Nonfunctional NaV1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects

Sandrine Cestèle, Emanuele Schiavon, Raffaella Rusconi, Silvana Franceschetti, Massimo Mantegazza

Research output: Contribution to journalArticlepeer-review


Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura. Mutations causing FHM type 3 have been identified in SCN1A, the gene encoding the Nav1.1 Na+ channel, which is also a major target of epileptogenic mutations and is particularly important for the excitability of GABAergic neurons. However, functional studies of NaV1.1 FHM mutations have generated controversial results. In particular, it has been shown that the NaV1.1-L1649Q mutant is nonfunctional when expressed in a human cell line because of impaired plasma membrane expression, similarly to NaV1.1 mutants that cause severe epilepsy, but we have observed gain-offunction effects for other NaV1.1 FHM mutants. Here we show that NaV1.1-L1649Q is nonfunctional because of folding defects that are rescuable by incubation at lower temperatures or coexpression of interacting proteins, and that a partial rescue is sufficient for inducing an overall gain of function because of the modifications in gating properties. Strikingly, when expressed in neurons, the mutant was partially rescued and was a constitutive gain of function. A computational model showed that 35% rescue can be sufficient for inducing gain of function. Interestingly, previously described folding-defective epileptogenic NaV1.1 mutants show loss of function also when rescued. Our results are consistent with gain of function as the functional effect of NaV1.1 FHM mutations and hyperexcitability of GABAergic neurons as the pathomechanism of FHM type 3.

Original languageEnglish
Pages (from-to)17546-17551
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number43
Publication statusPublished - Oct 22 2013


  • Ankyrin
  • Calmodulin
  • Dravet syndrome
  • Generalized epilepsy with febrile seizures plus
  • Spreading depression

ASJC Scopus subject areas

  • General
  • Medicine(all)


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