Mutation of the acetylcholine receptor epsilon-subunit promoter in congenital myasthenic syndrome

Congenital myasthenic syndrome comprises a heterogeneous group of inherited disorders of neuromuscular transmission. Acetylcholine receptor (AChR) def iciency is the most common form of congenital myasthenic syndrome and in mo st cases results from mutations within the coding region of the AChR epsilo n subunit. However, studies in mice have established that synapse-specific expression of AChR is dependent on a sequence contained within the AChR-sub unit promoter regions, termed an N-box. We describe a consanguineous family in which 2 of 7 siblings had clinical and electromyographic features consi stent with AChR deficiency. Muscle biopsy demonstrated low AChR numbers, es tablishing the disorder as postsynaptic. Single-strand conformational polym orphism analysis identified an abnormal conformer in the AChR epsilon-subun it gene promoter of the patients. DNA sequence and restriction endonuclease analysis shows that the disorder cosegregates with recessive inheritance o f a single point mutation, a transition (C-->T) in the N-box of the epsilon -subunit promoter. Analysis of an intercostal biopsy from 1 of the patients showed a dramatic reduction in epsilon-subunit mRNA levels compared with d isease and normal controls. This is the first evidence in humans that an N- box mutation can lead to disruption of epsilon-subunit transcription, resul ting in the loss of adult AChR synthesis and the clinical phenotype of AChR -deficiency congenital myasthenic syndrome.