MUSK

Summary

MUSK (muscle associated receptor tyrosine kinase, HGNC:7525) is a protein-coding gene on chromosome 9q31.3, encoding Muscle, skeletal receptor tyrosine-protein kinase (O15146). Receptor tyrosine kinase which plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between the motor neuron and the skeletal muscle.

This gene encodes a muscle-specific tyrosine kinase receptor. The encoded protein may play a role in clustering of the acetylcholine receptor in the postsynaptic neuromuscular junction. Mutations in this gene have been associated with congenital myasthenic syndrome. Alternatively spliced transcript variants have been described.

Source: NCBI Gene 4593 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital myasthenic syndrome 9 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 9
• Clinical variants (ClinVar): 914 total — 44 pathogenic, 36 likely-pathogenic (top 3% of genes corpus-wide)
• GTEx eGene: eQTL in 23 tissues, sQTL in 2 (q < 0.05)
• Phenotypes (HPO): 109
• ChEMBL bioactivity: 20 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.78 (unconstrained)
• MANE Select transcript: NM_005592

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7525
Approved symbol	MUSK
Name	muscle associated receptor tyrosine kinase
Location	9q31.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000030304
Ensembl biotype	protein_coding
OMIM	601296
Entrez	4593

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

MANE Select: ENST00000374448

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 3: 1, TSL 5: 5

ENST00000374448, ENST00000189978, ENST00000374438, ENST00000374439, ENST00000416899, ENST00000634612, ENST00001137053

RefSeq mRNA: 3 — MANE Select: NM_005592 NM_001166280, NM_001166281, NM_005592

CCDS: CCDS48005, CCDS75874

Canonical transcript exons

ENST00000374448 — 15 exons

Exon	Start	End
ENSE00000719983	110784815	110785016
ENSE00000720010	110785527	110785718
ENSE00000720035	110787690	110787838
ENSE00000926843	110747641	110747800
ENSE00001034292	110776632	110776655
ENSE00001646804	110775788	110775963
ENSE00001669334	110762202	110762208
ENSE00001671992	110767820	110768083
ENSE00001678191	110697325	110697466
ENSE00001766374	110695403	110695530
ENSE00001790353	110734251	110734375
ENSE00003508946	110668791	110668983
ENSE00003745850	110687117	110687268
ENSE00003747403	110682674	110682800
ENSE00003889215	110800306	110806558

Expression profiles

Bgee: expression breadth ubiquitous, 151 present calls, max score 82.37.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.9028 / max 90.2776, expressed in 155 samples.

Highest expression (Bgee): male germ line stem cell (sensu Vertebrata) in testis, mucosa of stomach, sural nerve, calcaneal tendon, colonic epithelium.

Genetic regulation across tissues (GTEx eQTL / sQTL)

MUSK is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 23 tissues and its splicing (sQTL) in 2 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 25 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Not Sun Exposed Suprapubic	eqtl	2.3e-27	-0.51	9:110733636:A:G
Skin Sun Exposed Lower leg	eqtl	5.3e-24	-0.44	9:110723681:A:C
Testis	eqtl	1.3e-17	+0.47	9:110649947:C:A
Thyroid	eqtl	1.5e-13	-0.36	9:110605711:C:T
Cells Cultured fibroblasts	eqtl	1.6e-10	-0.24	9:110788478:A:G
Artery Tibial	eqtl	2.5e-10	-0.30	9:110912125:G:A
Brain Nucleus accumbens basal ganglia	eqtl	5.0e-07	-0.42	9:110738285:TA:T
Adipose Visceral Omentum	eqtl	2.5e-06	-0.32	9:110628010:G:T
Lung	eqtl	1.8e-05	-0.16	9:110614718:G:A
Esophagus Muscularis	eqtl	7.4e-05	-0.23	9:110617268:T:G
Esophagus Gastroesophageal Junction	eqtl	1.0e-04	+0.21	9:110659863:C:A
Brain Putamen basal ganglia	eqtl	3.2e-04	-0.38	9:110731921:T:G
Nerve Tibial	eqtl	6.4e-04	-0.23	9:110887182:A:G
Brain Caudate basal ganglia	eqtl	1.1e-03	-0.20	9:110714922:G:A
Brain Hypothalamus	eqtl	1.7e-03	-0.27	9:110736122:T:C
Muscle Skeletal	eqtl	4.9e-03	+0.39	9:110702920:T:A
Ovary	eqtl	1.2e-02	-0.41	9:110620261:G:A
Colon Sigmoid	eqtl	1.2e-02	+0.23	9:109833677:A:C
Brain Spinal cord cervical c-1	eqtl	1.4e-02	-0.52	9:110721151:C:T
Artery Aorta	eqtl	1.7e-02	+0.23	9:109764432:C:T

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
98000	0.4549	107
97999	0.3523	104
98001	0.0393	21
98002	0.0385	24
97998	0.0179	9

