Alternative titles; symbols
HGNC Approved Gene Symbol: MUSK
SNOMEDCT: 401138005;
Cytogenetic location: 9q31.3 Genomic coordinates (GRCh38): 9:110,668,791-110,806,558 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 9q31.3 | Fetal akinesia deformation sequence 1 | 208150 | Autosomal recessive | 3 |
| Myasthenic syndrome, congenital, 9, associated with acetylcholine receptor deficiency | 616325 | Autosomal recessive | 3 |
Intercellular communication is often mediated by receptors on the surface of one cell that recognize and are activated by specific protein ligands released by other cells. Members of one class of cell surface receptors, receptor tyrosine kinases (RTKs), are characterized by having a cytoplasmic domain containing intrinsic tyrosine kinase activity. This kinase activity is regulated by the binding of a cognate ligand to the extracellular portion of the receptor. RTKs, known to be expressed in cell type-specific fashions, play a role critical for the growth and differentiation of those cell types. The MUSK gene is a muscle-specific kinase required for neuromuscular junction formation (summary by DeChiara et al., 1996).
Ganju et al. (1995) reported the cloning and developmental expression pattern of mouse Nsk2, a novel, structurally distinct mammalian receptor tyrosine kinase characterized by a putative extracellular region bearing 4 immunoglobulin-like domains. In the adult mouse, the gene was found to be expressed preferentially in skeletal muscle. Increased steady-state levels of mouse Nsk2 transcripts were apparent on terminal differentiation of committed skeletal myoblast cell lines in vitro, and multiple isoforms of Nsk2 were observed in skeletal myotube cultures. RNA in situ hybridization studies of mouse embryos confirmed skeletal myogenesis as the major site of Nsk2 expression during normal embryogenesis and identified other likely sites of Nsk2 function in neurogenesis and mesenchymal-epithelial interactions during organ formation.
Valenzuela et al. (1995) described the rat and human homologs of a mouse receptor tyrosine kinase that is specifically expressed in skeletal muscle and suggested the designation MuSK, for muscle-specific kinase. The rat MuSK gene was initially cloned by Valenzuela et al. (1995) using degenerate PCR primers from 2 regions conserved among RTK genes. The resulting fragments were screened to remove known RTKs, and a novel candidate RTK was identified and designated MuSK. Full-length cDNAs were then isolated from a rat denervated muscle library and from a human myoblast library. The deduced 879-amino acid human protein has an N-terminal signal peptide, followed by 3 immunoglobulin (Ig)-like domains, a C6 box, an additional Ig-like domain, a transmembrane domain, and a C-terminal kinase domain. The rat and human proteins share 94% identity and exhibit all the features of conventional RTKs, including a large ectodomain, a single transmembrane region, and a cytoplasmic domain which is highly homologous to other RTKs. Valenzuela et al. (1995) noted the existence of 2 splice variants among the human cDNAs isolated. They showed that MuSK is specifically expressed in cells of the skeletal muscle lineage in the neuromuscular junction.
Chevessier et al. (2004) noted that the MUSK gene contains 14 exons.
Lacazette et al. (2003) identified several E boxes, an N box, and several transcription factor-binding sites conserved in the upstream region and in intron 1 of mouse and human MUSK.
Valenzuela et al. (1995) mapped the MuSK gene to mouse chromosome 4 by interspecific backcross analysis and to human chromosome 9q31.3-q32 by fluorescence in situ hybridization. The authors noted that Fukuyama muscular dystrophy (253800) maps to the same region of chromosome 9.
Luo et al. (2002) found that Musk interacted with dishevelled (Dvl1; 601365) in a mouse muscle cell line and in HEK293 cells transfected with mouse constructs. They further demonstrated that the Musk-Dvl1 interaction regulated acetylcholine receptor (AChR; see 100690) clustering stimulated by agrin (103320), and a mutant form of Dvl that did not interact with Musk inhibited the ability of agrin to induce receptor clustering.
Agrin signals through MuSK to cluster acetylcholine receptors on the postsynaptic membrane of the neuromuscular junction. In mouse muscle and cultured myotube cells, Finn et al. (2003) showed that the tyrosine kinases Abl1 (189980) and Abl2 (164690) are concentrated at the postsynaptic neuromuscular junction and are mediators of postsynaptic AChR clustering downstream of agrin and MuSK signaling. The authors suggested that the Abl kinases influence cytoskeletal regulatory molecules important for synapse assembly and remodeling.
The formation of the neuromuscular synapse requires MuSK to orchestrate postsynaptic differentiation, including the clustering of receptors for the neurotransmitter acetylcholine. Upon innervation, neural agrin activates MuSK to establish the postsynaptic apparatus, although agrin-independent formation of neuromuscular synapses can also occur experimentally in the absence of neurotransmission. Okada et al. (2006) determined that DOK7 (610285), a MuSK-interacting cytoplasmic protein, is essential for MuSK activation in cultured myotubes; in particular, mice deficient in Dok7 formed neither AChR clusters nor neuromuscular synapses. Thus, Okada et al. (2006) concluded that DOK7 is essential for neuromuscular synaptogenesis through its interaction with MuSK.
