Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011570 (depression)
 172,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The field of migraine genetics has seen an explosion of information over the last year. In a recent breakthrough, missense mutations in a chromosome 1q23 gene, ATP1A2, encoding a Na+, K+-ATPase, have been identified in four distinct pedigrees with a rare form of familial hemiplegic migraine (FHM). ATP1A2 is expressed in the brain, like the voltage gated calcium channel gene, CACNA1A, previously identified as the first hemiplegic migraine gene (FHM1). The shared hemiplegic migraine phenotype of mutations in ATP1A2 and CACNA1A raises the possibility that they coordinately regulate ion homeostasis that determines susceptibility to the initiation of both migraine aura and the pain phase of migraine. For the more common and genetically complex forms of migraine, genome-wide screens have identified several new loci on 4q24, 6p12.2-21.1, 11q24, and 14q21.2-q22.3, suggesting additional migraine genes in these regions. In addition, a recent large case-control association study has linked single nucleotide polymorphisms in the insulin receptor/INSR gene with migraine. However, these polymorphisms do not result in detectable changes in receptor function. The continuing genetic identification of key proteins involved in migraine will refine our understanding of this common and sometimes debilitating disorder, which can strike during the most productive years of a person's life. Given the co-morbidity of migraine with depression and bipolar disorder, our knowledge of the causes of migraine may also contribute to our understanding of these disorders.
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PMID:Update on the genetics of migraine. 1462 54

Migraine is a common, disabling, multifactorial, episodic neurovascular disorder of unknown etiology. Familial hemiplegic migraine type 1 (FHM-1) is a Mendelian subtype of migraine with aura that is caused by missense mutations in the CACNA1A gene that encodes the alpha(1) subunit of neuronal Ca(v)2.1 Ca(2+) channels. We generated a knockin mouse model carrying the human pure FHM-1 R192Q mutation and found multiple gain-of-function effects. These include increased Ca(v)2.1 current density in cerebellar neurons, enhanced neurotransmission at the neuromuscular junction, and, in the intact animal, a reduced threshold and increased velocity of cortical spreading depression (CSD; the likely mechanism for the migraine aura). Our data show that the increased susceptibility for CSD and aura in migraine may be due to cortical hyperexcitability. The R192Q FHM-1 mouse is a promising animal model to study migraine mechanisms and treatments.
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PMID:A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading depression. 1500 66

Our knowledge about migraine pathogenesis has increased exponentially over the last decade and this greatly due to the advances in genetics. In familial hemiplegic migraine (FHM), the findings of mutations in the CACNA1A gene (19p13), coding for the pore-forming subunit (alpha1A) of neuronal voltage-dependent P/Q-type calcium channels (FHM1), and in the ATP1A2 gene (1q21-23), encoding the alpha2-subunit of the Na+, K+ ATPase ionic pump (FHM2) have focused attention on central nervous system ionic channels and helped to better understand FHM pathophysiology. A dysfunction of these channels modifies neuronal excitability (favouring spreading depression), chemical neurotransmission and, indirectly, neuronal metabolism. These channels may represent targets for novel anti-migraine drugs, which underscores their importance for the frequent forms of migraine (without or with aura). Studies of gene associations, neuromuscular transmission, cerebellar functions, neuronal excitability and metabolism and certain drug effects suggest indeed that ionic channels play a pathogenic role in migraine with aura patients. However, in the majority of patients they are probably not the sole culprit, since most of the frequent forms of migraine seem to have a more complex genetic predisposition based on a number of single nucleotide polymorphisms. The challenge for the next decade is to establish correlations between the geno- and the phenotype of migraine patients which needs more frequent and focused genetic studies and a more precise phenotype, based on clinical as well as on neurophysiologic and metabolic data.
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PMID:[Genetics of migraines: from ionic channels to single nucleotide polymorphisms?]. 1534 75

