ArticleHuman genetics2012
LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non-neural (z-) agrin.
Article in Human genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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52 citing papers in PubMed, 94 citations in OpenAlex.
- AGRN-, LRP4-, MUSK-Related CMS: Clinical, Neurophysiological, Morphological, Genetic and Pathological Mechanisms.Muscle & nerve · 2026Review
- Gene-specific response to muscle specific kinase agonist antibody in the treatment of congenital myasthenic syndromes.Brain communications · 2026Article
- Neuron-specific Agrin splicing by Nova RNA-binding proteins regulates conserved neuromuscular junction development in chordates.PLoS biology · 2025Article
- ProteinMolecules (Basel, Switzerland) · 2025Review
- Development and Application of a Cell-Based Assay for Detecting Anti-Agrin Antibodies Associated With Myasthenia Gravis.Journal of clinical neurology (Seoul, Korea) · 2025Article
- Congenital myasthenic syndromes a rare case of AGRN mutation.American journal of neurodegenerative disease · 2025Article
- A conserved RNA switch for acetylcholine receptor clustering at neuromuscular junctions in chordates.bioRxiv : the preprint server for biology · 2024Article
- Genetic and clinical evaluation of congenital myasthenic syndromes with long-term follow-up: experience of a tertiary center in Turkey.Acta neurologica Belgica · 2023Article
- Clinical and Pathologic Features of Congenital Myasthenic Syndromes Caused by 35 Genes-A Comprehensive Review.International journal of molecular sciences · 2023Review
- Bioinformatics-based analysis of the roles of basement membrane-related gene AGRN in systemic lupus erythematosus and pan-cancer development.Frontiers in immunology · 2023Article
- Deconstruction of Neurotrypsin Reveals a Multi-factorially Regulated Activity Affecting Myotube Formation and Neuronal Excitability.Molecular neurobiology · 2022Article
- Severe congenital myasthenic syndromes caused by agrin mutations affecting secretion by motoneurons.Acta neuropathologica · 2022Article
- Post-synaptic specialization of the neuromuscular junction: junctional folds formation, function, and disorders.Cell & bioscience · 2022Review
- Identification of two variants inClinical case reports · 2022Article
- Secreted Signaling Molecules at the Neuromuscular Junction in Physiology and Pathology.International journal of molecular sciences · 2021Review
- Mutational screening ofMolecular vision · 2021Article
- Antibodies to Full-Length Agrin Protein in Chinese Patients With Myasthenia Gravis.Frontiers in immunology · 2021Article
- Congenital Disorders of Deficiency in Glycosaminoglycan Biosynthesis.Frontiers in genetics · 2021Review
- Clinical features of LRP4/agrin-antibody-positive myasthenia gravis: A multicenter study.Muscle & nerve · 2020Article
- Congenital myasthenic syndrome-associated agrin variants affect clustering of acetylcholine receptors in a domain-specific manner.JCI insight · 2020Article
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Authors and funding
11 authors at 4 institutions in 3 countries.
Funding
Abstract
We describe a severe form of congenital myasthenic syndrome (CMS) caused by two heteroallelic mutations: a nonsense and a missense mutation in the gene encoding agrin (AGRN). The identified mutations, Q353X and V1727F, are located at the N-terminal and at the second laminin G-like (LG2) domain of agrin, respectively. A motor-point muscle biopsy demonstrated severe disruption of the architecture of the neuromuscular junction (NMJ), including: dispersion and fragmentation of endplate areas with normal expression of acetylcholinesterase; simplification of postsynaptic membranes; pronounced reduction of the axon terminal size; widening of the primary synaptic cleft; and, collection of membranous debris material in the primary synaptic cleft and in the subsynaptic cytoplasm. Expression studies in heterologous cells revealed that the Q353X mutation abolished expression of full-length agrin. Moreover, the V1727F mutation decreased agrin-induced clustering of the acetylcholine receptor (AChR) in cultured C2 muscle cells by >100-fold, and phosphorylation of the MuSK receptor and AChR beta subunit by ~tenfold. Surprisingly, the V1727F mutant also displayed increased binding to α-dystroglycan but decreased binding to a neural (z+) agrin-specific antibody. Our findings demonstrate that agrin mutations can associate with a severe form of CMS and cause profound distortion of the architecture and function of the NMJ. The impaired ability of V1727F agrin to activate MuSK and cluster AChRs, together with its increased affinity to α-dystroglycan, mimics non-neural (z-) agrin and are important determinants of the pathogenesis of the disease.
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