Abstract
The auxiliary spliceosomal protein SCNM1 contributes to recognition of nonconsensus splice donor sites. SCNM1 was first identified as a modifier of the severity of a sodium channelopathy in the mouse. The most severely affected strain, C57BL/6J, carries the variant allele SCNM1R187X, which is defective in splicing the mutated donor site in the Scn8a(medJ) transcript. To further probe the in vivo function of SCNM1, we constructed a floxed allele and generated a mouse with constitutive deletion of exons 3-5. The SCNM1Delta3-5 protein is produced and correctly localized to the nucleus, but is more functionally impaired than the C57BL/6J allele. Deficiency of SCNM1 did not significantly alter other brain transcripts. We characterized an ENU-induced allele of Scnm1 and evaluated the ability of wild-type SCNM1 to rescue lethal mutations of I-mfa and Brunol4. The phenotypes of the Scnm1Delta3-5 mutant confirm the role of this splice factor in processing the Scn8a(medJ) transcript and provide a new allele of greater severity for future studies.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Alleles
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Animals
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Blotting, Western
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Brain / metabolism
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CELF Proteins
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COS Cells
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Carrier Proteins / genetics*
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Cell Nucleus / genetics
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Cell Nucleus / metabolism
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Cells, Cultured
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Chlorocebus aethiops
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Female
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Fibroblasts / cytology
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Fibroblasts / metabolism
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Gene Deletion
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Gene Expression Profiling
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Gene Targeting*
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Immunoprecipitation
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Male
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Mice
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Mice, Inbred C57BL
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Movement Disorders / metabolism
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Movement Disorders / pathology
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Mutation / genetics
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Myogenic Regulatory Factors / genetics*
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Myogenic Regulatory Factors / metabolism
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NAV1.6 Voltage-Gated Sodium Channel
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Nerve Tissue Proteins / genetics*
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Nerve Tissue Proteins / metabolism
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Phenotype
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Protein Interaction Mapping
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RNA Splicing / genetics*
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RNA Splicing Factors
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RNA-Binding Proteins / genetics*
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RNA-Binding Proteins / metabolism
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Skin / cytology
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Skin / metabolism
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Sodium Channels / genetics*
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Sodium Channels / metabolism
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Spliceosomes / metabolism
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Transfection
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Two-Hybrid System Techniques
Substances
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CELF Proteins
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Carrier Proteins
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Celf4 protein, mouse
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Mdfi protein, mouse
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Myogenic Regulatory Factors
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NAV1.6 Voltage-Gated Sodium Channel
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Nerve Tissue Proteins
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RNA Splicing Factors
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RNA-Binding Proteins
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Scn8a protein, mouse
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Scnm1 protein, mouse
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Sodium Channels