Top tissues by expression

showing 100 of 277 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.37	gold quality
mucosa of stomach	UBERON:0001199	79.71	gold quality
sural nerve	UBERON:0015488	76.60	gold quality
calcaneal tendon	UBERON:0003701	75.75	gold quality
colonic epithelium	UBERON:0000397	71.85	gold quality
right lung	UBERON:0002167	70.90	gold quality
gastrocnemius	UBERON:0001388	70.74	gold quality
corpus callosum	UBERON:0002336	70.52	gold quality
rectum	UBERON:0001052	69.68	gold quality
muscle of leg	UBERON:0001383	68.83	gold quality
small intestine Peyer’s patch	UBERON:0003454	67.46	gold quality
small intestine	UBERON:0002108	66.53	gold quality
vermiform appendix	UBERON:0001154	65.37	gold quality
muscle organ	UBERON:0001630	65.27	gold quality
gall bladder	UBERON:0002110	65.27	gold quality
right atrium auricular region	UBERON:0006631	65.26	gold quality
caecum	UBERON:0001153	64.44	gold quality
tendon	UBERON:0000043	64.22	gold quality
cardiac atrium	UBERON:0002081	64.10	gold quality
vena cava	UBERON:0004087	63.91	gold quality
stomach	UBERON:0000945	61.95	gold quality
hindlimb stylopod muscle	UBERON:0004252	61.83	gold quality
intestine	UBERON:0000160	61.67	gold quality
fundus of stomach	UBERON:0001160	61.27	gold quality
lymph node	UBERON:0000029	60.88	gold quality
heart	UBERON:0000948	60.76	gold quality
right coronary artery	UBERON:0001625	60.70	gold quality
muscle layer of sigmoid colon	UBERON:0035805	60.60	gold quality
transverse colon	UBERON:0001157	60.57	gold quality
body of stomach	UBERON:0001161	60.27	gold quality
lower lobe of lung	UBERON:0008949	60.24	silver quality
lower esophagus mucosa	UBERON:0035834	60.18	gold quality
buccal mucosa cell	CL:0002336	60.17	silver quality
colon	UBERON:0001155	59.98	gold quality
stromal cell of endometrium	CL:0002255	59.89	gold quality
large intestine	UBERON:0000059	59.85	gold quality
left coronary artery	UBERON:0001626	59.85	gold quality
coronary artery	UBERON:0001621	59.72	gold quality
esophagus mucosa	UBERON:0002469	59.61	gold quality
upper lobe of lung	UBERON:0008948	59.24	gold quality
sigmoid colon	UBERON:0001159	59.15	gold quality
upper lobe of left lung	UBERON:0008952	59.15	gold quality
heart left ventricle	UBERON:0002084	59.13	gold quality
tonsil	UBERON:0002372	59.10	gold quality
substantia nigra pars compacta	UBERON:0001965	59.06	gold quality
pons	UBERON:0000988	58.97	gold quality
cardiac ventricle	UBERON:0002082	58.94	gold quality
substantia nigra pars reticulata	UBERON:0001966	58.90	gold quality
body of tongue	UBERON:0011876	58.66	gold quality
deltoid	UBERON:0001476	58.43	silver quality
skeletal muscle tissue	UBERON:0001134	58.29	gold quality
tibialis anterior	UBERON:0001385	58.24	silver quality
urinary bladder	UBERON:0001255	58.23	gold quality
lateral globus pallidus	UBERON:0002476	58.11	silver quality
inferior vagus X ganglion	UBERON:0005363	58.06	gold quality
muscle tissue	UBERON:0002385	57.88	gold quality
tongue	UBERON:0001723	57.69	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	57.32	gold quality
lung	UBERON:0002048	57.27	gold quality
saphenous vein	UBERON:0007318	57.27	gold quality
superficial temporal artery	UBERON:0001614	57.18	gold quality
myocardium	UBERON:0002349	57.17	gold quality
superior surface of tongue	UBERON:0007371	57.10	gold quality
pericardium	UBERON:0002407	57.07	gold quality
apex of heart	UBERON:0002098	57.01	gold quality
esophagus	UBERON:0001043	56.98	gold quality
quadriceps femoris	UBERON:0001377	56.97	gold quality
cerebellar vermis	UBERON:0004720	56.93	gold quality
nipple	UBERON:0002030	56.80	gold quality
vastus lateralis	UBERON:0001379	56.75	gold quality
ventral tegmental area	UBERON:0002691	56.69	gold quality
pylorus	UBERON:0001166	56.68	gold quality
trigeminal ganglion	UBERON:0001675	56.68	gold quality
synovial joint	UBERON:0002217	56.59	gold quality
medulla oblongata	UBERON:0001896	56.58	gold quality
popliteal artery	UBERON:0002250	56.55	gold quality
decidua	UBERON:0002450	56.55	gold quality
dorsal plus ventral thalamus	UBERON:0001897	56.51	gold quality
tibial artery	UBERON:0007610	56.46	gold quality
subthalamic nucleus	UBERON:0001906	56.41	gold quality
descending thoracic aorta	UBERON:0002345	56.36	gold quality
superior vestibular nucleus	UBERON:0007227	56.32	gold quality
penis	UBERON:0000989	56.30	gold quality
nasal cavity epithelium	UBERON:0005384	56.29	gold quality
aorta	UBERON:0000947	55.91	gold quality
smooth muscle tissue	UBERON:0001135	55.89	gold quality
lateral nuclear group of thalamus	UBERON:0002736	55.85	gold quality
trachea	UBERON:0003126	55.83	gold quality
pharyngeal mucosa	UBERON:0000355	55.75	gold quality
renal medulla	UBERON:0000362	55.37	gold quality
thymus	UBERON:0002370	55.31	gold quality
pancreatic ductal cell	CL:0002079	55.18	silver quality
layer of synovial tissue	UBERON:0007616	55.12	gold quality
thoracic aorta	UBERON:0001515	55.04	gold quality
jejunum	UBERON:0002115	54.89	gold quality
mucosa of transverse colon	UBERON:0004991	54.78	gold quality
ascending aorta	UBERON:0001496	54.73	gold quality
dorsal root ganglion	UBERON:0000044	54.53	gold quality
sperm	CL:0000019	54.07	gold quality
male germ cell	CL:0000015	54.02	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	16.09

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 62 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Caudate putamen	tissue	5.0
Choroid plexus	tissue	4.8
Nucleus accumbens	tissue	3.6
Locus coeruleus	tissue	2.5
Hippocampus	tissue	2.5
Rectum	tissue	2.3
Small intestine	tissue	2.2
Tongue	tissue	1.9
Tonsil	tissue	1.8
Colon	tissue	1.7
Appendix	tissue	1.6
Testis	tissue	1.4
Heart muscle	tissue	1.4
Esophagus	tissue	1.3
Stomach 1	tissue	1.2
Urinary bladder	tissue	1.2
Duodenum	tissue	1.1
Corpus callosum	tissue	1.1
Gallbladder	tissue	1.0
Spinal cord	tissue	1.0
Lung	tissue	0.9
Postcentral gyrus	tissue	0.7
Putamen	tissue	0.6
Amygdala	tissue	0.6
Medulla oblongata	tissue	0.6
Cerebellum	tissue	0.6
Lymph node	tissue	0.5
Cerebral cortex	tissue	0.5
Smooth muscle	tissue	0.5
Basal ganglia	tissue	0.5
Thalamus	tissue	0.5
Substantia nigra	tissue	0.5
Hippocampal formation	tissue	0.5
Ventral forebrain	tissue	0.5
Periaqueductal gray	tissue	0.5
Olfactory bulb	tissue	0.5
Septum	tissue	0.5
Insular cortex	tissue	0.5
Prefrontal cortex	tissue	0.4
Pons	tissue	0.4
Motor cortex	tissue	0.4
Midbrain	tissue	0.4
Hypothalamus	tissue	0.4
Superior colliculi	tissue	0.4
Entorhinal cortex	tissue	0.4
Retrosplenial and cingulate cortex	tissue	0.4
Retrosplenial cortex	tissue	0.4
Temporal cortex	tissue	0.4
Placenta	tissue	0.3
Liver	tissue	0.3
Somatosensory cortex	tissue	0.3
Occipital cortex	tissue	0.3
Skeletal muscle	tissue	0.2
Frontal cortex	tissue	0.2
Prostate	tissue	0.2
Adrenal gland	tissue	0.2
Skin 1	tissue	0.1
Ovary	tissue	0.1
Vagina	tissue	0.1
Adipose tissue	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Periaquaductal grey, lateral (14.5), Corpus callosum, splenium (white matter) (12.1), Corpus callosum, genu (white matter) (9.9), Parieto-temporal junction (white matter) (8.7), Periaquaductal grey, dorsal (8.6).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, HR, MYOD1, MYOG

Functional genomics

gnomAD constraint: pLI 4.92e-10, LOEUF 0.778, missense Z 1.27 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000374448 — one region, missense o/e 0.94.

Literature-anchored findings (GeneRIF, showing 40)

