Two novel families with hemiplegic migraine caused by recurrent SCN1A mutation p.F1499L

Background Familial hemiplegic migraine type 3 is a monogenic subtype of migraine caused by missense mutations in the neuronal voltage-gated sodium channel gene SCN1A, with 10 different mutations reported so far. In two familial hemiplegic migraine type 3 families, partial cosegregation with a rare eye phenotype (elicited repetitive daily blindness) was previously reported. Methods Two novel familial hemiplegic migraine pedigrees were subjected to genetic analysis and detailed work-up of associated clinical features. Results In both pedigrees, we identified SCN1A mutation p.F1499L, which has been previously associated with familial hemiplegic migraine type 3 and elicited repetitive daily blindness. Both families displayed a pure familial hemiplegic migraine phenotype without evidence of an episodic eye phenotype. Conclusion Like a substantial proportion of other familial hemiplegic migraine type 3 mutations, p.F1499L affects the intracellular linker between domains III and IV of SCN1A, which seems to be a mutational hot-spot. Our new data establish p.F1499L as a recurrent familial hemiplegic migraine type 3 mutation. Elicited repetitive daily blindness seems to be a rare phenomenon in familial hemiplegic migraine type 3, even in carriers of the same mutation.

Download Full-text

Novel SCN1A mutation in the IFMT motif of the α1 subunit of the voltage-gated NaV1.1 channel causing familial hemiplegic migraine

The Journal of Headache and Pain ◽

10.1186/1129-2377-14-s1-p19 ◽

2013 ◽

Vol 14 (S1) ◽

Cited By ~ 1

Author(s):

B De Vries ◽

CM Weller ◽

O De Fàbregues ◽

SC Koelewijn ◽

AH Stam ◽

...

Keyword(s):

Familial Hemiplegic Migraine ◽

Hemiplegic Migraine ◽

Voltage Gated ◽

Scn1a Mutation ◽

Α1 Subunit

Download Full-text

A novel SCN1A mutation identified in a Chinese family with familial hemiplegic migraine: A case report

Cephalalgia ◽

10.1177/0333102416677049 ◽

2016 ◽

Vol 37 (13) ◽

pp. 1294-1298 ◽

Cited By ~ 6

Author(s):

Yang Zhang ◽

Ning Chen ◽

Muke Zhou ◽

Jian Guo ◽

Jiang Guo ◽

...

Keyword(s):

Novel Mutation ◽

Clinical Manifestations ◽

Gene Mutations ◽

Familial Hemiplegic Migraine ◽

Chinese Family ◽

Hemiplegic Migraine ◽

Rare Type ◽

Scn1a Mutation ◽

Type 3 ◽

Scn1a Gene

Background Familial hemiplegic migraine (FHM) is a rare type of migraine with aura that is characterized by transient hemiparesis. Mutations in three genes (CACNA1A, ATP1A2, and SCN1A) have been found to cause FHM. Among these, nine SCN1A gene mutations were reported to cause familial hemiplegic migraine type 3 (FHM3). However, none of them was reported in China. Method The clinical manifestations of a Chinese FHM family were recorded and all coding exons and flanking intronic regions of the CACNA1A, ATP1A2, and SCN1A genes were tested for mutations. Results All FHM patients in the investigated family have typical hemiplegic migraine attacks characteristic of FHM. We identified a novel mutation (p.Leu1670Trp) of the SCN1A gene. The affected amino acid is highly conserved across different species and therefore likely plays an important role in SCN1A gene function. Conclusion The identification of a novel mutation in the SCN1A gene in the Chinese population may further aid in the understanding of FHM genetics.

Download Full-text

Novel SCN1A mutation in the IFMT motif of the α1 subunit of the voltage-gated NaV1.1 channel causing familial hemiplegic migraine

The Journal of Headache and Pain ◽

10.1186/1129-2377-1-s1-p19 ◽

2013 ◽

Vol 1 (Suppl 1) ◽

pp. P19

Author(s):

B De Vries ◽

CM Weller ◽

O De Fàbregues ◽

SC Koelewijn ◽

AH Stam ◽

...

Keyword(s):

Familial Hemiplegic Migraine ◽

Hemiplegic Migraine ◽

Voltage Gated ◽

Scn1a Mutation ◽

Α1 Subunit

Download Full-text

Familial Hemiplegic Migraine Type 3 (FHM3) With an SCN1A Mutation in a Chinese Family: A Case Report

Frontiers in Neurology ◽

10.3389/fneur.2018.00976 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 1

Author(s):

Na Shao ◽

Haining Zhang ◽

Xue Wang ◽

Wuqiong Zhang ◽

Miaomiao Yu ◽

...

