title: Gain-of-function of P2X7 receptor gene variants in multiple sclerosis.
abstract: We have previously shown that P2X7 receptor blockade prevents ATP excitotoxicity in oligodendrocytes and ameliorates chronic experimental autoimmune encephalomyelitis. Here, we have explored the putative association of functionally relevant single nucleotide polymorphisms of the P2X7 receptor gene with multiple sclerosis. We found that T allele of rs17525809 polymorphism, which yields an Ala-76 to Val change in the extracellular domain, is more frequent in multiple sclerosis patients than in controls. Importantly, P2X7 variants with Val show a gain-of-function consisting in higher calcium permeability, larger electrophysiological responses and higher ethidium uptake, and enhance the effect of the also gain-of-function His-155 to Tyr substitution (rs208294) in the haplotype formed by these two variants. These findings may contribute to define the genetic background predisposing for multiple sclerosis and its pathophysiology.
authors: Centro de Investigaciones Biomédicas en Red Enfermedades Neurodegenerativas (CIBERNED) and Departamento de Neurociencias, Universidad del País Vasco, Leioa, Spain.
authors: Olatz
authors: O
authors: Oyanguren-Desez
authors: Alfredo
authors: A
authors: Rodríguez-Antigüedad
authors: Pablo
authors: P
authors: Villoslada
authors: María
authors: M
authors: Domercq
authors: Elena
authors: E
authors: Alberdi
authors: Carlos
authors: C
authors: Matute
mesh_terms: D020013:Calcium Signaling / Q000235:genetics; D002199:Capillary Permeability / Q000235:genetics; D004594:Electrophysiology; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000235:genetics* / Q000503:physiopathology*; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D011110:Polymorphism, Genetic; D058486:Receptors, Purinergic P2X7 / Q000235:genetics*
chemical_list: D058486:Receptors, Purinergic P2X7