A mutation in a rare type of intron in a sodium-channel gene results in aberrant splicing and causes myotonia

Kubota, T., Roca, X., Kimura, T., Kokunai, Y., Nishino, I., Sakoda, S., Krainer, A. R., Takahashi, M. P. (July 2011) A mutation in a rare type of intron in a sodium-channel gene results in aberrant splicing and causes myotonia. Human Mutation, 32 (7). pp. 773-782. ISSN 10597794 (ISSN)

URL: http://www.ncbi.nlm.nih.gov/pubmed/21412952
DOI: 10.1002/humu.21501

Abstract

Many mutations in the skeletal-muscle sodium-channel gene SCN4A have been associated with myotonia and/or periodic paralysis, but so far all of these mutations are located in exons. We found a patient with myotonia caused by a deletion/insertion located in intron 21 of SCN4A, which is an AT-AC type II intron. This is a rare class of introns that, despite having AT-AC boundaries, are spliced by the major or U2-type spliceosome. The patient's skeletal muscle expressed aberrantly spliced SCN4A mRNA isoforms generated by activation of cryptic splice sites. In addition, genetic suppression experiments using an SCN4A minigene showed that the mutant 5' splice site has impaired binding to the U1 and U6 snRNPs, which are the cognate factors for recognition of U2-type 5' splice sites. One of the aberrantly spliced isoforms encodes a channel with a 35-amino acid insertion in the cytoplasmic loop between domains III and IV of Nav1.4. The mutant channel exhibited a marked disruption of fast inactivation, and a simulation in silico showed that the channel defect is consistent with the patient's myotonic symptoms. This is the first report of a disease-associated mutation in an AT-AC type II intron, and also the first intronic mutation in a voltage-gated ion channel gene showing a gain-of-function defect.

Item Type: Paper
Subjects: bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > genes, structure and function
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > introns > intron splicing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > introns
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > ion channel
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
CSHL Authors:
Communities: CSHL labs > Krainer lab
CSHL Cancer Center Shared Resources > DNA Sequencing Service
Depositing User: Matt Covey
Date: July 2011
Date Deposited: 06 Feb 2013 14:49
Last Modified: 26 Dec 2014 20:10
Related URLs:
URI: http://repository.cshl.edu/id/eprint/27194

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