• analysis of regulation of MuSK expression by a novel signaling pathway (PMID:12885777)
• Missense mutation does not affect MuSK catalytic kinase activity but diminishes expression and stability. (PMID:15496425)
• Thus, an agrin/MuSK complex may form part of a motor neuron stop signal involved in “reverse signaling” to the motor neuron. (PMID:15691710)
• A low-molecular weight isoform of muscle-specific receptor tyrosine kinase in human sperm localized in the flagellar mid-piece region. (PMID:16487930)
• Dok-7 is essential for neuromuscular synaptogenesis through its interaction with MuSK (PMID:16794080)
• Altogether, these results indicate that anti-MuSK Abs could be pathogenic by contributing to the muscle atrophy in MuSK+ MG patients. (PMID:16857268)
• muscle-specific receptor tyrosine kinase activation and binding to dystroglycan are regulated by alternative mRNA splicing of agrin (PMID:17012237)
• Testing of human myotubes for the presence and activation of MuSK by exposing them to laminin. (PMID:17192614)
• We describe a case of epileptic seizures secondary to myasthenia gravis caused by autoantibodies to the MUSK receptor. These autoantibodies affected the brain as well. (PMID:17661994)
• the COOH-terminal NES and Src homology 2 target motifs play key roles in Dok-7/MuSK signaling for neuromuscular synaptogenesis. (PMID:18165682)
• We describe a transient neonatal myasthenic syndrome with anti-musk antibodies. (PMID:18378885)
• IgG from anti-MuSK-positive patients can cause myasthenia gravis when injected into mice. (PMID:18384168)
• single-fiber electromyography of distal limb muscles tends to have a lower yield of abnormality in MuSK-antibody-positive patients than either acetylcholine receptor-antibody-positive or seronegative myasthenia gravis (PMID:18567855)
• Thymectomy is mostly considered scarcely effective; however, at present, no firm conclusions can be drawn on its role in the treatment of this form of myasthenia gravis (PMID:18567856)
• Anti-MuSK protein positive patients have more predominantly bulbar involvement and had more severe myasthenia gravis. (PMID:19327804)
• Anti-MuSK antibodies influence the activity of MuSK molecules without reducing their number, thereby diminishing the size of the endplate and affecting the functioning of acetylcholine receptors. (PMID:19745065)
• This study report a family known so far with a congenital myasthenic syndromes due to a mutation in the MUSK gene. (PMID:19949040)
• these findings demonstrate that missense mutations in MUSK can result in a severe form of congenital myasthenic syndrome and indicate that the inability of MuSK mutants to interact with Dok-7. (PMID:20371544)
• The importance of MuSK as a synapse organiser is highlighted by cases of autoimmune myasthenia gravis in which MuSK autoantibodies can deplete MuSK from the postsynaptic membrane, leading to complete disassembly of the adult neuromuscular junction. (PMID:20974278)
• Two family cases are reported that transmit MuSK antibody myasthenia gravis to the offspring by different maternal mechanisms. (PMID:21386774)
• Lrp4 is a cis-acting ligand for MuSK (PMID:21969364)
• The ability of immobilized MuSK extracellular domain to remove practically all anti-MuSK antibodies from patients’ sera should prove invaluable for development of an antigen-specific therapeutic approach for MuSK myasthenia gravis. (PMID:21993075)
• MuSK kinase activity is necessary for substrate-dependent acetylcholine receptor cluster formation (PMID:22210232)
• We report a novel mutation in MUSK leading to a Congenital myasthenic syndromes (PMID:23326516)
• MUSK is associated with a small but variable subgroup of distinct phenotypes in Thai patients with myasthenia gravis who have MUSK autoantibodies. (PMID:23352351)
• MuSK is activated in a complex spatio-temporal manner to cluster acetylcholine receptors on the postsynaptic (muscle) side of the synapse and to induce differentiation of the nerve terminal on the presynaptic side. (Review) (PMID:23467009)
• We proved that the missense mutations in ColQ-CTD cause endplate AChE deficiency by compromising ColQ-MuSK interaction at the NMJ. (PMID:23553736)
• MUSK antibodies may induce phenotypically disruptive actions at the neuromuscular junction by binding acetylcholinesterase (AChE) via its collagen tail, producing a reduction in synaptic AChE activity. (PMID:23720161)
• This study provides a replication of the highly significant associations of both HLA-DRB1( *)16,-DRB1( *)14 and -DQB1( *)05 with MuSK-MG. (PMID:23993985)
• Identification of a novel missense mutation c.114T > A; p.Asp38Glu heteroallelic to a genomic deletion encompassing exons 2-3 of MUSK that explain a limb-girdle congenital myasthenic syndrome in two affected brothers of a Turkish family. (PMID:24183479)
• MuSK myasthenia gravis IgG4 disrupts the interaction of LRP4 with MuSK but both IgG4 and IgG1-3 can disperse preformed agrin-independent AChR clusters (PMID:24244707)
• pathogenic IgG4 antibodies to MuSK bind to a structural epitope in the first Ig-like domain of MuSK, prevent binding between MuSK and Lrp4, and inhibit Agrin-stimulated MuSK phosphorylation. (PMID:24297891)
• HEp-2 M4 cells revealed a high specificity for the detection of MuSK autoantibodies from 25 patient sera. (PMID:24416182)
• [review] Recent discovery of two novel target proteins (MuSK and LRP4) has reduced the percentage of patients without known autoantibodies, although there are still some seronegative myasthenia gravis patients. (PMID:24530233)
• HnRNP C, YB-1 and hnRNP L coordinately enhance skipping of human MUSK exon 10 to generate a Wnt-insensitive MuSK isoform. (PMID:25354590)
• A Dutch founder mutation in MUSK causing fetal akinesia deformation sequence has been found in 14 fetuses. (PMID:25537362)
• To our knowledge, this is the first report showing that a mutation in MuSK is associated with Fetal akinesia deformation sequence syndrome (PMID:25612909)
• Immunosuppression attenuates the Th1 response in AChR-myasthenia gravis (MG) and MuSK-MG, but otherwise modulates immune responses in AChR-MG and MuSK-MG patients differentially. (PMID:25893403)
• Classical electromyography revealed the presence of myopathic changes more frequently in MuSK myasthenia gravis compared to acetylcholine receptor myasthenia gravis (PMID:26778359)
• Gene expression profiling showed that MuSK was required for the BMP4-induced expression of a subset of genes in myoblasts, including regulator of G protein signaling 4 (Rgs4). (PMID:27601729)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Musk	ENSMUSG00000057280
rattus_norvegicus	Musk	ENSRNOG00000033567
drosophila_melanogaster	Nrk	FBGN0020391

Paralogs (53): INSRR (ENSG00000027644), FLT4 (ENSG00000037280), EPHA3 (ENSG00000044524), ROS1 (ENSG00000047936), LTK (ENSG00000062524), ERBB3 (ENSG00000065361), TIE1 (ENSG00000066056), FGFR2 (ENSG00000066468), FGFR3 (ENSG00000068078), EPHA8 (ENSG00000070886), FGFR1 (ENSG00000077782), EPHA6 (ENSG00000080224), TYRO3 (ENSG00000092445), FLT1 (ENSG00000102755), MET (ENSG00000105976), EPHB6 (ENSG00000106123), PDGFRB (ENSG00000113721), EPHA4 (ENSG00000116106), TEK (ENSG00000120156), FLT3 (ENSG00000122025), KDR (ENSG00000128052), EPHB2 (ENSG00000133216), PDGFRA (ENSG00000134853), EPHA7 (ENSG00000135333), IGF1R (ENSG00000140443), NTRK3 (ENSG00000140538), ERBB2 (ENSG00000141736), EPHA2 (ENSG00000142627), EPHA5 (ENSG00000145242), EGFR (ENSG00000146648), EPHA1 (ENSG00000146904), NTRK2 (ENSG00000148053), MERTK (ENSG00000153208), EPHB1 (ENSG00000154928), KIT (ENSG00000157404), FGFR4 (ENSG00000160867), DDR2 (ENSG00000162733), RYK (ENSG00000163785), MST1R (ENSG00000164078), LMTK2 (ENSG00000164715), RET (ENSG00000165731), AXL (ENSG00000167601), ROR2 (ENSG00000169071), ALK (ENSG00000171094), INSR (ENSG00000171105), ERBB4 (ENSG00000178568), CSF1R (ENSG00000182578), EPHB3 (ENSG00000182580), EPHA10 (ENSG00000183317), ROR1 (ENSG00000185483), EPHB4 (ENSG00000196411), NTRK1 (ENSG00000198400), DDR1 (ENSG00000204580)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:103581) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 33 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal neuromuscular synapse morphology	4
kyphosis	3
decreased grip strength	3
muscle weakness	2
decreased body weight	2
respiratory failure	2
premature death	2
abnormal axon extension	2
abnormal spine curvature	2
neonatal lethality, complete penetrance	2
abnormal phrenic nerve innervation pattern to diaphragm	2
progressive muscle weakness	1
thin diaphragm muscle	1
abnormal motor neuron innervation pattern	1
abnormal innervation pattern to muscle	1
failure of neuromuscular synapse presynaptic differentiation	1
failure of neuromuscular synapse postsynaptic differentiation	1
weight loss	1
decreased body size	1
no spontaneous movement	1
impaired coordination	1
abnormal gait	1
unresponsive to tactile stimuli	1
cyanosis	1
abnormal motor capabilities/coordination/movement	1

