Immature end-plates and utrophin deficiency in congenital myasthenic syndrome caused by ε-AChR subunit truncating mutations

Abstract.

Congenital myasthenic syndromes (CMS) are inborn disorders due to presynaptic, synaptic, or postsynaptic defects of neuromuscular transmission. Some previously described kinships with typical signs of CMS showed a marked deficiency of acetylcholine receptors (AChR) and utrophin at the neuromuscular junctions. Additionally, the end-plate ultrastructure was immature, with reduced enfolding of the postsynaptic membrane. In two such families, we found truncating mutations of the ε-AChR subunit. In family 1, both affected siblings were heteroallelic for a ε911delT and a εIVS4+1G→A mutation within the AChR ε-subunit gene (CHRNE). In the affected member of family 2, a ε1030delC mutation and a previously described εR64X mutation were found. These deleterious εAChR mutations not only result in AChR deficiency, but also affect end-plate maturation, including the formation of secondary synaptic clefts during ontogenesis.