Exclusion of 5‐HT_2A and 5‐HT_2C Receptor Genes as Candidate Genes for Migraine

Abstract

Several lines of investigation suggest that the serotonergic system may be involved in the pathogenesis of migraine. In particular, drugs which block 5-HT2 receptor subtypes appear to be effective migraine prophylactic agents. Therefore, chromosomal DNA regions overlapping the 5-HT2A (13q14-q22) and 5-HT2C(Xq22-25) receptor loci were analyzed for possible linkage to the clinical diagnosis of migraine. No evidence for linkage to either chromosomal region was found, although a small subset of migrainous families showed positive likelihood of odds (LOD) scores. However, a homogeneity (HOMOG) analysis provided no statistical evidence for locus heterogeneity. The coding region of the 5-HT2A and 5-HT2C receptor genes was also analyzed in migraine patients and unaffected controls using polmerase chain reaction and direct sequencing. No mutations were found in the deduced amino acid sequence of either receptor in the sample of migraineurs tested. These results indicate that DNA-based mutations in the 5-HT2A and 5-HT2C receptors are not generally involved in the pathogenesis of migraine.

An investigation of the 5‐HT2C receptor gene as a migraine candidate gene

“…These factors considered, it is important to analyse genetic variants in serotonergic genes as possible candidates for migraine predisposition. Previous publications have reported a negative association [Burnet et al, 1997] and exclusion of linkage [Buchwalder et al, 1996] for the ORF polymorphism in typical migraine. This study confirms a negative association and no evidence of linkage with the ORF (Cys23Ser) variant, but also reports no association or evidence of linkage with the 3 0 UTR variant identified by Song et al [1999].…”

“…An open reading frame (ORF) polymorphism resulting in a guanine to cytosine transversion, and a subsequent amino acid substitution (Cys23Ser) has been identified previously within the 5-HT 2C gene [Lappalainen et al, 1995]. Migraine investigations of this locus have been negative to date for association [Burnet et al, 1997] and linkage [Buchwalder et al, 1996]. More recently, a single nucleotide polymorphism (SNP) in the 3 0 untranslated region (3 0 UTR) of the 5-HT 2C gene has been identified [Song et al, 1999].…”

Current and prospective pharmacological targets in relation to antimigraine action

“…Involvement of the 5-HT 2 receptor in migraine is suggested by the 5-HT 2 receptor antagonist methysergide, which is also a partial agonist at 5-HT 1 receptors, and is used for migraine prophylaxis in severe cases where other preventive drugs are not effective (Silberstein 1998). The 5-HT 2A/2C receptor genes have been studied as candidate genes for migraine (Buchwalder et al 1996), but no mutations in the deduced amino acid sequence of either receptor in the sample of migraineurs was observed. Thus, the authors concluded that DNA-based mutations in the 5-HT 2A and 5-HT 2C receptors are not generally involved in the pathogenesis of migraine.…”

Migraine genetics and prospects for pharmacotherapy

“…Other important components of the serotonergic system are the 5-HT receptors, of which there are many subtypes throughout the brain. Although several anti-migraine drugs are 5-HT 2 receptor antagonists [Porter et al, 1999;Schaerlinger et al, 2003;Schmuck et al, 1996] and the 5-HT 2 receptor agonist metachlorophenylpiperazine has been shown to induce a migraine attack [Brewerton et al, 1988], several studies investigating genes encoding various 5-HT receptor subtypes have shown insufficient evidence for a role in migraine [Buchwalder et al, 1996;Burnet et al, 1997;Johnson et al, 2003;Juhasz et al, 2003;Nyholt et al, 1996;Racchi et al, 2004].…”