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MUSK
muscle associated receptor tyrosine kinase
MUSK is located on the long (q) arm of chromosome 9, at band 9q31.3. Arm ratio per GRCh38 - banding schematic.
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Overview
MUSK (muscle associated receptor tyrosine kinase) is located on chromosome 9 and encodes a transmembrane receptor essential for the proper assembly of acetylcholine receptor clusters at the neuromuscular junction. This synapse enables voluntary muscle contraction by transmitting electrical signals from motor neurons to muscle fibres. The protein functions as a co-receptor alongside LRP4, binding to agrin released from the nerve terminal to initiate a cascade of intracellular signalling events. Disruption of MUSK function prevents normal neuromuscular transmission, resulting in congenital myasthenic syndrome, an autosomal recessive disorder presenting with episodes of muscle weakness that worsen with exertion and improve with rest.
What the gene does
The MUSK protein operates as a tyrosine kinase receptor that orchestrates the clustering of acetylcholine receptors at the postsynaptic muscle membrane. When agrin binds to the LRP4-MUSK complex, MUSK undergoes autophosphorylation and activates downstream targets including the adaptor protein DOK7 and the small GTPase RAC1. This signalling cascade reorganises the cytoskeleton and anchors acetylcholine receptors precisely opposite the nerve terminal's release sites. MUSK also recruits rapsyn, a scaffolding protein that stabilises receptor clusters and maintains synaptic architecture throughout life. Beyond initial synapse formation during embryonic development, MUSK continues to support neuromuscular junction integrity in adults by regulating receptor turnover and compensating for age-related changes. The kinase activity is tightly controlled to ensure appropriate receptor density and distribution across the muscle fibre surface.
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Chromosome location
MUSK is located at chromosomal band 9q31.3 on the long arm of chromosome 9. The gene spans multiple exons encoding a transmembrane protein of 869 amino acids. This genomic region is relatively stable, though pathogenic variants have been identified throughout the coding sequence affecting different functional domains of the mature receptor.
Protein structure
The MUSK protein comprises 869 amino acids organised into distinct functional domains. The extracellular region contains three immunoglobulin-like domains (Ig-like 1 spanning amino acids 28-116, Ig-like 2 from 121-205, and Ig-like 3 from 212-302) that mediate interactions with the LRP4 co-receptor and agrin ligand. Following these is a frizzled-like domain (FZ, amino acids 312-450) thought to contribute to receptor clustering and lateral interactions at the membrane. The intracellular portion harbours the protein kinase domain (amino acids 575-856), which catalyses phosphorylation of tyrosine residues on MUSK itself and downstream effector proteins. This kinase domain is essential for signal transduction and recruitment of cytoplasmic adaptors that link receptor activation to cytoskeletal reorganisation.
Key variants
Pathogenic variants in MUSK typically follow an autosomal recessive inheritance pattern, requiring biallelic changes to cause congenital myasthenic syndrome. Reported variants include missense mutations affecting the kinase domain that reduce catalytic activity, as well as truncating variants that eliminate essential functional regions. The severity of neuromuscular symptoms often correlates with the degree of residual kinase function, though genotype-phenotype relationships remain incompletely characterised.
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.1091_1092del | p.Pro364fs | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital myasthenic syndrome 9 |
c.1724T>C | p.Ile575Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Congenital myasthenic syndrome 9 |
c.2034_2035del | p.His680fs | Pathogenic/Likely pathogenic | ★★☆☆ | Fetal anomalies with a likely genetic cause |
c.2446C>T | p.Arg816Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fetal akinesia deformation sequence 1 |
c.2T>C | p.Met1Thr | Pathogenic | ★★☆☆ | Congenital myasthenic syndrome 9 |
c.790C>T | p.Arg264Ter | Pathogenic | ★★☆☆ | Fetal akinesia deformation sequence 1 |
c.79+2T>G | - | Pathogenic | ★★☆☆ | Congenital myasthenic syndrome 9 |
c.2268C>G | p.Tyr756Ter | Pathogenic | ★☆☆☆ | Congenital myasthenic syndrome 9 |
c.903dup | p.Ser302fs | Pathogenic | ★☆☆☆ | Congenital myasthenic syndrome 9 |
c.967G>T | p.Glu323Ter | Pathogenic | ★☆☆☆ | Fetal akinesia deformation sequence 1 |
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
Biallelic pathogenic variants in MUSK cause congenital myasthenic syndrome, a neuromuscular transmission disorder present from birth or early childhood. Affected individuals experience fluctuating muscle weakness that worsens with activity and improves with rest, often affecting facial, bulbar, and limb muscles. Respiratory muscles may be involved, occasionally requiring ventilatory support during acute episodes. Unlike autoimmune myasthenia gravis, congenital myasthenic syndrome due to MUSK variants does not respond to acetylcholinesterase inhibitors and may paradoxically worsen with these medications. Management typically involves alternative symptomatic treatments and supportive care tailored to individual clinical features.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic MUSK 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
Within the NHS Genomic Medicine Service, MUSK appears on three clinical diagnostic panels with green (high evidence) status. The gene is included in the Congenital myaesthenic syndrome panel (R80), the Arthrogryposis panel (R83), and the Fetal anomalies panel (R21), reflecting its role in neuromuscular junction disorders that may present prenatally or in early postnatal life with joint contractures or reduced foetal movement.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the role of MUSK at the neuromuscular junction?
MUSK functions as a receptor tyrosine kinase that responds to agrin signals from motor neurons, triggering the assembly and stabilisation of acetylcholine receptor clusters at the muscle membrane. This clustering is essential for efficient neuromuscular transmission and voluntary muscle contraction.
How are MUSK variants inherited?
MUSK variants causing congenital myasthenic syndrome follow an autosomal recessive inheritance pattern. An individual must inherit a pathogenic variant from both parents to develop the condition. Carrier parents typically show no symptoms.
Why don't standard myasthenia treatments work for MUSK-related congenital myasthenic syndrome?
Unlike autoimmune myasthenia gravis, MUSK-related congenital myasthenic syndrome results from defective synapse structure rather than antibody-mediated receptor blockade. Acetylcholinesterase inhibitors often prove ineffective or may worsen symptoms, necessitating alternative management strategies tailored to the underlying synaptic defect.