Keyword(s):

Case Report ◽

Familial Hemiplegic Migraine ◽

Chinese Family ◽

Hemiplegic Migraine ◽

Scn1a Mutation ◽

Type 3

Download Full-text

First Mutation in the Voltage-Gated Nav1.1 Subunit Gene SCN1A with Co-Occurring Familial Hemiplegic Migraine and Epilepsy

Cephalalgia ◽

10.1111/j.1468-2982.2008.01721.x ◽

2009 ◽

Vol 29 (3) ◽

pp. 308-313 ◽

Cited By ~ 57

Author(s):

M-J Castro ◽

AH Stam ◽

C Lemos ◽

B de Vries ◽

KRJ Vanmolkot ◽

...

Keyword(s):

Familial Hemiplegic Migraine ◽

Molecular Evidence ◽

Subunit Gene ◽

Hemiplegic Migraine ◽

Gene Encoding ◽

Voltage Gated ◽

Multiple Mutation ◽

Scn1a Mutation ◽

Almost All ◽

Scn1a Gene

Almost all mutations in the SCN1A gene, encoding the α1 subunit of neuronal voltage-gated Nav1.1 sodium channels, are associated with severe childhood epilepsy. Recently, two mutations were identified in patients with pure familial hemiplegic migraine (FHM). Here, we identified a novel SCN1A L263V mutation in a Portuguese family with partly co-segregating hemiplegic migraine and epilepsy. The L263V mutation segregated in five FHM patients, three of whom also had epileptic attacks, occurring independently from their hemiplegic migraine attacks. L263V is the first SCN1A mutation associated with FHM and co-occurring epilepsy in multiple mutation carriers, and is the clearest molecular link between migraine and epilepsy thus far. The results extend the clinical spectrum associated with SCN1A mutations and further strengthen the molecular evidence that FHM and epilepsy share, at least in part, similar molecular pathways.

Download Full-text

The familial hemiplegic migraine type 1 mutation K1336E affects direct G protein-mediated regulation of neuronal P/Q-type Ca2+ channels

Cephalalgia ◽

10.1177/0333102412475236 ◽

2013 ◽

Vol 33 (6) ◽

pp. 398-407 ◽

Cited By ~ 8

Author(s):

Edgar Garza-López ◽

Ricardo González-Ramírez ◽

María A Gandini ◽

Alejandro Sandoval ◽

Ricardo Felix

Keyword(s):

G Protein ◽

Familial Hemiplegic Migraine ◽

Inactivation Kinetics ◽

Missense Mutations ◽

Hemiplegic Migraine ◽

Gene Encoding ◽

Dominant Form ◽

Hek 293 ◽

Autosomal Dominant Form

Background Familial hemiplegic migraine type 1 (FHM-1) is an autosomal dominant form of migraine with aura characterized by recurrent migraine, hemiparesis and ataxia. FHM-1 has been linked to missense mutations in the CACNA1A gene encoding the pore-forming subunit of the neuronal voltage-gated P/Q-type Ca2+ channel (CaV2.1α1). Methods Here, we explored the effects of the FHM-1 K1336E mutation on G protein-dependent modulation of the recombinant P/Q-type channel. The mutation was introduced into the human CaV2.1α1 subunit and its functional consequences investigated after heterologous expression in HEK-293 cells using patch-clamp recordings. Results Functional analysis of the K1336E mutation revealed a reduction of Ca2+ current densities, a ∼10 mV left-shift in the current-voltage relationship, and the slowing of current inactivation kinetics. When co-expressed along with the human μ-opioid receptor, application of the agonist DAMGO inhibited whole-cell currents through both the wild-type and the mutant channels. Prepulse facilitation was also reduced by the K1336E mutation. Likewise, the kinetic analysis of the onset and decay of facilitation showed that the mutation affects the apparent dissociation and reassociation rates of the Gβγ dimer from the channel complex. Conclusions These results suggest that the extent of G-protein-mediated inhibition is significantly reduced in the K1336E mutant CaV2.1 Ca2+ channels. This alteration would contribute to render the neuronal network hyperexcitable, possibly as a consequence of reduced presynaptic inhibition, and may help to explain some aspects of the FHM-1 pathophysiology.

Download Full-text