Abstract:Familial hemiplegic migraine (FHM) is a rare autosomal-dominant subtype of migraine with aura, associated with hemiparesis during the aura. Here we describe a unique FHM family in which two novel allelic missense mutations in the Na,K-ATPase gene ATP1A2 segregate in the proband with hemiplegic migraine. Both mutations show reduced penetrance in family members of the proband. Cellular survival assays revealed Na,K-ATPase dysfunction for both ATP1A2 mutants, indicating that both mutations are disease causative. … Show more
“…These residues have been mapped onto a common structure for clarity. Citations for human ATP1A2 mutations: Ambrosini et al (2005), Castro et al (2008), De Fusco et al (2003), Fernandez et al (2008), Gallanti et al (2008), Jen et al (2007), Jurkat-Rott et al (2004), Kaunisto et al (2004), Koenderink et al (2005), Pierelli et al (2006), Riant et al (2005), Segall et al (2004, 2005), Spadaro et al (2004), Swoboda et al (2004), Todt et al (2005), Vanmolkot et al (2003, 2006a, b, 2007). Citations for human ATP1A3 mutations: Brashear et al (2007), de Carvalho Aguiar et al (2004), Kamm et al (2008), Zanotti-Fregonara et al (2008)Fig.…”
Mutations affecting the Na+, K+ ATPase alpha subunit have been implicated in at least two distinct human diseases, rapid-onset dystonia Parkinsonism (RDP), and familial hemiplegic migraine (FHM). Over 40 mutations have been mapped to the human ATP1A2 and ATP1A3 genes and are known to result in RDP, FHM or a variant of FHM with neurological complications. To develop a genetically tractable model system for investigating the role of the Na+, K+ ATPase in neural pathologies we performed genetic screens in Drosophila melanogaster to isolate loss-of-function alleles affecting the Na+, K+ ATPase alpha subunit. Flies heterozygous for these mutations all exhibit reduced respiration, consistent with a loss-of-function in the major ATPase. However, these mutations do not affect all functions of the Na+, K+ ATPase alpha protein since embryos homozygous for these mutations have normal septate junction paracellular barrier function and tracheal morphology. Importantly, all of these mutations cause neurological phenotypes and, akin to the mutations that cause RDP and FHM, these new alleles are missense mutations. All of these alleles exhibit progressive stress-induced locomotor impairment suggesting neuromuscular dysfunction, yet neurodegeneration is observed in an allele-specific manner. Surprisingly, studies of longevity demonstrate that mild hypomorphic mutations in the sodium pump significantly improve longevity, which was verified using the Na+, K+ ATPase antagonist ouabain. The isolation and characterization of a series of new missense alleles of ATPalpha in Drosophila provides the foundation for further studies of these neurological diseases and the role of sodium pump impairment in animal longevity.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-009-0673-2) contains supplementary material, which is available to authorized users.
“…These residues have been mapped onto a common structure for clarity. Citations for human ATP1A2 mutations: Ambrosini et al (2005), Castro et al (2008), De Fusco et al (2003), Fernandez et al (2008), Gallanti et al (2008), Jen et al (2007), Jurkat-Rott et al (2004), Kaunisto et al (2004), Koenderink et al (2005), Pierelli et al (2006), Riant et al (2005), Segall et al (2004, 2005), Spadaro et al (2004), Swoboda et al (2004), Todt et al (2005), Vanmolkot et al (2003, 2006a, b, 2007). Citations for human ATP1A3 mutations: Brashear et al (2007), de Carvalho Aguiar et al (2004), Kamm et al (2008), Zanotti-Fregonara et al (2008)Fig.…”
Mutations affecting the Na+, K+ ATPase alpha subunit have been implicated in at least two distinct human diseases, rapid-onset dystonia Parkinsonism (RDP), and familial hemiplegic migraine (FHM). Over 40 mutations have been mapped to the human ATP1A2 and ATP1A3 genes and are known to result in RDP, FHM or a variant of FHM with neurological complications. To develop a genetically tractable model system for investigating the role of the Na+, K+ ATPase in neural pathologies we performed genetic screens in Drosophila melanogaster to isolate loss-of-function alleles affecting the Na+, K+ ATPase alpha subunit. Flies heterozygous for these mutations all exhibit reduced respiration, consistent with a loss-of-function in the major ATPase. However, these mutations do not affect all functions of the Na+, K+ ATPase alpha protein since embryos homozygous for these mutations have normal septate junction paracellular barrier function and tracheal morphology. Importantly, all of these mutations cause neurological phenotypes and, akin to the mutations that cause RDP and FHM, these new alleles are missense mutations. All of these alleles exhibit progressive stress-induced locomotor impairment suggesting neuromuscular dysfunction, yet neurodegeneration is observed in an allele-specific manner. Surprisingly, studies of longevity demonstrate that mild hypomorphic mutations in the sodium pump significantly improve longevity, which was verified using the Na+, K+ ATPase antagonist ouabain. The isolation and characterization of a series of new missense alleles of ATPalpha in Drosophila provides the foundation for further studies of these neurological diseases and the role of sodium pump impairment in animal longevity.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-009-0673-2) contains supplementary material, which is available to authorized users.