+8 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Pan troglodytes	Q7YR43	99.6%	Diamond
Bos taurus	P43481	99.4%	Diamond
Capra hircus	Q28317	99.4%	Diamond
Macaca fascicularis	Q5IFJ9	99.4%	Diamond
Felis catus	Q28889	99.2%	Diamond
Drosophila sechellia	B4HNW4	99.0%	Diamond
Drosophila simulans	B4QC63	99.0%	Diamond
Saimiri boliviensis boliviensis	Q5IS82	99.0%	Diamond
Drosophila persimilis	B4GBH0	98.9%	Diamond
Drosophila pseudoobscura pseudoobscura	Q290N5	98.9%	Diamond
Gallus gallus	P08941	98.7%	Diamond
Canis lupus familiaris	O97799	98.4%	Diamond
Sus scrofa	Q2HWD6	98.1%	Diamond
Drosophila erecta	B3NS99	97.4%	Diamond
Drosophila yakuba	B4P5Q9	97.4%	Diamond
Meleagris gallopavo	P56276	96.4%	Diamond
Callithrix jacchus	Q76II0	94.6%	Diamond
Cavia porcellus	P14617	89.8%	Diamond
Feline sarcoma virus (STRAIN HARDY-ZUCKERMAN 4)	P04048	99.2%	Diamond
Feline sarcoma virus (STRAIN MCDONOUGH)	P00545	99.1%	Diamond
UR2 sarcoma virus	P00529	98.7%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
LPAR1	protein-coding	1902
SVEP1	protein-coding	79987
MIR7702	ncRNA	102465800

Protein

Protein identifiers

Muscle, skeletal receptor tyrosine-protein kinase — O15146 (reviewed: O15146)

Alternative names: Muscle-specific tyrosine-protein kinase receptor

All UniProt accessions (3): A0A087WSY1, O15146, F6XAJ2

UniProt curated annotations — full annotation on UniProt →

Function. Receptor tyrosine kinase which plays a central role in the formation and the maintenance of the neuromuscular junction (NMJ), the synapse between the motor neuron and the skeletal muscle. Recruitment of AGRIN by LRP4 to the MUSK signaling complex induces phosphorylation and activation of MUSK, the kinase of the complex. The activation of MUSK in myotubes regulates the formation of NMJs through the regulation of different processes including the specific expression of genes in subsynaptic nuclei, the reorganization of the actin cytoskeleton and the clustering of the acetylcholine receptors (AChR) in the postsynaptic membrane. May regulate AChR phosphorylation and clustering through activation of ABL1 and Src family kinases which in turn regulate MUSK. DVL1 and PAK1 that form a ternary complex with MUSK are also important for MUSK-dependent regulation of AChR clustering. May positively regulate Rho family GTPases through FNTA. Mediates the phosphorylation of FNTA which promotes prenylation, recruitment to membranes and activation of RAC1 a regulator of the actin cytoskeleton and of gene expression. Other effectors of the MUSK signaling include DNAJA3 which functions downstream of MUSK. May also play a role in acetylcholinesterase (AChE) localization at the neuromuscular junctions (NMJ) via its interaction wit COLQ. May also play a role within the central nervous system by mediating cholinergic responses, synaptic plasticity and memory formation.

Subunit / interactions. Monomer. Homodimer. Interacts with LRP4; the heterodimer forms an AGRIN receptor complex that binds AGRIN resulting in activation of MUSK. Forms a heterotetramer composed of 2 DOK7 and 2 MUSK molecules which facilitates MUSK trans-autophosphorylation on tyrosine residue and activation. Interacts (via cytoplasmic part) with DOK7 (via IRS-type PTB domain); requires MUSK phosphorylation. Interacts with DVL1 (via DEP domain); the interaction is direct and mediates the formation of a DVL1, MUSK and PAK1 ternary complex involved in AChR clustering. Interacts with PDZRN3; this interaction is enhanced by agrin. Interacts with FNTA; the interaction is direct and mediates AGRIN-induced phosphorylation and activation of FNTA. Interacts with CSNK2B; mediates regulation by CK2. Interacts (via the cytoplasmic domain) with DNAJA3. Interacts with NSF; may regulate MUSK endocytosis and activity. Interacts with CAV3; may regulate MUSK signaling. Interacts with RNF31. Interacts with DOK7. Interacts with the acetylcholinesterase collagenic tail peptide (COLQ); the interaction may play a role in acetylcholinesterase (AChE) localization at the neuromuscular junctions (NMJ).

Subcellular location. Postsynaptic cell membrane.

Post-translational modifications. Ubiquitinated by PDZRN3. Ubiquitination promotes endocytosis and lysosomal degradation. Phosphorylated. Phosphorylation is induced by AGRIN in a LRP4-dependent manner. Autophosphorylated. Autophosphorylation at Tyr-554 is required for interaction with DOK7 which in turn stimulates the phosphorylation and the activation of MUSK. Neddylated.

Disease relevance. Myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency (CMS9) [MIM:616325] A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features are easy fatigability and muscle weakness affecting the axial and limb muscles (with hypotonia in early-onset forms), the ocular muscles (leading to ptosis and ophthalmoplegia), and the facial and bulbar musculature (affecting sucking and swallowing, and leading to dysphonia). The symptoms fluctuate and worsen with physical effort. CMS9 is a disorder of postsynaptic neuromuscular transmission, due to deficiency of AChR at the endplate that results in low amplitude of the miniature endplate potential and current. The disease is caused by variants affecting the gene represented in this entry. MUSK mutations lead to decreased agrin-dependent AChR aggregation, a critical step in the formation of the neuromuscular junction. Fetal akinesia deformation sequence 1 (FADS1) [MIM:208150] A clinically and genetically heterogeneous group of disorders with congenital malformations related to impaired fetal movement. Clinical features include fetal akinesia, intrauterine growth retardation, polyhydramnios, arthrogryposis, pulmonary hypoplasia, craniofacial abnormalities, and cryptorchidism. FADS1 inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Positively regulated by CK2.

Similarity. Belongs to the protein kinase superfamily. Tyr protein kinase family.