Using mouse Musk promoter-reporter constructs and constructs from several vertebrate species with innervated rat soleus muscle, mouse myogenic C2C12 cells, and transfected HEK293 cells, Lacazette et al. (2003) showed that agrin activated Musk expression via 2 pathways that converged on a Gabp (see 600609)-binding N box in the Musk promoter. The pathway used by developing muscle and cultured myocytes used neuregulin to regulate Musk expression at the synapse. The other pathway, used by adult fibers, involved activation of Rac (RAC1; 602048) and Jnk (MAPK8; 601158).
Congenital Myasthenic Syndrome 9 Associated with Acetylcholine Receptor Deficiency
In a 27-year-old French woman with congenital myasthenic syndrome-9 (CMS9; 616325) associated with AChR deficiency, Chevessier et al. (2004) identified compound heterozygous mutations in the MUSK gene (601296.0001 and 601296.0002).
Mihaylova et al. (2009) identified a homozygous mutation in the MUSK gene (P344R; 601296.0003) in 5 sibs, born of consanguineous Sudanese parents, with congenital myasthenic syndrome.
Maselli et al. (2010) described a severe congenital myasthenic syndrome phenotype caused by compound heterozygosity for missense mutations M605I (601296.0004) and A727V (601296.0005) in the kinase domain of MUSK.
Fetal Akinesia Deformation Sequence 1
In 11 affected fetuses from a Dutch genetic isolate with fetal akinesia deformation sequence (FADS1; 208150), Tan-Sindhunata et al. (2015) identified a homozygous missense mutation in the MUSK gene (I575T; 601296.0006). The variant had a carrier frequency of 8% in controls from this population, consistent with a founder effect.
In 5 affected fetuses, born of Swedish parents, with FADS1, Wilbe et al. (2015) identified a homozygous truncating mutation in the MUSK gene (601296.0007). The severe phenotype was similar to that observed in mice with homozygous knockdown of the MuSK gene (DeChiara et al., 1996) (see ANIMAL MODEL).
DeChiara et al. (1996) generated mice with a targeted disruption for the gene encoding MuSK. Neuromuscular synapses did not form in these mice, suggesting a failure in the induction of synapse formation. In connection with other findings, DeChiara et al. (1996) interpreted this to indicate that MuSK responds to a critical signal by agrin (103320) and that it, in turn, activates signaling cascades responsible for all aspects of synapse formation, including organization of the postsynaptic membrane, synapse-specific transcription, and presynaptic differentiation.
Lin et al. (2001) analyzed early stages of postsynaptic differentiation in muscles of mutant mice lacking agrin, MuSK, rapsyn (601592), and/or motor nerves. Lin et al. (2001) found that the defect in MuSK mutants is due to an absence of initiation of postsynaptic differentiation, whereas the impairment in agrin mutants is caused by loss of agrin-dependent maintenance of the postsynaptic apparatus. On the basis of these and previous studies, Lin et al. (2001) proposed the existence of 3 early overlapping steps in the formation of the postsynaptic apparatus at the neuromuscular junction. First, a muscle-intrinsic, nerve/agrin-independent and MuSK-dependent mechanism initiates formation of postsynaptic specialization in an end-plate band. Second, nerve-derived agrin acts through MuSK to promote apposition of nerve terminals to these nerve-independent acetylcholine receptor clusters and/or to induce new postsynaptic sites. Agrin is also required for the growth and maintenance of most, if not all, synaptic sites. Third, motor axons, or Schwann cells that accompany them, provide an agrin-independent signal that destabilizes or disperses postsynaptic apparatus that have not been stabilized by agrin.
Chevessier et al. (2008) found that mice carrying a homozygous V789M mutation (homologous to the human V790M mutation; 601296.0001) in the MUSK gene showed no obvious phenotypic abnormalities. In contrast, mice who were hemizygous for the V789M mutation (V789M/-) had progressive severe muscle weakness, showed pelvic and scapular region atrophy, and developed kyphosis. The diaphragm of hemizygous mice showed fatigable muscle weakness and impaired neuromuscular transmission. Muscle biopsy showed pronounced changes in endplate architecture, decreased AChR distribution, and innervation pattern. The findings indicated that the V789M mutation acts as a hypomorphic mutation and leads to insufficiency of MuSK function.
Ganju et al. (1995) mapped the Nsk2 gene to mouse chromosome 13 by analysis of recombinant inbred (RI) strains.
