José Pereira-Monteiro

A dominant-negative mutation in the TRESK potassium channel is linked to familial migraine with aura

Migraine with aura is a common, debilitating, recurrent headache disorder associated with transient and reversible focal neurological symptoms. A role has been suggested for the two-pore domain (K2P) potassium channel, TWIK-related spinal cord potassium channel (TRESK, encoded by KCNK18), in pain pathways and general anaesthesia. We therefore examined whether TRESK is involved in migraine by screening the KCNK18 gene in subjects diagnosed with migraine. Here we report a frameshift mutation, F139WfsX24, which segregates perfectly with typical migraine with aura in a large pedigree. We also identified prominent TRESK expression in migraine-salient areas such as the trigeminal ganglion. Functional characterization of this mutation demonstrates that it causes a complete loss of TRESK function and that the mutant subunit suppresses wild-type channel function through a dominant-negative effect, thus explaining the dominant penetrance of this allele. These results therefore support a role for TRESK in the pathogenesis of typical migraine with aura and further support the role of this channel as a potential therapeutic target.

Divergent sodium channel defects in familial hemiplegic migraine

Familial hemiplegic migraine type 3 (FHM3) is a severe autosomal dominant migraine disorder caused by mutations in the voltage-gated sodium channel NaV1.1 encoded by SCN1A. We determined the functional consequences of three mutations linked to FHM3 (L263V, Q1489K, and L1649Q) in an effort to identify molecular defects that underlie this inherited migraine disorder. Only L263V and Q1489K generated quantifiable sodium currents when coexpressed in tsA201 cells with the human β1 and β2 accessory subunits. The third mutant, L1649Q, failed to generate measurable whole-cell current because of markedly reduced cell surface expression. Compared to WT-NaV1.1, Q1489K exhibited increased persistent current but also enhanced entry into slow inactivation as well as delayed recovery from fast and slow inactivation, thus resulting in a predominantly loss-of-function phenotype further demonstrated by a greater loss of channel availability during repetitive stimulation. In contrast, L263V exhibited gain-of-function features, including delayed entry into, as well as accelerated recovery from, fast inactivation; depolarizing shifts in the steady-state voltage dependence of fast and slow inactivation; increased persistent current; and delayed entry into slow inactivation. Notably, the two mutations (Q1489K and L1649Q) that exhibited partial or complete loss of function are linked to typical FHM, whereas the gain-of-function mutation L263V occurred in a family having both FHM and a high incidence of generalized epilepsy. We infer from these data that a complex spectrum of NaV1.1 defects can cause FHM3. Our results also emphasize the complex relationship between migraine and epilepsy and provide further evidence that both disorders may share common molecular mechanisms.

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

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.

BDNF and CGRP interaction: implications in migraine susceptibility.

Objectives: Migraine pathophysiology involves several pathways. Our aims were to explore a possible role of the brain-derived neurotrophic factor gene (BDNF) in migraine susceptibility; to study, for the first time, the calcitonin gene-related peptide gene (CGRP); and a possible interaction between the two. Methods: Using a case-control approach, four tagging single nucleotide polymorphisms (SNPs) (rs7124442, rs6265, rs11030107, and rs2049046) of BDNF and one tagging SNP—rs1553005—of CGRP were analyzed in 188 cases and 287 controls. A multivariable logistic regression was performed, adjusting for gender. Allelic and haplotypic frequencies were estimated. Interaction was assessed by a stepwise multivariable-logistic regression and confirmed by a multifactor dimensionality reduction analysis. Results: No significant main effects were found; however, a significant interaction was found between BDNF and CGRP, showing an increased risk for the AT-genotype of rs2049046 and the GC-genotype of rs1553005 (odds ratio = 1.88, 95% confidence interval: 1.20–2.93) for migraineurs. Conclusion: Our data support the hypothesis of an interaction between BDNF and CGRP in migraine susceptibility that should be further explored.

Two novel functional mutations in the Na+,K+-ATPase alpha2-subunit ATP1A2 gene in patients with familial hemiplegic migraine and associated neurological phenotypes.

Mutations in the ATP1A2 gene, encoding the α2‐subunit of the Na+,K+‐ATPase, are associated with familial hemiplegic migraine type 2. The majority of ATP1A2 mutations were reported in patients with hemiplegic migraine without any additional neurological findings. Here, we report on two novel ATP1A2 mutations that were identified in two Portuguese probands with hemiplegic migraine and interesting additional clinical features. The proband’s of family 1 (with a V362E mutation) had mood alterations, classified as a borderline personality. The proband in family 2 (with a P796S mutation) had mild mental impairment, in addition to hemiplegic migraine; more severe mental retardation was observed in his brother, who also had hemiplegic migraine and carried the same mutation. Cell‐survival assays clearly showed abnormal functioning of mutant Na+,K+‐ATPase, indicating that both ATP1A2 mutants are disease causing. Additionally, our results suggest a possible causal relationship of the ATP1A2 mutations with the complex clinical phenotypes observed in the probands.