Isoforms (3)

UniProt ID	Names	Canonical?
O15146-1	1	yes
O15146-2	2
O15146-3	3

RefSeq proteins (3): NP_001159752, NP_001159753, NP_005583* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR013098	Ig_I-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR020067	Frizzled_dom	Domain
IPR020635	Tyr_kinase_cat_dom	Domain
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR036790	Frizzled_dom_sf	Homologous_superfamily
IPR050122	RTK	Family

Pfam: PF01392, PF07679, PF07714, PF13927

Catalyzed reactions (Rhea)

• L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] + ADP + H(+) (RHEA:10596)

UniProt features (55 total): sequence variant 21, disulfide bond 9, domain 5, modified residue 4, splice variant 3, mutagenesis site 3, binding site 2, glycosylation site 2, topological domain 2, signal peptide 1, chain 1, active site 1, transmembrane region 1

Structure

Experimental structures (PDB)

6 structures by resolution:

PDB	Title	Method	Resolution (Å)
9NWG	Crystal Structure of the Third Immunoglobulin-Like Domain of Human Muscle-Specific Kinase	X-RAY DIFFRACTION	1.7
9SN0	TKD of human Muscle Specific Kinase (MuSK)	X-RAY DIFFRACTION	2.2
9SNU	TKD of human Muscle Specific Kinase (MuSK) S752D mutant	X-RAY DIFFRACTION	2.62
9LGG	Crystal structure of the human MuSK(Ig3_Fz)/L1 peptide complex	X-RAY DIFFRACTION	2.69
9NWH	Long-wavelength SAD Crystal Structure of the Third Immunoglobulin-Like Domain of Human …	X-RAY DIFFRACTION	2.8
8S9P	1:1:1 agrin/LRP4/MuSK complex	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15146-F1	76.57	0.37

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Transferases, Kinases, Tyr protein kinases, Transporters, Accessory Factors Involved in Transport, Predicted membrane proteins, Predicted intracellular proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital malformations, Other congenital malformations

Protein evidence: Evidence at protein level

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1)

Position	Role
725	proton acceptor

Ligand- & substrate-binding residues (2)

Position	Role
581–589	ATP
609	ATP

Post-translational modifications (4)

Type	Positions
Phosphotyrosine	554, 755
Phosphoserine	681, 698

Disulfide bonds (9)

Type	Positions
Disulfide bond	49–99, 98–112, 142–190, 233–282, 317–382, 325–375, 366–406, 394–447, 398–434

Glycosylation sites (2)

Type	Positions
N-linked (glcnac…) asparagine	222, 338

Mutagenesis-validated functional residues (3)

Position	Phenotype
584	mild decrease in kinase activity.
609	severe loss of kinase activity.
743	severe loss of kinase activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 2; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

2 pathways:

ID	Pathway	Evidence
R-HSA-3000178	ECM proteoglycans	electronic
R-HSA-1474244	Extracellular matrix organization	—

MSigDB gene sets: 402 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, MORF_RAGE, GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, GOBP_MEMORY, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_SYNAPSE_ASSEMBLY, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GCANCTGNY_MYOD_Q6, MODULE_64, GOBP_GROWTH, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, CAGCTG_AP4_Q5

GO Biological Process (14): positive regulation of protein phosphorylation (GO:0001934), cell surface receptor protein tyrosine kinase signaling pathway (GO:0007169), neuromuscular junction development (GO:0007528), memory (GO:0007613), regulation of synaptic assembly at neuromuscular junction (GO:0008582), positive regulation of gene expression (GO:0010628), cell differentiation (GO:0030154), skeletal muscle acetylcholine-gated channel clustering (GO:0071340), positive regulation of protein geranylgeranylation (GO:2000541), protein phosphorylation (GO:0006468), enzyme-linked receptor protein signaling pathway (GO:0007167), positive regulation of macromolecule metabolic process (GO:0010604), positive regulation of Rac protein signal transduction (GO:0035022), positive regulation of skeletal muscle acetylcholine-gated channel clustering (GO:1904395)

GO Molecular Function (11): protein tyrosine kinase activity (GO:0004713), transmembrane receptor protein tyrosine kinase activity (GO:0004714), ATP binding (GO:0005524), Wnt-protein binding (GO:0017147), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740), PDZ domain binding (GO:0030165)

GO Cellular Component (6): plasma membrane (GO:0005886), neuromuscular junction (GO:0031594), signaling receptor complex (GO:0043235), postsynaptic membrane (GO:0045211), membrane (GO:0016020), synapse (GO:0045202)

Reactome top-level categories

1 top-level categories:

Category	Pathways
Extracellular matrix organization	1

GO top-level categories

57 GO namespaces:

Category	Terms
positive regulation of protein modification process	2
regulation of protein phosphorylation	1
protein phosphorylation	1
positive regulation of phosphorylation	1
enzyme-linked receptor protein signaling pathway	1
synapse organization	1
learning or memory	1
regulation of developmental growth	1
synaptic assembly at neuromuscular junction	1
regulation of synapse assembly	1
regulation of neuromuscular junction development	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
cellular developmental process	1
postsynaptic membrane organization	1
neuromuscular junction development	1
receptor clustering	1
protein geranylgeranylation	1
regulation of protein geranylgeranylation	1
phosphorylation	1
protein modification process	1
cell surface receptor signaling pathway	1
positive regulation of metabolic process	1
macromolecule metabolic process	1
regulation of macromolecule metabolic process	1
Rac protein signal transduction	1
regulation of Rac protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
skeletal muscle acetylcholine-gated channel clustering	1
positive regulation of receptor clustering	1
regulation of skeletal muscle acetylcholine-gated channel clustering	1
protein kinase activity	1
protein tyrosine kinase activity	1
transmembrane receptor protein kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
anion binding	1
protein binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
protein domain specific binding	1
membrane	1
cell periphery	1
synapse	1
protein-containing complex	1
synaptic membrane	1
postsynapse	1
cellular anatomical structure	1
cell junction	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 3 of 31 annotations. The rest are phylogenetic / computational / electronic (IEA).

3 experimentally-supported GO terms:

GO term	NS	Evidence
neuromuscular junction development	BP	direct assay
positive regulation of protein phosphorylation	BP	mutant phenotype
signaling receptor complex	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 978 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MUSK	RAPSN	Q13702	980
MUSK	AGRN	O00468	980
MUSK	DOK7	Q18PE1	976
MUSK	LRP4	O75096	888
MUSK	COLQ	Q9Y215	879
MUSK	CHRNE	Q04844	843
MUSK	CHRNB1	P11230	774
MUSK	CHRND	Q07001	772
MUSK	CHRNG	P07510	771
MUSK	BCHE	P06276	722
MUSK	ACHE	P22303	712
MUSK	CHRNA1	P02708	692
MUSK	UTRN	P46939	671
MUSK	DAG1	Q14118	625
MUSK	CTTN	Q14247	573

IntAct

Human interaction partners of MUSK in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

12 partners by confidence:

Partner	Interaction type	MIscore	Records
CDC37	physical association	0.600	1
HSP90AB1	physical association	0.520	3
YWHAE	physical association	0.400	2
FKBP5	physical association	0.400	1
HSP90AA1	physical association	0.400	1
IL6	physical association	0.400	1
SFN	physical association	0.400	1
ILKAP	physical association	0.370	1
STYX	physical association	0.370	1
DNAJC13	association	0.350	1
HLA-B	association	0.350	1
ARHGAP32	proximity	0.270	1

BioGRID (89 interactions; top human partners by supporting records): ERBB2IP (Affinity Capture-Western; 4 records), ADAM30 (Affinity Capture-MS; 2 records), CALM3 (Affinity Capture-MS; 2 records), CDC37 (Affinity Capture-MS; 2 records), DNAJC13 (Affinity Capture-MS; 2 records), HLA-C (Affinity Capture-MS; 2 records), HSPA1B (Affinity Capture-MS; 2 records), PDZRN3 (Affinity Capture-Western; 2 records), RBSN (Affinity Capture-MS; 2 records), SYNE1 (Two-hybrid; 2 records), AAAS (Proximity Label-MS), ACBD3 (Proximity Label-MS), ALDH3A2 (Proximity Label-MS), ANKLE2 (Proximity Label-MS), APMAP (Proximity Label-MS)

SIGNOR signaling

showing 8 of 10 signaling interactions:

A	Effect	B	Mechanism
DOK7	up-regulates	MUSK	binding
WNT11	up-regulates	MUSK	binding
WNT9A	up-regulates	MUSK	binding
MUSK	up-regulates	WNT11	binding
LRP4	“up-regulates activity”	MUSK	binding
MUSK	“up-regulates activity”	MUSK	phosphorylation
MUSK	“up-regulates activity”	DOK7	phosphorylation
PDZRN3	“down-regulates quantity”	MUSK	ubiquitination

Protein complexes (CORUM) (1)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

1 complexes by size:

Complex	Subunits	Members
COLQ-MUSK complex	2	COLQ, MUSK

Ligand–receptor pairs (CellPhoneDB) (1)

Curated ligand–receptor partners (cell-cell communication), distinct from the protein–protein interactions above.

1 ligand–receptor pairs:

Partner	This gene’s role	Signaling class
MUSK;LRP4		Signaling by Agrin

Disease & clinical

Genetic variants

Variant evidence for MUSK: 914 ClinVar records (80 pathogenic / likely pathogenic); 9 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

914 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	44
Likely pathogenic	36
Uncertain significance	321
Likely benign	374
Benign	58

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 80 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
211542	NM_005592.4(MUSK):c.79+2T>G	Pathogenic	criteria provided, multiple submitters, no conflicts	5
2951981	NM_005592.4(MUSK):c.790C>T (p.Arg264Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
2936081	NM_005592.4(MUSK):c.2T>C (p.Met1Thr)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
559926	NM_005592.4(MUSK):c.2357G>A (p.Trp786Ter)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
1324751	NM_005592.4(MUSK):c.909dup (p.Ala304fs)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
2933320	NM_005592.4(MUSK):c.1586+1G>A	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
2949331	NM_005592.4(MUSK):c.114T>A (p.Asp38Glu)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
4854837	NM_005592.4(MUSK):c.2158A>G (p.Lys720Glu)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2
849716	NM_005592.4(MUSK):c.496C>T (p.Arg166Ter)	Pathogenic	criteria provided, single submitter	1
858181	NM_005592.4(MUSK):c.2165T>C (p.Val722Ala)	Pathogenic	criteria provided, single submitter	1
947675	NM_005592.4(MUSK):c.1735A>T (p.Arg579Ter)	Pathogenic	criteria provided, single submitter	1
963084	NM_005592.4(MUSK):c.1626del (p.Glu542fs)	Pathogenic	criteria provided, single submitter	1
1068787	NM_005592.4(MUSK):c.581dup (p.Asn194fs)	Pathogenic	criteria provided, single submitter	1
1452397	NM_005592.4(MUSK):c.2170C>T (p.Arg724Ter)	Pathogenic	criteria provided, single submitter	1
1458702	NM_005592.4(MUSK):c.582del (p.Asn194fs)	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore MUSK’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 32 predictions of 1,529):

Position(s)	Effect	Δscore	Sites
9:110682672–110682673	acceptor_loss	1.0000	6
9:110682801	donor_loss	1.0000
9:110685053	donor_gain	1.0000
9:110687115	acceptor_loss	1.0000	3
9:110687265	donor_gain	1.0000
9:110695401–110695402	acceptor_loss	1.0000	5
9:110695531–110695532	donor_loss	1.0000	5
9:110699967	acceptor_gain	1.0000
9:110747639–110747640	acceptor_loss	1.0000	6
9:110747801–110747802	donor_loss	1.0000	3

AlphaMissense

2,456 missense substitutions predicted likely pathogenic (of 5,707 scored), across 661 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M713	9	0.889	0.984
M835	9	0.872	0.983
D743	8	0.995	0.999
D725	8	0.989	0.998
D784	8	0.989	0.997
D184	8	0.975	0.994
H723	8	0.960	0.989
N730	8	0.960	0.995
F744	8	0.958	0.997
F47	8	0.953	0.999
F796	8	0.948	0.991
N194	8	0.931	0.996
F849	8	0.931	0.994
F623	8	0.924	0.995
D93	8	0.916	0.970
N286	8	0.910	0.993
D580	8	0.887	0.947
D72	8	0.843	0.968
W245	7	0.997	1.000
W61	7	0.995	0.999

HPA cancer prognostics

RNA cancer specificity: Not detected

Disease associations

OMIM: gene MIM:601296 | disease phenotypes: MIM:616325, MIM:208150, MIM:608931

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
congenital myasthenic syndrome 9	Strong	Autosomal recessive	3
fetal akinesia deformation sequence 1	Strong	Autosomal recessive	2

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
congenital myasthenic syndrome 9	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (6 panels, 6 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

6 panels:

Panel	Rating
Arthrogryposis	green
Congenital myaesthenic syndrome	green
Fetal anomalies	green
Fetal hydrops	green
Hypotonic infant	green
Other rare neuromuscular disorders	green

Mondo (3): congenital myasthenic syndrome 9 (MONDO:0014587), fetal akinesia deformation sequence 1 (MONDO:0100101), congenital myasthenic syndrome 4C (MONDO:0012157)

Orphanet (2): Congenital myasthenic syndrome (Orphanet:590), Fetal akinesia deformation sequence (Orphanet:994)

HPO phenotypes

showing 60 of 109 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000238	Hydrocephalus
HP:0000276	Long face
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000437	Depressed nasal tip
HP:0000467	Neck muscle weakness
HP:0000470	Short neck
HP:0000476	Cystic hygroma
HP:0000486	Strabismus
HP:0000506	Telecanthus
HP:0000508	Ptosis
HP:0000520	Proptosis
HP:0000581	Blepharophimosis
HP:0000597	Ophthalmoparesis
HP:0000602	Ophthalmoplegia
HP:0000689	Dental malocclusion
HP:0000883	Thin ribs
HP:0001059	Pterygium
HP:0001193	Ulnar deviation of the hand or of fingers of the hand
HP:0001196	Short umbilical cord
HP:0001239	Wrist flexion contracture
HP:0001252	Hypotonia
HP:0001260	Dysarthria
HP:0001262	Excessive daytime somnolence
HP:0001270	Motor delay
HP:0001290	Generalized hypotonia
HP:0001305	Dandy-Walker malformation
HP:0001319	Neonatal hypotonia
HP:0001321	Cerebellar hypoplasia
HP:0001331	Absent septum pellucidum
HP:0001371	Flexion contracture
HP:0001511	Intrauterine growth retardation
HP:0001518	Small for gestational age
HP:0001558	Decreased fetal movement
HP:0001561	Polyhydramnios
HP:0001611	Hypernasal speech
HP:0001612	Weak cry
HP:0001622	Premature birth
HP:0001762	Talipes equinovarus
HP:0001790	Nonimmune hydrops fetalis
HP:0001838	Rocker bottom foot
HP:0001989	Fetal akinesia sequence
HP:0002015	Dysphagia
HP:0002089	Pulmonary hypoplasia
HP:0002093	Respiratory insufficiency
HP:0002304	Akinesia
HP:0002375	Hypokinesia
HP:0002380	Fasciculations
HP:0002389	Cavum septum pellucidum
HP:0002515	Waddling gait
HP:0002650	Scoliosis

GWAS associations

9 associations:

