AGRN – Congenital Myasthenic Syndrome

Agrin, encoded by AGRN, is a heparan sulfate proteoglycan secreted by motor neurons that orchestrates acetylcholine receptor (AChR) clustering at the neuromuscular junction (NMJ). Pathogenic variants in AGRN cause autosomal recessive congenital myasthenic syndrome (congenital myasthenic syndrome, CMS), characterized by fatigable muscle weakness, ptosis, hypotonia, and respiratory compromise.

Genetic studies have identified over 20 unrelated probands harboring biallelic AGRN variants across multiple populations, including homozygous missense changes (e.g., c.5125G>C (p.Gly1709Arg)) and compound heterozygous alleles (PMID:19631309; PMID:24951643; PMID:32271162). Segregation analyses in sibships (e.g., Chinese limb-girdle CMS pedigree with three affected siblings) support autosomal recessive inheritance with at least 4 additional affected relatives across reports. The variant spectrum includes missense substitutions, nonsense/truncating alleles, splice‐site changes, small indels, and multi‐exon deletions.

Functional assays demonstrate that AGRN mutations disrupt NMJ structure and signaling. In vitro expression of p.Gly1709Arg in C2C12 myotubes showed preserved MuSK activation but perturbed junction maintenance (PMID:19631309). A SEA‐domain F1061S mouse model recapitulates progressive NMJ degradation with reduced AChR density and denervation (PMID:21890498). LG2 domain variants (e.g., p.Val1727Phe, p.Gln353Ter) impair MuSK phosphorylation and AChR clustering by >100-fold and alter α-dystroglycan binding (PMID:22205389), while the same mutation shows isoform‐specific secretion defects and reduced affinity for heparin and LRP4 (PMID:30994901).

Collectively, the weight of genetic evidence (≥20 probands; multiple families; segregation) and robust functional concordance (in vitro, in vivo, and animal models) supports a Strong gene–disease association. Genetic evidence reaches ClinGen “Strong” tier given the diversity and recurrence of pathogenic alleles in independent lineages. Functional evidence attains a “Moderate” tier owing to multiple experimental systems replicating NMJ pathology.

No significant conflicting reports have emerged, and treatment responses (e.g., partial response to adrenergic agonists) vary by genotype, underscoring the importance of molecular diagnosis. Additional large‐scale natural history and rescue studies may further solidify definitive classification.

Key Take-home: AGRN variants cause a clinically actionable, autosomal recessive CMS subtype; genetic testing for AGRN is recommended in patients with fatigable weakness, ptosis, hypotonia, and decremental EMG responses.

References

• American journal of human genetics • 2009 • Identification of an agrin mutation that causes congenital myasthenia and affects synapse function. PMID:19631309
• Human molecular genetics • 2011 • A valid mouse model of AGRIN-associated congenital myasthenic syndrome. PMID:21890498
• Human genetics • 2012 • LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non-neural (z-) agrin. PMID:22205389
• Brain • 2014 • Agrin mutations lead to a congenital myasthenic syndrome with distal muscle weakness and atrophy. PMID:24951643
• JCI insight • 2020 • Congenital myasthenic syndrome-associated agrin variants affect clustering of acetylcholine receptors in a domain-specific manner. PMID:32271162
• Human molecular genetics • 2019 • Pathogenic effects of agrin V1727F mutation are isoform specific and decrease its expression and affinity for HSPGs and LRP4. PMID:30994901

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