A rescuable folding defective Nav1.1 (SCN1A) sodium channel mutant causes GEFS+: Common mechanism in Nav1.1 related epilepsies?

Rusconi, Raffaella; Combi, Romina; Cestèle, Sandrine; Grioni, Daniele; Franceschetti, Silvana; Dalprà, Leda; Mantegazza, Massimo

doi:10.1002/humu.21041

Cited by 57 publications

(43 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Na + channel principal α subunits are associated with accessory β subunits, and have stable interactions also with several other proteins (26,27). As highlighted previously, accessory β1 or β2 subunits did not rescue L1649Q, differently than for other Na V 1.1 mutants (21,22,24). However, ankyrin G and calmodulin did, even if to a much lower extent than incubation at 30°C.…”

Section: Significancementioning

confidence: 54%

“…Thus, a limited partial rescue is sufficient for transforming L1649Q into a gain-of-function mutant, as shown by our computational model. Importantly, the epileptogenic folding-defective Na V 1.1 mutants that we and others have studied are characterized by loss of function also when rescued (21)(22)(23)(24).…”

Section: Significancementioning

confidence: 71%

“…L1649Q has been identified in a four-generation family with eight members presenting with FHM, without epilepsy or other neurologic symptoms (19); this is a puzzling result more consistent with a phenotype of severe epilepsy (7,8). We have found that Na V 1.1 epileptogenic mutations can induce loss of function by causing folding defects (20), which can be partially rescued by incubation of the transfected cells at lower temperatures (≤30°C) or by molecular interactions (21,22), as recently confirmed also for other epileptogenic Na V 1.1 mutants (23,24). We report here that L1649Q is a folding-defective mutant that, when partially rescued, is characterized by an overall gain of function, consistent with our hypothesis of FHM type 3 pathomechanism (16).…”

mentioning

confidence: 85%

“…1A). To find out if L1649Q induced this nearly complete loss of function because of folding defects, we incubated the transfected cells at 30°C for 36-48 h before the recordings (which were performed at room temperature as for the other experiments), a condition that can rescue several foldingdefective proteins (20)(21)(22). Fig.…”

Section: Significancementioning

confidence: 99%

“…Thus, L1649Q is a folding-defective mutant that can be functional in permissive conditions. Furthermore, we tested the effect of interacting proteins that can rescue folding-defective Na V 1.1 mutants (21,22). As displayed in Fig.…”

Section: Significancementioning

confidence: 99%

See 4 more Smart Citations

Nonfunctional Na _V 1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects

Cestèle

Schiavon

Rusconi

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

137

View full text Add to dashboard Cite

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 Na v 1.1 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 Na V 1.1 FHM mutations have generated controversial results. In particular, it has been shown that the Na V 1.1-L1649Q mutant is nonfunctional when expressed in a human cell line because of impaired plasma membrane expression, similarly to Na V 1.1 mutants that cause severe epilepsy, but we have observed gain-offunction effects for other Na V 1.1 FHM mutants. Here we show that Na V 1.1-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 Na V 1.1 mutants show loss of function also when rescued. Our results are consistent with gain of function as the functional effect of Na V 1.1 FHM mutations and hyperexcitability of GABAergic neurons as the pathomechanism of FHM type 3.spreading depression | Dravet syndrome | generalized epilepsy with febrile seizures plus | calmodulin | ankyrin

show abstract