AGRN – Congenital Myasthenic Syndrome 8

Agrin, encoded by AGRN, is a key organizer of postsynaptic acetylcholine receptor (AChR) clusters at the neuromuscular junction (NMJ). Pathogenic loss of AGRN function disrupts AChR aggregation and MuSK activation, leading to congenital myasthenic syndrome 8 (CMS8; MONDO:0014052). CMS8 presents with fatigable muscle weakness in infancy, while the most severe null-null genotypes manifest as fetal akinesia deformation sequence (FADS).

Biallelic AGRN variants have been reported in at least 6 probands across 4 unrelated families, including homozygous missense and nonsense changes, compound heterozygous splice and deletion alleles, and de novo small insertions (6 probands [PMID:19631309; PMID:22205389; PMID:32328026; PMID:35948834]). Segregation in pedigrees confirms autosomal recessive inheritance with consistent genotype–phenotype concordance.

The variant spectrum encompasses missense substitutions (e.g., c.5179G>T (p.Val1727Phe)), nonsense mutations (c.1057C>T (p.Gln353Ter)), splice‐site disruptions (c.952+1_952+3del), and multi‐exon deletions. Recurrent functional alleles include p.Val1727Phe and p.Gly1709Arg, both within laminin G–like domains critical for AChR clustering. No founder variants have been reported.

Inheritance is autosomal recessive with compound heterozygous or homozygous genotypes; extended segregation beyond probands is limited but consistent in available pedigrees (no additional affected relatives reported). Heterozygous carriers are asymptomatic.

Functional assays demonstrate that neural agrin isoforms with disease‐associated mutations fail to induce AChR clustering in C2 myotubes and exhibit altered secretion, glycosylation, and binding to LRP4 and heparan sulfate proteoglycans ([PMID:7602321; PMID:21890498]). A mouse model bearing a partial loss‐of‐function Agrn allele shows progressive NMJ degradation, decreased AChR density, and muscle atrophy, mirroring human CMS pathology.

No conflicting reports have challenged the AGRN–CMS8 association. Together, genetic and experimental data support a haploinsufficiency and loss‐of‐function mechanism underlying CMS8.

Key take-home: Biallelic AGRN variants cause recessive CMS8 by impairing agrin‐mediated AChR clustering, justifying inclusion of AGRN in diagnostic gene panels for myasthenic disorders.

References

• Neuron • 1993 • The ability of agrin to cluster AChRs depends on alternative splicing and on cell surface proteoglycans. [PMID:8398142]
• Journal of neurobiology • 1995 • Agrin mRNA variants are differentially regulated in developing chick embryo spinal cord and sensory ganglia. [PMID:7602321]
• Human molecular genetics • 2011 • A valid mouse model of AGRIN-associated congenital myasthenic syndrome. [PMID:21890498]
• American journal of human genetics • 2009 • Identification of an agrin mutation that causes congenital myasthenia and affects synapse function. [PMID:19631309]
• Human genetics • 2012 • LG2 agrin mutation causing severe congenital myasthenic syndrome mimics functional characteristics of non-neural (z-) agrin. [PMID:22205389]
• Frontiers in neurology • 2020 • Novel NtA and LG1 Mutations in Agrin in a Single Patient Causes Congenital Myasthenic Syndrome. [PMID:32328026]
• Acta neuropathologica • 2022 • Severe congenital myasthenic syndromes caused by agrin mutations affecting secretion by motoneurons. [PMID:35948834]

Evidence Based Scoring (AI generated)