Intragenic complementation of amino and carboxy terminal SMN missense mutations can rescue Smn null mice
| Autor: | Aurélie Massoni-Laporte, Kaitlyn M Kray, Daniel J. Battle, Eileen Workman, Vicki L. McGovern, Arthur H.M. Burghes, W. David Arnold, Sandra I Duque, Chitra C. Iyer, Aalapi Patel |
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| Rok vydání: | 2020 |
| Předmět: |
animal diseases
Transgene Mutation Missense SMN1 Biology medicine.disease_cause Muscular Atrophy Spinal Mice 03 medical and health sciences 0302 clinical medicine Genetics medicine Animals Humans Missense mutation Genetic Predisposition to Disease snRNP Amino Acids Allele Molecular Biology Alleles Genetics (clinical) 030304 developmental biology Mice Knockout Motor Neurons 0303 health sciences Mutation SMN Complex Proteins Exons General Medicine Spinal muscular atrophy Ribonucleoproteins Small Nuclear medicine.disease Survival of Motor Neuron 1 Protein nervous system diseases Survival of Motor Neuron 2 Protein Complementation Disease Models Animal nervous system General Article Protein Multimerization 030217 neurology & neurosurgery |
| Zdroj: | Hum Mol Genet |
| ISSN: | 1460-2083 0964-6906 |
| DOI: | 10.1093/hmg/ddaa235 |
| Popis: | Spinal muscular atrophy is caused by reduced levels of SMN resulting from the loss of SMN1 and reliance on SMN2 for the production of SMN. Loss of SMN entirely is embryonic lethal in mammals. There are several SMN missense mutations found in humans. These alleles do not show partial function in the absence of wild-type SMN and cannot rescue a null Smn allele in mice. However, these human SMN missense allele transgenes can rescue a null Smn allele when SMN2 is present. We find that the N- and C-terminal regions constitute two independent domains of SMN that can be separated genetically and undergo intragenic complementation. These SMN protein heteromers restore snRNP assembly of Sm proteins onto snRNA and completely rescue both survival of Smn null mice and motor neuron electrophysiology demonstrating that the essential functional unit of SMN is the oligomer. |
| Databáze: | OpenAIRE |
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