Abstract
ObjectiveNaturally occurring in-frame deletion is a unique type of genetic variations, causing the loss of one or more amino acids of proteins. A number of in-frame deletion variants in an epilepsy-associated gene SCN1A, encoding voltage gated sodium channel alpha unit 1.1 (Nav1.1), have been reported in public database. In contrast to the missense and truncation variants, the in-frame deletions in SCN1A remains largely uncharacterized.MethodsWe summarized the basic information of forty-four SCN1A in-frame deletion variants and performed further analysis on six variants identified in our cases with epilepsy. Mutants of the six in-frame deletions and one truncating variant used as comparison were generated and co-transfected with beta-1 and -2 subunits in tsA201 cells, followed by patch clamp recordings.ResultsReviewing all the in-frame deletions showed that they spread over the entire Nav1.1 protein, without obvious “hot spots.” The dominant type (54%) was single residue loss. There was no obvious relationship between the length or locations of deletions and their clinical phenotypes. The six in-frame deletions were two single residue deletions (p.M400del and p.I1772del), one microdeletion (p.S128_F130del) and three macrodeletions (p.T303_R322del, p.T160_Y202del, and p.V1335_V1428del). They scatter and affect different functional domains, including transmembrane helices, pore region, and P-loop. Electrophysiological recordings revealed no measurable sodium current in all of the six mutants. In contrast, the truncating mutant p.M1619Ifs*7 that loses a long stretch of peptides retains partial function.SignificanceThe complete loss-of-function in these shortened, abnormal mutants indicates that Nav1.1 protein is a highly accurate structure, and many of the residues have no redundancy to ion conductance. In-frame deletions caused particularly deleterious effect on protein function possibly due to the disruption of ordered residues.
Highlights
Voltage-gated sodium channels (Nav) are responsible for the generation and propagation of action potentials in excitable membrane
Six in-frame deletions in SCN1A were identified in our cases with severe myoclonic epilepsy of infancy (SMEI), generalized epilepsy with febrile seizures plus (GEFS+), partial epilepsy with febrile seizures plus (PEFS+) and Lennox–Gastaut syndrome (LGS) (Table 1)
Genetic defects in the Nav α subunit can lead to various excitability diseases in brain, muscle, and heart, such as muscle paralysis, cardiac arrhythmias, and epileptic disorders (Meisler and Kearney, 2005; Lee et al, 2009; Remme and Bezzina, 2010; Kasperaviciute et al, 2013)
Summary
Voltage-gated sodium channels (Nav) are responsible for the generation and propagation of action potentials in excitable membrane These channels are complexes of one α subunit in association with two auxiliary β subunits. More than 1,800 epilepsy associated variants annotated for SCN1A have been reported in different databases, such as SCN1A database, the Human Gene Mutation Database (HGMD), and the ClinVar database of NCBI. Most of these are missense variants that lead to a single amino acid substitution, while there are a significant number of inframe deletions and premature truncations that lacks one or more amino acids. The naturally occurring inframe deletions would be unique and useful models to explore the underlying biology of Nav1.1, and the genotype-phenotype relationship as well
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