, NY, USA.
  • McGovern VL; Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
  • Le TT; Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
  • Zaworski PG; Department of Biological Chemistry and Pharmacology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
  • Arnold WD; PharmOptima, LLC, Portage, MI, USA.
  • Pellizzoni L; Department of Neurology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
  • Burghes AHM; Center for Motor Neuron Biology and Disease, Columbia University, New York, NY, USA.
Hum Mol Genet ; 27(19): 3404-3416, 2018 10 01.
Article en En | MEDLINE | ID: mdl-29982416
Spinal muscular atrophy (SMA) is caused by reduced levels of full-length SMN (FL-SMN). In SMA patients with one or two copies of the Survival Motor Neuron 2 (SMN2) gene there are a number of SMN missense mutations that result in milder-than-predicted SMA phenotypes. These mild SMN missense mutation alleles are often assumed to have partial function. However, it is important to consider the contribution of FL-SMN as these missense alleles never occur in the absence of SMN2. We propose that these patients contain a partially functional oligomeric SMN complex consisting of FL-SMN from SMN2 and mutant SMN protein produced from the missense allele. Here we show that mild SMN missense mutations SMND44V, SMNT74I or SMNQ282A alone do not rescue mice lacking wild-type FL-SMN. Thus, missense mutations are not functional in the absence of FL-SMN. In contrast, when the same mild SMN missense mutations are expressed in a mouse containing two SMN2 copies, functional SMN complexes are formed with the small amount of wild-type FL-SMN produced by SMN2 and the SMA phenotype is completely rescued. This contrasts with SMN missense alleles when studied in C. elegans, Drosophila and zebrafish. Here we demonstrate that the heteromeric SMN complex formed with FL-SMN is functional and sufficient to rescue small nuclear ribonucleoprotein assembly, motor neuron function and rescue the SMA mice. We conclude that mild SMN missense alleles are not partially functional but rather they are completely non-functional in the absence of wild-type SMN in mammals.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Atrofia Muscular Espinal / Ribonucleoproteínas Nucleares Pequeñas / Proteínas del Complejo SMN Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Hum Mol Genet Asunto de la revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Atrofia Muscular Espinal / Ribonucleoproteínas Nucleares Pequeñas / Proteínas del Complejo SMN Tipo de estudio: Prognostic_studies Límite: Animals / Humans Idioma: En Revista: Hum Mol Genet Asunto de la revista: BIOLOGIA MOLECULAR / GENETICA MEDICA Año: 2018 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido