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BACKGROUND: Congenital myasthenic syndrome caused by mutations in AGRN, a gene encoding a protein with a crucial function at the neuromuscular junction, is a rare disorder. There are few studies in this area. We here present two cases with novel mutations of AGRN of which we further investigated possible pathogenesis. RESULTS: Patient 1 had general limb weakness with fluctuation and deterioration in the afternoon and in hot weather. Patient 2 had early-onset weakness of lower extremities with suspected fluctuation in the early stages, which then progressed to the upper limbs. Both distal and proximal muscles were involved. Repetitive stimulation on EMG in both patients showed decrement in proximal and distal limbs. Patient 2 showed a marked response to salbutamol while Patient 1 did not. By targeted exome sequencing, two novel homozygous missense variants, p.L1176P and p.R1698C, in the SEA and LG2 domain of agrin were identified respectively. Further functional analysis revealed instability of the protein and impaired clustering of the acetylcholine receptor (AChR) by both mutations. CONCLUSIONS: The mutations identified in AGRN in our study may cause congenital myasthenic syndrome by damaging protein stability and interfering with AChR clustering. These results broaden the understandings on the phenotype, genotype and pathogenesis of this rare disorder.

Original publication




Journal article


Orphanet J Rare Dis

Publication Date





Agrin, Congenital Myasthenic syndrome, Distal myopathy, Neuromuscular junction, Salbutamol, Adult, Agrin, Albuterol, Electrophysiology, Exons, HEK293 Cells, Humans, Male, Muscle Fibers, Skeletal, Mutation, Myasthenic Syndromes, Congenital, Neuromuscular Junction, Receptors, Cholinergic