MUSK

Highest pathogenic variant AF is 0.00012578398

Gene type

protein_coding

Transcript type

protein_coding

Transcript

ENST00000374448

Coding exons

15

Length

132809

Individuals with no LoFs

124609

Homozygous LoFs

0

Heterozygous LoFs

56

Defined

124665

p

0.000225

Function

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 (PubMed:25537362). 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 within the central nervous system by mediating cholinergic responses, synaptic plasticity and memory formation (By similarity). {ECO:0000250, ECO:0000269|PubMed:25537362}.;

Disease

DISEASE: 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. {ECO:0000269|PubMed:15496425, ECO:0000269|PubMed:19949040, ECO:0000269|PubMed:20371544, ECO:0000269|PubMed:23326516, ECO:0000269|PubMed:24183479}. Note=The disease is caused by mutations 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.; DISEASE: Fetal akinesia deformation sequence (FADS) [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. {ECO:0000269|PubMed:25537362, ECO:0000269|PubMed:25612909}. Note=The disease is caused by mutations affecting the gene represented in this entry.;