Study	Trait	p-value
GCST006979_222	Heel bone mineral density	4e-13
GCST006979_221	Heel bone mineral density	1e-10
GCST012367_2	Orofacial cleft x maternal periconceptional smoking interaction (1df)	2e-7
GCST001444_7	Pulmonary function decline	7e-7
GCST001843_3	Type 2 diabetes (dietary heme iron intake interaction)	1e-6
GCST009391_788	Metabolite levels	1e-6
GCST008462_5	Plasma factor V levels in venous thrombosis (conditioned on rs6027)	2e-6
GCST008158_16	Body mass index	3e-6
GCST009391_1050	Metabolite levels	4e-6

EFO canonical traits (from GWAS)

7 canonical traits:

EFO ID	Trait name
EFO:0004314	forced expiratory volume
EFO:0008355	dietary heme iron intake measurement
EFO:0009270	heel bone mineral density
EFO:0004340	body mass index
EFO:0010540	thiamine measurement
EFO:0010397	sphingomyelin 24:0 measurement
EFO:0006527	smoking status measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5684 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 220,762 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

20 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL601719	CRIZOTINIB	4	15,133
CHEMBL1287853	FEDRATINIB	4	3,770
CHEMBL502835	NINTEDANIB	4	8,978
CHEMBL576982	QUIZARTINIB	4	4,647
CHEMBL1336	SORAFENIB	4	87,476
CHEMBL535	SUNITINIB	4	80,232
CHEMBL522892	DOVITINIB	3	5,162
CHEMBL603469	LESTAURTINIB	3
CHEMBL223360	LINIFANIB	3	4,094
CHEMBL575448	BMS-754807	2	418
CHEMBL215152	DEFOSBARASERTIB	2	381
CHEMBL103667	DORAMAPIMOD	2	1,746
CHEMBL1230609	FORETINIB	2	3,230
CHEMBL5077961	MILREBRUTINIB	2	26
CHEMBL475251	R-406	2	787
CHEMBL1721885	SU-014813	2	375
CHEMBL572878	TOZASERTIB	2	3,128
CHEMBL574738	AST-487	1	468
CHEMBL1908397	KW-2449	1	655
CHEMBL4212531	PF-06273340	1	56

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: catalytic receptor — Type IX RTKs: MuSK

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
compound 1d [PMID: 21493067]	Inhibition	6.65	pIC50
compound 25 [PMID: 17935989]	Inhibition	5.78	pKi

Binding affinities (BindingDB)

33 measured of 101 human assays (102 total across all organisms); most potent 33 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
1-[2-(4-methylphenyl)-5-tert-butyl-pyrazol-3-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	KD	0.37 nM
Staurosporine	KD	1.7 nM
CEP-701	KD	3.4 nM
Pf-06273340	IC50	4 nM
4-[4-[(5-tert-butyl-2-quinolin-6-ylpyrazol-3-yl)carbamoylamino]-3-fluorophenoxy]-N-methylpyridine-2-carboxamide	IC50	5.5 nM
3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	IC50	5.6 nM	US-8822500: Tyrosine kinase inhibitors
Staurosporine, 8	IC50	6.5 nM
Momelotinib	IC50	8 nM	US-9469613: (N-(cyanomethyl)-4-(2-(4-morpholinophenylamino)pyrimidin-4-yl)benzamide
ASP-3026	IC50	10 nM
N-[4-[[(2-hydroxy-1H-indol-3-yl)-phenylmethylidene]amino]phenyl]-N-methyl-2-(4-methylpiperazin-1-yl)acetamide	KI	15 nM	US-10981896: Indolinone derivatives as inhibitors of maternal embryonic leucine zipper kinase
CHEMBL1240703	KD	15 nM
2-(2-Chloro-4-iodo-phenylamino)-N-cyclopropylmethoxy-3,4-difluoro-benzamide	IC50	17 nM
CHEMBL4553037	IC50	37 nM
CHEMBL5423601	IC50	66 nM
CHEMBL6091929	IC50	97 nM
PKC-412	KD	110 nM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	KD	120 nM	US-9145414: 1,2,4-triazine-6-carboxamide derivative
CHEMBL4792981	KD	150 nM
(S)-5-fluoro-2-(1-(5-fluoropyridin-2-yl)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)nicotinonitrile	IC50	174 nM
CHEMBL1908397	KD	650 nM
CHEMBL5559304	IC50	697 nM
4-[6-methoxy-7-(3-piperidin-1-ylpropoxy)quinazolin-4-yl]-N-(4-propan-2-yloxyphenyl)piperazine-1-carboxamide	KD	740 nM
(9S)-9-[(dimethylamino)methyl]-6,7,10,11-tetrahydro-9H,18H-5,21:12,17-di(metheno)dibenzo[e,k]pyrrolo[3,4-h][1,4,13]oxadiazacyclohexadecine-18,20(19H)-dione	IC50	743 nM
1-[4-[(4-ethyl-1-piperazinyl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[[6-(methylamino)-4-pyrimidinyl]oxy]phenyl]urea	KD	1400 nM
7-chloro-3-oxo-8-[(thiazol-5-ylmethyl)-amino]-11,16-dioxa-2,4,19,21-tetraaza-tricyclo[15.3.1.0*5,10*]henicosa-1(21),5,7,9,17,19-hexaene-18-crbonitrile	KI	1540 nM
3-(4-morpholin-4-ylpyrido[2,3]furo[2,4-b]pyrimidin-2-yl)phenol	KD	2400 nM
5-[(Z)-(5-fluoranyl-2-oxidanylidene-1H-indol-3-ylidene)methyl]-2,4-dimethyl-N-[(2S)-3-morpholin-4-yl-2-oxidanyl-propyl]-1H-pyrrole-3-carboxamide	KD	2600 nM
5-({4-[(2,3-dimethyl-2H-indazol-6-yl)(methyl)amino]pyrimidin-2-yl}amino)-2-methylbenzene-1-sulfonamide	KD	2900 nM
1-Acyl-1H-[1,2,4]triazole-3,5-diamine Analogue 3b	KD	3100 nM
SUNITINIB MALATE	KD	3500 nM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide	KD	3900 nM	US-20250129067: PLATELET-DERIVED GROWTH FACTOR RECEPTOR (PDGFR) ALPHA INHIBITORS AND USES THEREOF
(4-chlorophenyl)-[4-(4-pyridylmethyl)phthalazin-1-yl]amine	KD	8800 nM
1-{4-[(3-cyclopropyl-1H-pyrazol-5-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl}-N-(6-fluoropyridin-3-yl)-2-methyl-L-prolinamide	KD	13000 nM

ChEMBL bioactivities

53 potent at pChembl≥5 of 53 total, top 38 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.51	Kd	3.1	nM	AST-487
8.42	IC50	3.8	nM	STAUROSPORINE
8.04	IC50	9.1	nM	CRIZOTINIB
8.00	Kd	10	nM	LINIFANIB
7.89	IC50	12.83	nM	CHEMBL5423601
7.89	Kd	13	nM	FORETINIB
7.28	IC50	53	nM	PF-06273340
7.26	IC50	54.4	nM	STAUROSPORINE
7.07	Kd	86	nM	STAUROSPORINE
7.00	Kd	100	nM	SU-014813
7.00	Kd	100	nM	R-406
6.96	Kd	110	nM	CHEMBL4792981
6.89	Kd	130	nM	SORAFENIB
6.80	IC50	158	nM	STAUROSPORINE
6.70	Kd	200	nM	KW-2449
6.65	IC50	224	nM	CHEMBL1774056
6.64	Kd	230	nM	CRIZOTINIB
6.59	IC50	257	nM	CHEMBL5559304
6.58	Kd	260	nM	TAE-684
6.54	IC50	290	nM	STAUROSPORINE
6.52	Kd	300	nM	TOZASERTIB
6.51	IC50	306	nM	MILREBRUTINIB
6.41	Kd	390	nM	QUIZARTINIB
6.31	Kd	490	nM	SUNITINIB
6.28	Kd	530	nM	CHEMBL4553037
6.23	Kd	590	nM	NINTEDANIB
6.16	IC50	690	nM	CHEMBL3422092
6.10	Kd	800	nM	FEDRATINIB
6.08	Kd	830	nM	DOVITINIB
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n
6.00	Kd	1000	nM	QUIZARTINIB
5.82	Kd	1500	nM	DEFOSBARASERTIB
5.72	Kd	1900	nM	DORAMAPIMOD
5.39	Kd	4100	nM	LESTAURTINIB
5.25	Kd	5600	nM	CHEMBL1908395
5.22	Kd	6000	nM	BMS-754807

