Abstract
Mutations in the voltage-gated sodium channel Nav1.1 (SCN1A) are linked to various epileptic phenotypes with different severities, however, the consequences of newly identified SCN1A variants on patient phenotype is uncertain so far. The functional impact of nine SCN1A variants, including five novel variants identified in this study, was studied using whole-cell patch-clamp recordings measurement of mutant Nav1.1 channels expressed in HEK293T mammalian cells. E78X, W384X, E1587K, and R1596C channels failed to produce measurable sodium currents, indicating complete loss of channel function. E788K and M909K variants resulted in partial loss of function by exhibiting reduced current density, depolarizing shifts of the activation and hyperpolarizing shifts of the inactivation curves, and slower recovery from inactivation. Hyperpolarizing shifts of the activation and inactivation curves were observed in D249E channels along with slower recovery from inactivation. Slower recovery from inactivation was observed in E78D and T1934I with reduced current density in T1934I channels. Various functional effects were observed with the lack of sodium current being mainly associated with severe phenotypes and milder symptoms with less damaging channel alteration. In vitro functional analysis is thus fundamental for elucidation of the molecular mechanisms of epilepsy, to guide patients’ treatment, and finally indicate misdiagnosis of SCN1A related epilepsies.
Highlights
In almost 50% of epilepsy patients, SCN1A mutations arise de novo, whereas only around 9% of the patients inherit the mutation from an unaffected parent
The aim of this study was to investigate the electrophysiological properties of nine variants (p.Asp249Glu, p.Glu788Lys, p.Thr1934Ile, p.Arg1596Cys, p.Met909Lys, p.Trp384*, p.Glu78*, p.Glu78Asp, p.Glu1587Lys), which were identified in patients suffering from various epileptic phenotypes, such as GEFS+, EE, MAS, DS, as well as to determine the possible genotype-phenotype relationships
Our aim was to functionally characterise 9 SCN1A variants that were identified in this study (p.Asp249Glu, p.Glu788Lys, p.Met909Lys, p.Glu1587Lys, p.Thr1934Ile), including those from our previous study[19] (p.Trp384*, p.Glu78*) and the study by Mancardi (2006) (p.Glu78Asp)[20], as well as p.Arg1596Cys reported by several authors[6,21,22,23,24]
Summary
In almost 50% of epilepsy patients, SCN1A mutations arise de novo, whereas only around 9% of the patients inherit the mutation from an unaffected parent. De novo SCN1A mutations are observed in the severe phenotype of DS up to 60%. In comparison with others, such as GEFS+, de novo mutations are identified only in 3.7%12. Most of the identified mutations are novel, and difficult to predict the type of phenotype that will develop. In DS, more than 60% of the mutations are truncating, whereas in other syndromes, more than 60% are missense with almost 90% identified in GEFS+12. Gender Age at onset Normal development before onset Seizure types Family history Psychomotor retardation after 2 y of age Pharmaco-resistant
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