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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

Familial hemiplegic migraine (FHM) is a rare, autosomal dominant subtype of migraine, associated in half of the families with mutations in the CACNA1A gene located on chromosome 19p13, which encodes the Cav2.1-subunit of brain-specific P/Q-type calcium channels. Recently, mutations in a second gene, ATP1A2 on chromosome 1q23, which encodes a sodium-potassium exchange pump subunit, have been identified. The first functional studies indicate that A TP1A2 FHM mutations result in a loss of function of the pump, leading to an increase in extracellular potassium. This is known to evoke cortical spreading depression, the underlying mechanism of migraine aura.
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PMID:[From gene to disease; familial hemiplegic migraine as a result of mutations in a sodium-potassium pump gene]. 1549 90

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

Migraine is a complex, disabling disorder of the brain that manifests itself as attacks of often severe, throbbing head pain with sensory sensitivity to light, sound and head movement. There is a clear familial tendency to migraine, which has been well defined in a rare autosomal dominant form of familial hemiplegic migraine (FHM). FHM mutations so far identified include those in CACNA1A (P/Q voltage-gated Ca(2+) channel), ATP1A2 (N(+)-K(+)-ATPase) and SCN1A (Na(+) channel) genes. Physiological studies in humans and studies of the experimental correlate--cortical spreading depression (CSD)--provide understanding of aura, and have explored in recent years the effect of migraine preventives in CSD. Therapeutic developments in migraine have come by targeting the trigeminovascular system, with the most-recent being the proof-of-principle study of calcitonin gene-related peptide (CGRP) receptor antagonists in acute migraine. To understand the basic pathophysiology of migraine, brain imaging studies have firmly established reproducible changes in the brainstem in regions that include areas that are involved in sensory modulation. These data lead to the view that migraine is a form of sensory dysmodulatio--a system failure of normal sensory processing.
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PMID:Recent advances in understanding migraine mechanisms, molecules and therapeutics. 1714 70

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 an episodic headache disorder affecting as many as 10% of people worldwide. Familial hemiplegic migraine (FHM) is an autosomal dominant subtype of severe migraine accompanied by visual disturbances known as aura. Migrainous aura is caused by cortical spreading depression (CSD) - a slowly advancing wave of tissue depolarization in the cortex. More than half of FHM cases are caused by mutations in the CACNA1A gene, which encodes a neuronal Cav2.1 Ca2+ channel, resulting in increased Ca2+ flow into dendrites and excessive release of the excitatory neurotransmitter glutamate. In this issue of the JCI, Eikermann-Haerter et al. show that transgenic mice with FHM-associated mutations in Cacna1a have increased susceptibility to CSD compared with wild-type animals, likely due to augmentation of excitatory neurotransmission (see the related article beginning on page 99). Additional as-yet-undefined channel mutations may similarly render the migraine brain more susceptible to the initiation of CSD, with implications not only for the genesis of migraine but also for the hypoxic injury that accompanies its worst manifestation, complicated migraine.
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PMID:Deciphering migraine. 1910 50


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