SCN1A gain‐of‐function in early infantile encephalopathy

ABSTRACT

Objective

To elucidate the biophysical basis underlying the distinct and severe clinical presentation in patients with the recurrent missense SCN1A variant, p.Thr226Met. Patients with this variant show a well‐defined genotype‐phenotype correlation and present with developmental and early‐infantile epileptic encephalopathy that is far more severe than the typical SCN1A Dravet syndrome.

Methods

Whole cell patch clamp and dynamic action potential clamp were used to study T226M Na_v1.1 channels expressed in mammalian cells. Computational modeling was used to explore the neuronal scale mechanisms that account for altered action potential firing.

Results

T226M channels exhibited hyperpolarizing shifts of the activation and inactivation curves and enhanced fast inactivation. Dynamic action potential clamp hybrid simulation showed that model neurons containing T226M conductance displayed a left shift in rheobase relative to control. At current stimulation levels that produced repetitive active potential firing in control model neurons, depolarization block and cessation of action potential firing occurred in T226M model neuron. Fully computationally simulated neuron models recapitulated the findings from dynamic action potential clamp and also showed that heterozygous T226M models were also more susceptible to depolarization block.

Interpretation

From a biophysical perspective the T226M mutation produces gain‐of‐function. Somewhat paradoxically our data suggest that this gain‐of‐function would cause interneurons to more readily develop depolarization block. This "functional dominant negative" interaction would produce a more profound disinhibition than seen with haploinsufficiency that is typical of Dravet syndrome and could readily explain the more severe phenotype of patients with T226M mutation.

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