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Human Molecular Genetics Advance Access published online on July 26, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm206
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© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Evidence for a direct role of the disease modifier SCNM1 in splicing

Viive M. Howell, Julie M. Jones, Sarah Bergren, Li Li, Allison C. Billi, Matthew R. Avenarius and Miriam H. Meisler*

Department of Human Genetics, University of Michigan School of Medicine, Ann Arbor, MI 48109-0618, USA

* Corresponding Author Details Miriam H. Meisler, Department of Human Genetics, University of Michigan School of Medicine, Ann Arbor, MI 48109-0618, USA. Telephone: 734 763 5546 Fax: 734 763 9691 Email: meislerm{at}umich.edu

Received July 9, 2007; Revised July 9, 2007; Accepted July 22, 2007

We originally isolated Scnm1 as a disease modifier gene that is required for efficient in vivo splicing of a mutant splice donor site in the sodium channel Scn8a. It was previously unclear whether the modifier effect on splicing was direct or indirect. We now report evidence that SCNM1 has a direct role in splicing. SCNM1 protein interacts with the spliceosome protein U1-70K in the yeast two-hybrid system, and is co-localized with U1-70K in nuclear speckles in mammalian cells. SCNM1 is also co-immunoprecipitated with the spliceosomal core Sm proteins and demonstrates functional activity in a minigene splicing assay. In a yeast two-hybrid screen, SCNM1 interacted with LUC7L2, a mammalian homolog of a yeast protein involved in recognition of nonconsensus splice donor sites. This interaction requires the acidic C-terminal domain of SCNM1 which is truncated by the disease susceptibility variant Scnm1R187X in mouse strain C57BL/6J. Luc7L2 transcripts are widely distributed in mammalian tissues, and undergo alternative splicing and polyadenylation. LUC7L2 is also co-localized with U1-70K and may function with SCNM1 in recognition of weak splice donor sites. In summary, Scnm1 is the first example of a modifier gene which influences disease severity through a trans effect on splicing of the disease gene transcript.


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