“…Also, given the reported functional interaction between M-type KCNQ2 and KCNQ3 potassium channels (19) and their modulation by the KCNE2 subunit (20), plus an account of compound heterozygosity for two novel allelic ATP1A2 missense mutations in the proband of a FHM family (21), we also tested for interactions between SNPs with nominally significant ( P < 0.005) association signals in the Finnish sample.…”
The clinical overlap between monogenic Familial Hemiplegic Migraine (FHM) and common migraine subtypes, and the fact that all three FHM genes are involved in the transport of ions, suggest that ion transport genes may underlie susceptibility to common forms of migraine. To test this leading hypothesis, we examined common variation in 155 ion transport genes using 5257 single nucleotide polymorphisms (SNPs) in a Finnish sample of 841 unrelated migraine with aura cases and 884 unrelated non-migraine controls. The top signals were then tested for replication in four independent migraine caseâcontrol samples from the Netherlands, Germany and Australia, totalling 2835 unrelated migraine cases and 2740 unrelated controls. SNPs within 12 genes (KCNB2, KCNQ3, CLIC5, ATP2C2, CACNA1E, CACNB2, KCNE2, KCNK12, KCNK2, KCNS3, SCN5A and SCN9A) with promising nominal association (0.00041 < P < 0.005) in the Finnish sample were selected for replication. Although no variant remained significant after adjusting for multiple testing nor produced consistent evidence for association across all cohorts, a significant epistatic interaction between KCNB2 SNP rs1431656 (chromosome 8q13.3) and CACNB2 SNP rs7076100 (chromosome 10p12.33) (pointwise P = 0.00002; global P = 0.02) was observed in the Finnish caseâcontrol sample. We conclude that common variants of moderate effect size in ion transport genes do not play a major role in susceptibility to common migraine within these European populations, although there is some evidence for epistatic interaction between potassium and calcium channel genes, KCNB2 and CACNB2. Multiple rare variants or trans-regulatory elements of these genes are not ruled out.
“…All mutants except I286T showed no or hardly any cell survival. Mutant I286T showed abnormal, but partial, cell survival [11]. I286T was identified in the proband of a British family with FHM who also had mutation T415M, but in the other allele.…”
Section: Recent Findingsmentioning
confidence: 90%
“…Four mutations (i.e. R65W [10], I286T [11], T415M [11], and R763C [7]) were associated with pure FHM, that is without additional clinical features such as seizures or ataxia. Two FHM mutations (i.e.…”
Section: Recent Findingsmentioning
confidence: 99%
“…Only for five of the eleven (i.e. I286T [11], V362E [12], T415M [11], P796S [12] and R1002Q [14]) novel FHM2 mutations were such functional tests performed. All mutants except I286T showed no or hardly any cell survival.…”
Many novel ATP1A2 mutations were identified in patients with familial and sporadic hemiplegic migraine. In sporadic patients, ATP1A2 screening has the highest chance of finding a causal mutation. A second FHM3 mutation definitely established the epilepsy SCN1A gene as a migraine gene. The discovery of genes in monogenic diseases in which migraine is prominent may lead to new insights in the molecular pathways involved in migraine pathophysiology.
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