Variants in Human Prostacyclin Receptor Gene in Patients with Migraine Headache
AbstractObjective: Prostaglandin I2 receptor plays a major physiologic role in the relaxation of arterial smooth muscle and vasodilation and possibly during migraine attacks. Therefore, in this study, the coding and noncoding exons and exon-intron boundaries of Prostaglandin I2 receptor gene were examined in patients with migraine headache and healthy controls and the potential effects of identified single nucleotide variations were evaluated using direct PCR-sequencing and in silico analysis. Method: In this study, the peripheral blood samples of 50 patients and 50 controls were examined to find any mutation in coding and noncoding exons and exon-intron boundaries of PTGIR gene. DNA was extracted and all the samples were amplified by polymerase chain reaction (PCR) and sequenced. Results: In this study, the patients had a mean age of 35.235 ± 10.99 years (range, 9–60 yrs.), and female to male ratio was 4:1 in this group. The controls had a mean age of 35.058 ± 11.116 years (range, 8–59 yrs.), and female to male ratio was 3.7:1.3 in this group. Two patients had mutations in exon 2. The first mutation was located in exon 2 (at amino acid position 251) of PTGIR gene at nucleotide position c.866A > T, a synonymous variant described previously in the database. The second mutation was located in exon 2 c.867G > A, which is a missense variant. Sequence analysis revealed high occurrence of previously reported intronic variants mostly in a homozygous statue. Conclusion: The data supported the hypothesis that mutations in PTGIR gene, particularly the mutation we described, should be considered even in cases of migraine. The presence of this mutation in patients with family history raises important issues regarding genetic counselling.
Haut SR, Bigal ME, Lipton RB. Chronic disorders with episodic manifestations: focus on epilepsy and migraine. Lancet Neurol. 2006; 5: 148-157.
Society HCCotIH. The international classification of headache disorders, (beta version). Cephalalgia. 2013; 33: 629-808.
Jacobs B, Dussor G. Neurovascular contributions to migraine: Moving beyond vasodilation. Neuroscience 2016; 338: 130-144.
Honkasalo ML, Kaprio J, Winter T, Heikkilä K, Sillanpää M, Koskenvuo M. Migraine and concomitant symptoms among 8167 adult twin pairs. Headache 1995; 35: 70-78.
Gardner KL. Genetics of migraine: an update. Headache 2006; 46 Suppl 1: S19-S24.
Parsons AA, Strijbos PJ. The neuronal versus vascular hypothesis of migraine and cortical spreading depression. Curr Opin Pharmacol 2003; 3: 73-77.
Dodick DW. Examining the essence of migraine—is it the blood vessel or the brain? A debate. Headache 2008; 48: 661-667.
Tanaka Y, Yamaki F, Koike K, Toro L. New insights into the intracellular mechanisms by which PGI2 analogues elicit vascular relaxation: cyclic AMP-independent, Gs-protein mediated-activation of MaxiK channel. Curr Med Chem Cardiovasc Hematol Agents 2004; 2: 257-265.
Armstead W. Role of nitric oxide and cAMP in prostaglandin-induced pial arterial vasodilation. Am J Physiol 1995; 268: H1436-H1440.
Wienecke T, Olesen J, Ashina M. Prostaglandin I2 (epoprostenol) triggers migraine‐like attacks in migraineurs. Cephalalgia 2009; 30: 179-190.
Negash S, Gao Y, Zhou W, Liu J, Chinta S, Raj JU. Regulation of cGMP-dependent protein kinase-mediated vasodilation by hypoxia-induced reactive species in ovine fetal pulmonary veins. Am J Physiol Lung Cell Mol Physiol 2007; 293: L1012-L1020.
Kheirollahi M, Kazemi M, Amini G, Khorvash F, Ahangari F, Kolahdouz M, et al. Expression of prostaglandin I2 (prostacyclin) receptor in blood of migraine patients: A potential biomarker. Adv Biomed Res 2015; 4: 121.
Kheirollahi M, Pourreza MR, Khorvash F, Kazemi M, Amini G. A Report of a Novel Mutation in Human Prostacyclin Receptor Gene in Patients Affected with Migraine. Iran J Psychiatry 2017; 12: 219-222.
Stitham J, Stojanovic A, Hwa J. Impaired receptor binding and activation associated with a human prostacyclin receptor polymorphism. J Biol Chem 2002; 277: 15439-15444.
Saito S, Iida A, Sekine A, Kawauchi S, Higuchi S, Ogawa C, et al. Catalog of 178 variations in the Japanese population among eight human genes encoding G protein-coupled receptors (GPCRs). J Hum Genet 2003; 48: 461–468.
Stitham J, Arehart EJ, Gleim S, Douville KL, MacKenzie T, Hwa J. Arginine (CGC) codon targeting in the human prostacyclin receptor gene (PTGIR) and G-protein coupled receptors (GPCR). Gene 2007; 396: 180–187.
Stitham J, Arehart E, Gleim SR, Li N, Douville K, Hwa J. New insights into human prostacyclin receptor structure and function through natural and synthetic mutations of transmembrane charged residues. Br J Pharmacol 2007; 152: 513–522.
Arehart E, Stitham J, Asselbergs FW, Douville K, MacKenzie T, Fetalvero KM, et al. Acceleration of cardiovascular disease by a dysfunctional prostacyclin receptor mutation: potential implications for cyclooxygenase-2 inhibition. Circ Res 2008; 102: 986-993.
Stitham J, Arehart E, Elderon L, Gleim SR, Douville K, Kasza Z, et al. Comprehensive biochemical analysis of rare prostacyclin receptor variants: study of association of signaling with coronary artery obstruction. J Biol Chem 2011; 286: 7060-7069.