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Epilepsy-Associated Variants of a Single SCN1A Codon Exhibit Divergent Functional Properties.

Lanie N Liebovitz1, Christopher H Thompson1, Linda C Laux2

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SCN1A variants cause epilepsy, but predicting their function is hard. Even variants at the same codon can have different effects, showing position alone isn't enough to predict pathogenicity.

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Area of Science:

  • Neurogenetics
  • Molecular biology
  • Epilepsy research

Background:

  • Pathogenic variants in SCN1A, encoding the NaV1.1 channel, cause various epilepsy syndromes.
  • Dravet syndrome is linked to loss-of-function variants, while DEE is linked to gain-of-function variants.
  • Predicting SCN1A variant pathogenicity is challenging due to limited data.

Purpose of the Study:

  • Investigate functional properties of four SCN1A variants at the same codon (I1347).
  • Correlate channel dysfunction with clinical phenotype in epilepsy.
  • Improve strategies for predicting SCN1A variant pathogenicity.

Main Methods:

  • Performed whole-cell manual patch-clamp recordings on heterologously expressed NaV1.1 variants.
  • Utilized AlphaFold 3 for structural modeling of NaV1.1 variant proteins.
  • Analyzed clinical data from a patient and literature/ClinVar cases.

Main Results:

  • Described a DEE case with SCN1A-I1347T; identified three other cases with I1347N, I1347V, I1347F variants.
  • Functional studies revealed mixed function for I1347T, I1347V, I1347F, and loss-of-function for I1347N.
  • Structural models indicated disrupted interactions at isoleucine-1347, especially with I1347N.

Conclusions:

  • SCN1A variants at the same codon can exhibit diverse functional effects.
  • Predicting SCN1A variant pathogenicity solely based on position is unreliable.
  • Understanding variant function requires comprehensive analysis beyond simple location.