A targeted deleterious allele of the splicing factor SCNM1 in the mouse.
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.
Howell
Viive M
VM
Department of Human Genetics, University of Michigan, Ann Arbor, Michigan 48109-5618, USA.
de Haan
Georgius
G
Bergren
Sarah
S
Jones
Julie M
JM
Culiat
Cymbeline T
CT
Michaud
Edward J
EJ
Frankel
Wayne N
WN
Meisler
Miriam H
MH
D000483:Alleles; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D000067878:CELF Proteins; D019556:COS Cells; D002352:Carrier Proteins / Q000235:genetics*; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D018390:Gene Targeting; D047468:Immunoprecipitation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009069:Movement Disorders / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D018006:Myogenic Regulatory Factors / Q000235:genetics* / Q000378:metabolism; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D025941:Protein Interaction Mapping; D012326:RNA Splicing / Q000235:genetics*; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D012867:Skin / Q000166:cytology / Q000378:metabolism; D015222:Sodium Channels / Q000235:genetics* / Q000378:metabolism; D017381:Spliceosomes / Q000378:metabolism; D014162:Transfection; D020798:Two-Hybrid System Techniques
D000067878:CELF Proteins; D002352:Carrier Proteins; C470022:Celf4 protein, mouse; C491077:Mdfi protein, mouse; D018006:Myogenic Regulatory Factors; D062557:NAV1.6 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D000072260:RNA Splicing Factors; D016601:RNA-Binding Proteins; C491046:Scn8a protein, mouse; C476996:Scnm1 protein, mouse; D015222:Sodium Channels
J Med Genet. 2005 May;42(5):e29
15863661
Genes Dev. 1999 Sep 15;13(18):2425-38
10500099
J Mol Med (Berl). 2007 Feb;85(2):149-61
17206408
Annu Rev Neurosci. 2003;26:657-700
14527271
Biotechniques. 2001 Nov;31(5):1022-4, 1026
11730008
RNA. 2005 May;11(5):683-98
15840817
Cell. 2005 Oct 7;123(1):105-18
16213216
PLoS Genet. 2007 Jul;3(7):e124
17677002
EMBO J. 1998 Nov 2;17(21):6276-88
9799236
J Neurosci. 2005 Jan 19;25(3):748-57
15659613
Genetica. 2004 Sep;122(1):37-45
15619959
Biochem Biophys Res Commun. 2004 Jul 16;320(1):233-40
15207726
BMC Genomics. 2005 Nov 21;6:164
16300676
Nature. 2006 Nov 30;444(7119):580-6
17065982
Hum Mol Genet. 2002 Oct 15;11(22):2765-75
12374766
J Biol Chem. 1996 Jul 19;271(29):17576-81
8663325
Methods. 2005 Dec;37(4):345-59
16314264
Trends Genet. 2005 Sep;21(9):480-3
16039004
Am J Hum Genet. 2008 Apr;82(4):834-48
18371932
Cancer Sci. 2003 Aug;94(8):725-8
12901799
Cell. 2005 Jan 14;120(1):59-72
15652482
Am J Med Genet. 1998 May 18;77(3):228-33
9605590
Hum Mol Genet. 2007 Oct 15;16(20):2506-16
17656373
Ann Neurol. 2008 Jan;63(1):81-9
18059005
Mamm Genome. 2007 Jul;18(6-7):412-24
17514509
Genesis. 2007 Dec;45(12):768-75
18064676
Cell. 1996 Sep 6;86(5):731-41
8797820
Genes Immun. 2001 Dec;2(8):422-32
11781709
Nat Genet. 2005 Aug;37(8):844-52
16041372
Science. 2003 Aug 15;301(5635):967-9
12920299
Proc Natl Acad Sci U S A. 1996 Jun 11;93(12):5860-5
8650183
EMBO Rep. 2004 Nov;5(11):1071-7
15472711