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AGRN
agrin
AGRN is located on the short (p) arm of chromosome 1, at band 1p36.33. Arm ratio per GRCh38 - banding schematic.
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Overview
The AGRN gene provides instructions for making agrin, a large secreted protein that plays an essential role in the development and maintenance of the neuromuscular junction. This specialised synapse is the site where motor neurones communicate with muscle fibres, enabling voluntary movement. Agrin organises the clustering of acetylcholine receptors on the muscle membrane, ensuring efficient signal transmission from nerve to muscle.
Pathogenic variants in AGRN are associated with congenital myasthenic syndrome, a neuromuscular disorder present from birth or early childhood. The gene is located on chromosome 1 and follows an autosomal recessive inheritance pattern, meaning two altered copies are required for disease manifestation. Understanding AGRN function is important for diagnosis and clinical management of neuromuscular conditions.
What the gene does
Agrin functions primarily as an organising molecule at the neuromuscular junction, where it coordinates the assembly of the postsynaptic apparatus on muscle fibres. The protein is secreted by motor neurones and binds to receptors on the muscle surface, triggering a signalling cascade that leads to the clustering of acetylcholine receptors directly opposite the nerve terminal. This precise alignment ensures rapid and reliable transmission of nerve impulses to muscle.
The protein achieves these effects through multiple functional domains that mediate binding to different partners. Agrin interacts with the muscle-specific kinase MuSK and the co-receptor LRP4, initiating intracellular signalling pathways that stabilise receptor clusters and recruit additional synaptic components. Beyond the neuromuscular junction, agrin is also present in basement membranes throughout the body, where it contributes to extracellular matrix organisation and may influence cell adhesion and migration during development.
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Chromosome location
AGRN is located on the short arm of chromosome 1 at position p36.33, a region near the telomere of the chromosome. The gene spans a substantial genomic region and produces a protein of 2,068 amino acids. The chromosomal location places AGRN in a gene-dense region that has been associated with various developmental and neurological processes.
Protein structure
The agrin protein comprises 2,068 amino acids organised into multiple functional domains that mediate its diverse interactions. The N-terminal region contains an NtA domain (amino acids 31-157) followed by nine Kazal-like domains distributed throughout the sequence: Kazal-like 1 (amino acids 191-244), Kazal-like 2 (264-319), Kazal-like 3 (337-391), Kazal-like 4 (408-463), Kazal-like 5 (484-536), Kazal-like 6 (540-601), Kazal-like 7 (607-666), Kazal-like 8 (699-752), and Kazal-like 9 (917-971). These Kazal-like domains are thought to mediate protein-protein interactions.
The central portion includes two laminin EGF-like domains (amino acids 793-846 and 847-893), which are characteristic of extracellular matrix proteins. Two disordered regions are present at amino acids 995-1,096 and 1,277-1,334, which may provide structural flexibility. The protein also contains a SEA domain (amino acids 1,130-1,252), a module found in various cell-surface and secreted proteins. The C-terminal region is particularly important for neuromuscular junction function and contains binding sites for key receptors.
Key variants
Pathogenic variants in AGRN typically result in reduced or absent agrin protein function, disrupting neuromuscular junction formation and maintenance. Most disease-causing variants are inherited in an autosomal recessive manner, requiring alterations in both gene copies to cause clinical manifestations. The variant spectrum includes missense changes affecting critical functional domains, nonsense variants leading to truncated proteins, and splice-site alterations that disrupt normal transcript processing.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1177+4_1177+50del | - | Pathogenic/Likely pathogenic | ★★☆☆ | Presynaptic congenital myasthenic syndrome |
c.3003dup | p.Gly1002fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital myasthenic syndrome 8 |
c.4217_4218del | p.Gln1406fs | Pathogenic | ★★☆☆ | Congenital myasthenic syndrome 8 |
c.4744G>A | p.Gly1582Arg | Pathogenic | ★★☆☆ | Congenital myasthenic syndrome 8 |
c.5011C>T | p.Arg1671Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital myasthenic syndrome 8 |
c.5023G>A | p.Gly1675Ser | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital myasthenic syndrome 8 |
c.574_578dup | p.Ser194fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital myasthenic syndrome 8 |
c.1112del | p.Gly371fs | Pathogenic | ★☆☆☆ | Congenital myasthenic syndrome 8 |
c.2251C>T | p.Arg751Ter | Pathogenic | ★☆☆☆ | Congenital myasthenic syndrome 8 |
c.5484del | p.Asn1828fs | Pathogenic | ★☆☆☆ | Congenital myasthenic syndrome 8 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in AGRN are associated with congenital myasthenic syndrome, a group of inherited disorders affecting neuromuscular transmission. Individuals with AGRN-related myasthenic syndrome typically present with muscle weakness that worsens with activity, often affecting the eyes, face, and limbs. Symptoms may be present from birth or emerge in early childhood, and severity can range from mild weakness to significant motor impairment requiring supportive interventions. The condition is distinct from autoimmune myasthenia gravis and requires specific diagnostic approaches including genetic testing.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic AGRN variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
AGRN is included on NHS Genomic Medicine Service gene panels reflecting its clinical relevance for diagnosis in the UK healthcare system. The gene appears on the Congenital myaesthenic syndrome panel with green (high evidence) classification, indicating strong evidence for its role in this condition. AGRN is also listed on the Fetal anomalies panel with green classification, recognising its potential involvement in prenatal presentations. These panel memberships guide clinicians in requesting appropriate genetic testing when clinical features suggest AGRN-related conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What inheritance pattern does AGRN follow?
AGRN-related conditions follow an autosomal recessive inheritance pattern. This means an individual must inherit two altered copies of the gene, one from each parent, to develop the associated condition. Parents who each carry one altered copy typically do not show symptoms.
How does agrin contribute to muscle function?
Agrin organises the neuromuscular junction by clustering acetylcholine receptors on the muscle surface directly opposite nerve terminals. This precise arrangement enables efficient transmission of nerve signals to muscle fibres, which is essential for voluntary movement. Without functional agrin, neuromuscular signalling is impaired, leading to muscle weakness.
Can AGRN variants be detected through genetic testing?
Yes, pathogenic variants in AGRN can be identified through genetic testing, typically using whole-exome or targeted gene panel sequencing. Such testing is often considered when an individual presents with clinical features of congenital myasthenic syndrome, particularly when symptoms begin in infancy or early childhood.