Familial Clustering of Migraine: Further Evidence From a Portuguese Study

Objective.— Our aim was to evaluate familial aggregation of migraine in a large group of Portuguese families, and to assess if familial aggregation differs between MA and MO.

Recurrent ATP1A2 mutations in Portuguese families with familial hemiplegic migraine

AbstractFamilial hemiplegic migraine is a rare autosomal dominant subtype of migraine with aura. Three genes have been identified, all involved in ion transport. There is considerable clinical variation associated with FHM mutations. Genotype-phenotype correlation studies are needed, but are challenging mainly because the number of carriers of individual mutations is low. One exception is the recurrent T666M mutation in the FHM1 CACNA1A gene that was identified in almost one-third of FHM families and showed variable associated clinical features and severity, both within and among FHM families. Similar studies in the FHM2 ATP1A2 gene have not been performed because of the low number of carriers with individual mutations. Here we report on the recurrence of ATP1A2 mutations M731T and T376M that affect sodium-potassium pump functioning in two Portuguese FHM families. Considerably increasing the number of mutation carriers with these mutations indicated a clear genotype-phenotype correlation: both mutations are associated with pure FHM. In addition, we show that recurrent mutations for ATP1A2 are more frequent than previously thought, which has implications for genotype-phenotype correlations and genetic testing.

The C677T Polymorphism in MTHFR Is Not Associated with Migraine in Portugal

Migraine is a debilitating disorder affecting a large proportion of the population. The effect of methylenetrathydrofolate reductase (GeneID: 4524) polymorphisms in migraine etiology and development has been a theme of great interest. Several populations were evaluated with contradictory results. In this case-control study, we investigated the effect of the C677T polymorphism in MTHFR, as a genetic risk factor for migraine, in the Portuguese population. We observed that, overall, there was no significant difference in the frequencies of MTHFR C677T genotypes or of the T-allele among the Portuguese migraineurs when compared to controls. There was also no association of migraine with aura with MTHFR genotypes or with the T-allele, in contrast with previous studies. Regarding the risk of the T-allele homozygote carriers, there was an equal probability to develop migraine with aura over migraine without aura in our patients. Thus, we conclude that the C677T MTHFR polymorphism, responsible for a reduction of the MTHFR activity in folate metabolism, is not a major genetic susceptibility factor for migraine in the Portuguese population.

Cerebellar Ataxia, Hemiplegic Migraine, and Related Phenotypes Due to a CACNA1A Missense Mutation 12-Year Follow-up of a Large Portuguese Family

OBJECTIVE To document and discuss the broad phenotypic variability in a Portuguese family with cerebellar ataxia, hemiplegic migraine, and related syndromes caused by missense mutation c.1748 (p.R583Q) in the CACNA1A gene. DESIGN Observational 12-year follow-up study. SETTING Community and hospital care. PATIENTS Sixteen patients in a 4-generation family were identified in 1998 in a population-based survey. The follow-up revealed 28 patients (25 of whom were observed) and 32 unaffected relatives with an a priori risk of 50%. RESULTS Four major phenotypes (migraine with multiple auras, transient focal neurological deficits without headache, coma triggered by minor head trauma, and slowly progressive cerebellar ataxia) were present in various combinations. The initial manifestation was ataxia in 16 patients and a transient episode in 12 patients. Eighteen patients did not have migraine, and 11 showed only ataxia. The c.1748 (p.R583Q) mutation in CACNA1A was confirmed in all 23 of the patients who were tested but was not found in any of the 27 adult relatives. The CACNA1A CAG repeat expansion was excluded. CONCLUSIONS A unique missense mutation in the CACNA1A gene, which exhibits a very high penetrance and expressivity, may present a phenotypic spectrum that is broader than current descriptions. Single-gene disorders can behave as complex traits, which reinforces the importance of genetic modifiers in the tightly regulated function of P/Q-type calcium channels. The clinical spectrum of missense mutation CACNA1A -related disorders is much broader than strictly familial hemiplegic migraine.

A role for endothelin receptor type A in migraine without aura susceptibility? A study in Portuguese patients.

Background and purpose:  Migraine is a common neurological disabling disorder, and anomalies of vascular function have been implied in its pathophysiology. Several findings point to a possible role of the endothelin receptor type A (EDNRA) in migraine. We aim to assess the involvement of endothelin receptor type A (EDNRA) in migraine susceptibility in a sample of Portuguese migraineurs.