Recent advances in the studies of the genetic liability to migraine include the discovery of two genes responsible for familial hemiplegic migraine (FHM) and the analysis of several sites of linkage or genetic association for the so-called typical migraines, e. g., migraine with (MA) and without aura (MO). The 2 genes implicated in the genetics of FHM are CACNA1A for FHM1 and ATP1A2 for FHM2. It is still unclear how dysfunction in these genes may trigger attacks of migraine with hemiplegic features and, in at least part of the families with FHM, also paroxysmal or progressive ataxia and epileptic seizures. It appears that mutations in CACNA1A responsible for FHM1 alter calcium influx and calcium currents in neurons, possible factors of spreading depression like events. On the other hand, abnormal regulation of intracellular calcium concentrations could alter neurotransmitter release and other cellular functions. In the case of ATP1A2 mutations, haplo-insufficiency of the gene has been hypothesised to result in abnormal potassium level regulation because of faulty Na/K exchange with subsequent depolarisation and increased liability to spreading depression, or/and in abnormal calcium levels because of the concomitant activation of the Na/Ca exchanger, with a mechanism therefore comparable to that at work in FHM1. Much more work is clearly necessary to elucidate these pathophysiological mechanisms; advances in genetics however may represent important steps in the clarification of the physiopathology of the migraine attack.
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PMID:The physiopathology of migraine: the contribution of genetics. 1554 78

A growing interest in genetic research in migraine has resulted in the identification of several chromosomal regions that are involved in migraine. However, the identification of mutations in the genes for familial hemiplegic migraine (FHM) forms the only true molecular genetic knowledge of migraine thus far. The increased number of mutations in the FHM1 (CACNA1A) and the FHM2 (ATP1A2) genes allow studying the relationship between genetic findings in both genes and the clinical features in patients. A wide spectrum of symptoms is seen in patients. Additional cerebellar ataxia and (childhood) epilepsy can occur in FHM1 and FHM2. Functional studies show a dysfunction in ion transport as the key factor in the pathophysiology of (familial hemiplegic) migraine that predict an increased susceptibility to cortical spreading depression--the underlying mechanism of migraine aura.
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PMID:Migraine genetics: an update. 1590 61

Twin and family studies provide evidence of a genetic component in migraine, in particular migraine with aura (MA). Familial hemiplegic migraine (FHM) is a rare monogenic subtype of MA for which three causative genes have been identified: CACNA1A (FHM1), ATP1A2 (FHM2), and SCN1A (FHM3). Mutations in these genes are also found in some patients with sporadic hemiplegic migraine. Linkage studies have identified several gene loci for the more common forms of migraine; however, identification of the respective causative genes is still pending. This review summarizes recent developments in the genetics of migraine and their implications for molecular genetic testing. We further discuss the roles of CACNA1A, ATP1A2, and SCN1A in the pathophysiology of cortical spreading depression, which is the likely correlate of migraine aura.
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PMID:[Genetics of migraine]. 1691 77

Familial hemiplegic migraine (FHM) is a rare and genetically heterogeneous autosomal dominant subtype of migraine with aura. Mutations in the genes CACNA1A and SCNA1A, encoding the pore-forming alpha(1) subunits of the neuronal voltage-gated Ca2+ channels Ca(V)2.1 and Na+ channels Na(V)1.1, are responsible for FHM1 and FHM3, respectively, whereas mutations in ATP1A2, encoding the alpha2 subunit of the Na+, K+ adenosinetriphosphatase (ATPase), are responsible for FHM2. This review discusses the functional studies of two FHM1 knockin mice and of several FHM mutants in heterologous expression systems (12 FHM1, 8 FHM2, and 1 FHM3). These studies show the following: (1) FHM1 mutations produce gain-of-function of the Ca(V)2.1 channel and, as a consequence, increased Ca(V)2.1-dependent neurotransmitter release from cortical neurons and facilitation of in vivo induction and propagation of cortical spreading depression (CSD: the phenomenon underlying migraine aura); (2) FHM2 mutations produce loss-of-function of the alpha2 Na+,K+-ATPase; and (3) the FHM3 mutation accelerates recovery from fast inactivation of Na(V)1.5 (and presumably Na(V)1.1) channels. These findings are consistent with the hypothesis that FHM mutations share the ability of rendering the brain more susceptible to CSD by causing either excessive synaptic glutamate release (FHM1) or decreased removal of K+ and glutamate from the synaptic cleft (FHM2) or excessive extracellular K+ (FHM3). The FHM data support a key role of CSD in migraine pathogenesis and point to cortical hyperexcitability as the basis for vulnerability to CSD and to migraine attacks. Hence, they support novel therapeutic strategies that consider CSD and cortical hyperexcitability as key targets for preventive migraine treatment.
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PMID:Familial hemiplegic migraine. 1739 38

