RESUMEN
Single nucleotide polymorphisms (SNPs) in microRNA-target sites influence an individual's risk and prognosis for autoimmune diseases. Myotubularin-related protein 3 (MTMR3), an autophagy-related gene, is a direct target of miR-181a. We investigated whether MTMR3 SNP rs12537 in the miR-181a-binding site is associated with the susceptibility and progression of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Overall, 94 patients with RA, 80 patients with SLE, and 104 healthy volunteers were recruited. Genotyping and expression analysis of circulating MTMR3 and miR-181a were performed by qPCR. The autophagic marker MAP1LC3B was measured by ELISA. The rs12537 minor homozygote (TT) genotype was a candidate risk factor of both RA and SLE. rs12537TT was associated with lower serum MTMR3 expression and higher LC3B levels than other genotypes in patients with both diseases. Serum miR-181a expression was higher in rs12537TT carriers than in other genotypes among SLE patients. Serum miR-181a and MTMR3 levels were inversely correlated in SLE but not in RA patients. rs12537TT and serum miR-181a were positively associated with disease severity in both diseases. Our results identify a novel role of rs12537 in the susceptibility and progression of RA and SLE, possibly through impacting the interaction between miR-181a and MTMR3 leading to increased autophagy.
Asunto(s)
Artritis Reumatoide/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Lupus Eritematoso Sistémico/genética , MicroARNs/metabolismo , Polimorfismo de Nucleótido Simple/genética , Proteínas Tirosina Fosfatasas no Receptoras/genética , Adulto , Artritis Reumatoide/sangre , Sitios de Unión , Estudios de Casos y Controles , Egipto , Femenino , Frecuencia de los Genes/genética , Humanos , Lupus Eritematoso Sistémico/sangre , Masculino , MicroARNs/genética , Proteínas Asociadas a Microtúbulos/metabolismo , Persona de Mediana Edad , Proteínas Tirosina Fosfatasas no Receptoras/sangre , Factores de Riesgo , Adulto JovenRESUMEN
Phosphoinositides play a key role in the spatiotemporal control of central intracellular processes and several specific kinases and phosphatases regulating the level of these lipids are implicated in human diseases. Myotubularins are a family of 3-phosphatases acting specifically on phosphatidylinositol 3-monophosphate and phosphatidylinositol 3,5 bisphosphate. Members of this family are mutated in genetic diseases including myotubularin 1 (MTM1) and myotubularin-related protein 2 (MTMR2) which mutations are responsible of X-linked centronuclear myopathy and Charcot-Marie-Tooth neuropathy, respectively. Here we show that MTM1 is expressed in blood platelets and that hundred microliters of blood is sufficient to detect the protein by western blotting. Since the most severe cases of pathogenic mutations of MTM1 lead to loss of expression of the protein, we propose that a minimal amount of blood can allow a rapid diagnostic test of X-linked myotubular myopathy, which is currently based on histopathology of muscle biopsy and molecular genetic testing. In platelets, MTM1 is a highly active 3-phosphatase mainly associated to membranes and found on the dense granules and to a lesser extent on alpha-granules. However, deletion of MTM1 in mouse had no significant effect on platelet count and on platelet secretion and aggregation induced by thrombin or collagen stimulation. Potential compensation by other members of the myotubularin family is conceivable since MTMR2 was easily detectable by western blotting and the mRNA of several members of the family increased during in vitro differentiation of human megakaryocytes and MEG-01 cells. In conclusion, we show the presence of several myotubularins in platelets and propose that minimal amounts of blood can be used to develop a rapid diagnostic test for genetic pathologies linked to loss of expression of these phosphatases.