ArticleHuman mutation2011
A mutation in a rare type of intron in a sodium-channel gene results in aberrant splicing and causes myotonia.
Article in Human mutation, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 27 citations in OpenAlex.
- Molecular genetics of skeletal muscle channelopathies.Journal of human genetics · 2025Review
- U6 snRNA m6A modification is required for accurate and efficient splicing of C. elegans and human pre-mRNAs.Nucleic acids research · 2024Article
- Clinical and molecular characterization of myotonia congenita using whole-exome sequencing in Egyptian patients.Molecular biology reports · 2024Article
- Article
- An Up-to-Date Overview of the Complexity of Genotype-Phenotype Relationships in Myotonic Channelopathies.Frontiers in neurology · 2019Review
- Quantitative Activity Profile and Context Dependence of All Human 5' Splice Sites.Molecular cell · 2018Article
- Polymorphism in ion channel genes of Dirofilaria immitis: Relevant knowledge for future anthelmintic drug design.International journal for parasitology. Drugs and drug resistance · 2016Article
- Noncanonical registers and base pairs in human 5' splice-site selection.Nucleic acids research · 2016Article
- Channelopathies of skeletal muscle excitability.Comprehensive Physiology · 2015Review
- Therapeutic strategies based on modified U1 snRNAs and chaperones for Sanfilippo C splicing mutations.Orphanet journal of rare diseases · 2014Article
- The maternal ITPK1 gene polymorphism is associated with neural tube defects in a high-risk Chinese population.PloS one · 2014Article
- Pick one, but be quick: 5' splice sites and the problems of too many choices.Genes & development · 2013Review
- Widespread recognition of 5' splice sites by noncanonical base-pairing to U1 snRNA involving bulged nucleotides.Genes & development · 2012Article
- Novel insights into the pathomechanisms of skeletal muscle channelopathies.Current neurology and neuroscience reports · 2012Review
- A novel N440K sodium channel mutation causes myotonia with exercise-induced weakness--exclusion of CLCN1 exon deletion/duplication by MLPA.Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology · 2011Article
Corrections and comments
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Authors and funding
8 authors at 4 institutions in 2 countries.
Funding
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.
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