REGULATION OF ACETYLCHOLINE-RECEPTOR GENE-EXPRESSION IN HUMAN MYASTHENIA-GRAVIS MUSCLES - EVIDENCES FOR A COMPENSATORY MECHANISM TRIGGERED BY RECEPTOR LOSS

Myasthenia gravis (MG) is a neuromuscular disorder mediated by antibod ies directed against the acetylcholine receptor (nAChR) resulting in a functional nAChR loss. To analyze the molecular mechanisms involved a t the muscular target site, we studied the expression of nAChR subunit s in muscle biopsy specimens from MG patients. By using quantitative P CR with an internal standard for each subunit, we found that the level s of beta-, delta-, and epsilon-subunit mRNA coding for the adult nACh R were increased in severely affected MG patients, matching our previo us data on the oc-subunit. Messenger levels were highly variable in MG patients but not in controls, pointing to individual factors involved in the regulation of nAChR genes. The fetal subunit (gamma-chain) tra nscripts were almost undetectable in the extrajunctional region of MG muscle, suggesting that gene regulation in MG differs from that in the denervation model, in which nAChR gamma-subunit mRNA is reexpressed. Nicotinic AChR loss mediated by monoclonal anti-nAChR antibodies in bo th the TE671 muscle cell line and cultured normal human myotubes induc es a similar increase in beta- alpha nd delta-subunit mRNA levels, sug gesting the existence of a new muscular signaling pathway system coupl ed to nAChR internalization and independent of muscle electrical activ ity. These data demonstrate the existence of a compensatory mechanism regulating the expression of the genes coding for the adult nAChR in p atients with MG.