Migraine is a common disabling brain disorder. A subtype of migraine with aura (familial hemiplegic migraine type 1: FHM1) is caused by mutations in Ca(V)2.1 (P/Q-type) Ca(2+) channels. Knockin mice carrying a FHM1 mutation show increased neuronal P/Q-type current and facilitation of induction and propagation of cortical spreading depression (CSD), the phenomenon that underlies migraine aura and may activate migraine headache mechanisms. We studied cortical neurotransmission in neuronal microcultures and brain slices of FHM1 mice. We show gain of function of excitatory neurotransmission due to increased action-potential-evoked Ca(2+) influx and increased probability of glutamate release at pyramidal cell synapses but unaltered inhibitory neurotransmission at fast-spiking interneuron synapses. Using an in vitro model of CSD, we show a causative link between enhanced glutamate release and CSD facilitation. The synapse-specific effect of FHM1 mutations points to disruption of excitation-inhibition balance and neuronal hyperactivity as the basis for episodic vulnerability to CSD ignition in migraine.
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PMID:Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading depression in Ca(v)2.1 knockin migraine mice. 1928 60

Migraine is a very common disabling brain disorder with unclear pathogenesis. A subtype of migraine with aura (familial hemiplegic migraine type 1: FHM1) is caused by mutations in CaV2.1 (P/Q-type) Ca2+ channels. This review describes the functional consequences of FHM1 mutations in knockin mouse models carrying the mild R192Q or severe S218L mutations in the orthologous gene. The FHM1 knockin mice show allele dosage-dependent gain-of-function of neuronal P/Q-type Ca2+ current, reflecting activation of mutant channels at lower voltages, and allele dosage- and sex-dependent facilitation of induction and propagation of cortical spreading depression (CSD), the phenomenon that underlies migraine aura. Gain-of-function of neuronal Ca2+ current, facilitation of CSD and post-CSD motor deficits were larger in S218L than R192Q knockin mice, in correlation with the more severe human S218L phenotype. Enhanced cortical excitatory neurotransmission, due to increased action potential-evoked Ca2+ influx and increased probability of glutamate release at pyramidal cell synapses, but unaltered inhibitory neurotransmission at fast-spiking interneuron synapses, were demonstrated in R192Q knockin mice. Evidence for a causative link between enhanced glutamate release and CSD facilitation was obtained. The data from FHM1 mice strengthen the view of CSD as a key player in the pathogenesis of migraine, give insight into CSD mechanisms and point to episodic disruption of excitation-inhibition balance and neuronal hyperactivity as the basis for vulnerability to CSD ignition in migraine.
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PMID:Insights into migraine mechanisms and CaV2.1 calcium channel function from mouse models of familial hemiplegic migraine. 2019 27

Familial hemiplegic migraine type 1 (FHM1) is caused by mutations in the CACNA1A gene, encoding neuronal presynaptic Ca(V)2.1 (P/Q-type) Ca(2+) channels. These channels mediate neurotransmitter release at many central synapses and at the neuromuscular junction (NMJ). Mutation S218L causes a severe neurological phenotype of FHM and, additionally, ataxia and susceptibility to seizures, delayed brain edema, and fatal coma after minor head trauma. Recently, we generated a Cacna1a S218L knock-in mutant mouse, displaying these features and reduced survival. A first electrophysiological study showed high susceptibility for cortical spreading depression, enhanced neuronal soma Ca(2+) influx, and at diaphragm NMJs, a considerable increase of neurotransmitter release. We here assessed the function of S218L knock-in NMJs at several muscle types in great detail. Pharmacological analyses using specific Ca(V) subtype-blocking toxins excluded compensatory contribution of non-Ca(V)2.1 channels. Endplate potentials were considerably broadened at many NMJs. High rate (40 Hz)-evoked acetylcholine release was slightly reduced; however, it was not associated with block of neurotransmission causing weakness, as assessed with grip strength measurements and in vitro muscle contraction experiments. The synaptopathy clearly progressed with age, including development of an increased acetylcholine release at low-rate nerve stimulation at physiological extracellular Ca(2+) concentration and further endplate potential broadening. Our results suggest enhanced Ca(2+) influx into motor nerve terminals through S218L-mutated presynaptic Ca(V)2.1 channels, likely because of the earlier reported negative shift of activation potential and reduced inactivation. Similar severe aberrations at central synapses of S218L mutant mice and humans may underlie or contribute to the drastic neurological phenotype.
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PMID:Severe and progressive neurotransmitter release aberrations in familial hemiplegic migraine type 1 Cacna1a S218L knock-in mice. 2063 Dec 22


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