PubChem BioAssay actives

49 with measured affinity, of 711 total; 31 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	435678: Binding constant for MUSK kinase domain	kd	0.0031	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1308970: Inhibition of MUSK (unknown origin) incubated for 1 hr by spectrophotometric analysis	ic50	0.0038	uM
Crizotinib	2161835: Inhibition of human N-terminal GST-fused MUSK catalytic domain (527 to 869(end) residues) expressed in baculovirus expression system using CSKtide as substrate measured after 5 hrs by off-chip mobility shift assay relative to control	ic50	0.0091	uM
1-[4-(3-amino-1H-indazol-4-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea	435678: Binding constant for MUSK kinase domain	kd	0.0100	uM
N-[3-cyclopropyl-5-[(4-methylpiperazin-1-yl)methyl]phenyl]-5-methyl-18-oxo-9-oxa-17,23,25,26-tetrazatetracyclo[17.5.2.14,8.022,25]heptacosa-1(24),4,6,8(27),19(26),20,22-heptaen-2-yne-6-carboxamide	2014041: Inhibition of Musk (unknown origin)	ic50	0.0128	uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	625022: Binding constant for MUSK kinase domain	kd	0.0130	uM
N-[5-[2-amino-7-(1-hydroxy-2-methylpropan-2-yl)pyrrolo[2,3-d]pyrimidine-5-carbonyl]-3-pyridinyl]-2-(5-chloro-2-pyridinyl)acetamide	1686419: Inhibition of MUSK (unknown origin)	ic50	0.0530	uM
5-[(Z)-(5-fluoro-2-oxo-1H-indol-3-ylidene)methyl]-N-[(2S)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide	435678: Binding constant for MUSK kinase domain	kd	0.1000	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	625022: Binding constant for MUSK kinase domain	kd	0.1000	uM
N-[(1S)-1-(5-fluoro-2-pyridinyl)ethyl]-3-(3-propan-2-yloxy-1H-pyrazol-5-yl)imidazo[4,5-b]pyridin-5-amine	692574: Inhibition of MuSk	ic50	0.1000	uM
N-[(1R)-1-(3,5-difluorophenyl)ethyl]-3-[(E)-2-pyridin-2-ylethenyl]-2H-indazol-5-amine	1741257: Binding affinity to wild-type human partial length MUSK (M553 to V869 residues) expressed in bacterial expression system by Kinomescan method relative to control	kd	0.1100	uM
Sorafenib	435678: Binding constant for MUSK kinase domain	kd	0.1300	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	625022: Binding constant for MUSK kinase domain	kd	0.2000	uM
5-fluoro-2-[[(1S)-1-(5-fluoro-2-pyridinyl)ethyl]amino]-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyridine-3-carbonitrile	596575: Inhibition of human MuSk	ic50	0.2240	uM
N-[(2S)-1-(azetidin-1-yl)propan-2-yl]-3-[2-(3,5-dimethoxyanilino)pyrimidin-4-yl]-1-methylpyrazole-5-carboxamide	2075969: Inhibition of MUSK (unknown origin)	ic50	0.2570	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	625022: Binding constant for MUSK kinase domain	kd	0.2600	uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide	435678: Binding constant for MUSK kinase domain	kd	0.3000	uM
2-[3-[2-amino-6-[1-(oxetan-3-yl)-3,6-dihydro-2H-pyridin-4-yl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-2-(hydroxymethyl)phenyl]-6-cyclopropyl-8-fluoroisoquinolin-1-one	1830226: Inhibition of human MUSK expressed in baculovirus expression system by mobility shift assay	ic50	0.3060	uM
Sunitinib	435678: Binding constant for MUSK kinase domain	kd	0.4900	uM
(4R)-4-methyl-N-[3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl]-2-pyrimidin-5-yl-3,4-dihydro-1H-isoquinoline-7-carboxamide	1625889: Binding affinity to wild type human partial length MUSK (553 to 869 residues) expressed in bacterial expression system preincubated for 1 hr measured after 30 mins by qPCR method	kd	0.5300	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	625022: Binding constant for MUSK kinase domain	kd	0.5900	uM
N-[(R)-cyclopropyl(pyridin-2-yl)methyl]-3-[4-[(1S,5S)-3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl]phenyl]-1H-indazole-5-carboxamide	1203315: Inhibition of human MuSK by millipore radiometric assay	ic50	0.6900	uM
Fedratinib	625022: Binding constant for MUSK kinase domain	kd	0.8000	uM
4-amino-5-fluoro-3-[6-(4-methylpiperazin-1-yl)-1H-benzimidazol-2-yl]-1H-quinolin-2-one	435678: Binding constant for MUSK kinase domain	kd	0.8300	uM
Quizartinib	507636: Binding affinity to MUSK	kd	1.0000	uM
Momelotinib	2183911: Inhibition of MUSK (unknown origin)	ic50	1.0000	uM
2-[3-[[7-[3-[ethyl(2-hydroxyethyl)amino]propoxy]quinazolin-4-yl]amino]-1H-pyrazol-5-yl]-N-(3-fluorophenyl)acetamide	435678: Binding constant for MUSK kinase domain	kd	1.5000	uM
1-[3-tert-butyl-1-(4-methylphenyl)pyrazol-5-yl]-3-[4-(2-morpholin-4-ylethoxy)naphthalen-1-yl]urea	435678: Binding constant for MUSK kinase domain	kd	1.9000	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	625022: Binding constant for MUSK kinase domain	kd	4.1000	uM
5-cyano-N-[2-(cyclohexen-1-yl)-4-[1-[2-(dimethylamino)acetyl]piperidin-4-yl]phenyl]-1H-imidazole-2-carboxamide;hydrochloride	625022: Binding constant for MUSK kinase domain	kd	5.6000	uM
(2S)-1-[4-[(5-cyclopropyl-1H-pyrazol-3-yl)amino]pyrrolo[2,1-f][1,2,4]triazin-2-yl]-N-(6-fluoro-3-pyridinyl)-2-methylpyrrolidine-2-carboxamide	2167422: Binding affinity to MUSK (unknown origin) by phage based competition assay	kd	6.0000	uM

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression	1
Zoledronic Acid	decreases expression	1
Asbestos	affects expression	1
Sarin	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	decreases methylation	1

ChEMBL screening assays

247 unique, capped per target: 247 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1035907	Binding	Binding affinity to human MUSK at 10 uM relative to control	Assessment of chemical coverage of kinome space and its implications for kinase drug discovery. — *J Med Chem*

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_E2CY	HAP1 MUSK (-) 1	Cancer cell line	Male
CVCL_E2CZ	HAP1 MUSK (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for MUSK across ~30M SureChEMBL compounds — explore on Sugi Predict.