In a 27-year-old French woman with congenital myasthenic syndrome-9 (CMS9; 616325) associated with AChR deficiency, Chevessier et al. (2004) identified compound heterozygosity for a 2368G-A transition in exon 14 of the MUSK gene, resulting in a val790-to-met (V790M) substitution, and a 1-bp insertion (220insC; 601296.0002) in exon3, resulting in a frameshift and premature termination at codon 92. Muscle biopsy showed dramatic pre- and postsynaptic structural abnormalities of the neuromuscular junction and severe decrease in CHRNE (100725) and MUSK expression. Genetic analysis of biopsy sections from her similarly affected brother, who died at age 1.5 years, showed that he was also compound heterozygous for both mutations. Expression experiments revealed that the frameshift mutation led to the absence of MUSK expression. The missense mutation did not affect MUSK catalytic kinase activity but diminished expression and stability of MUSK, leading to decreased agrin-dependent AChR aggregation, which is a critical step in the formation of the neuromuscular junction. In electroporated mouse muscle, overexpression of V790M mutant induced, within a week, a severe decrease in synaptic AChR and an aberrant axonal outgrowth.
For discussion of the c.220delC mutation in the MUSCK gene that was found in compound heterozygous state in a patient with congenital myasthenic syndrome-9 (CMS9; 616325) associated with AChR deficiency by Chevessier et al. (2004), see 601296.0001.
In 5 sibs, born of consanguineous Sudanese parents, with congenital myasthenic syndrome-9 (CMS9; 616325) associated with AChR deficiency, Mihaylova et al. (2009) identified a homozygous c.1031C-G transversion in exon 8 of the MUSK gene, resulting in a pro344-to-arg (P344R) substitution in the frizzled-like cysteine-rich domain in the extracellular domain. The mutation was not found in 100 controls. Between ages 1 and 3 years, all patients were noted to have ptosis and easy fatigability when walking long distances. At the time of the report, the patients ranged in age from 9 to 20 years. Features included ophthalmoparesis, mild facial weakness, Gowers sign, and proximal muscle weakness in the upper and lower limbs. One patient had a waddling gait, and 2 had lordosis. One patient experienced respiratory insufficiency at age 20.
In a 19-year-old woman with severe congenital myasthenic syndrome-9 (CMS9; 616325) associated with AChR deficiency, Maselli et al. (2010) detected compound heterozygosity for missense mutations in MUSK, met605-to-ile (M605I) and ala727-to-val (A727V; 601296.0005), both in the kinase domain. The M605I mutation arose in exon 14 and was present in the patient's unaffected mother and younger brother, while the A727V mutation arose in exon 15 and was present in the patient's unaffected father. The M605I substitution is located in the N-terminal lobe of the highly conserved tyrosine kinase domain (TKD) of the protein. The A727V mutation is located in the C-terminal lobe of the TKD, within the catalytic loop of the enzyme. Intracellular microelectrode recordings and microscopy studies of the neuromuscular junction in a muscle biopsy revealed decreased miniature endplate potential amplitudes, reduced endplate size, and simplification of secondary synaptic folds, which were consistent with a postsynaptic deficit. There was a striking reduction of the endplate potential quantal content, consistent with additional presynaptic failure. Expression studies in mouse Musk-deficient myotubes revealed that A727V caused severe impairment of agrin-dependent Musk phosphorylation, aggregation of acetylcholine receptors (AChRs), and interaction of Musk with Dok7 (610285), an essential intracellular binding protein of Musk. In contrast, M605I resulted in only moderate impairment of agrin-dependent Musk phosphorylation, aggregation of AChRs, and interaction of Musk with Dok7. There was no impairment of interaction of mutants with either the low density lipoprotein receptor-related protein Lrp4 (604270), a coreceptor of agrin, or with the mammalian homolog of Drosophila Tid1 (DNAJA3; 608382).
For discussion of the ala727-to-val (A727V) mutation in the MUSK gene that was found in compound heterozygous state in a patient with congenital myasthenic syndrome-9 (CMS9; 616325) associated with AChR deficiency by Maselli et al. (2010), see 601296.0004.
In 11 affected fetuses with fetal akinesia deformation sequence (FADS1; 208150) from a Dutch genetic isolate, Tan-Sindhunata et al. (2015) identified a homozygous c.1724T-C transition (c.1724T-C, NM_005592.3) in the MUSK gene, resulting in an ile575-to-thr (I575T) substitution at a highly conserved residue at the boundary of the juxtamembrane and kinase domains. The mutation was found by homozygosity mapping and candidate gene sequencing and was not found in the dbSNP (build 132), 1000 Genomes Project, or Exome Variant Server (ESP5400) databases. The variant had a carrier frequency of 8% in controls from this genetic isolate, consistent with a founder effect. Muscle biopsy from an affected fetus showed a strong reduction in AChR clusters at motor endplates as well as impaired phosphorylation; overexpression of wildtype MUSK in myocytes derived from the fetus significantly increased agrin (AGRN; 103320)-induced AChR clustering. Tan-Sindhunata et al. (2015) concluded that the I575T mutation halts neuromuscular synaptogenesis at an early stage, resulting in a severe phenotype and perinatal death.
In 5 affected fetuses, born of Swedish parents, with fetal akinesia deformation sequence (FADS1; 208150), Wilbe et al. (2015) identified a homozygous 1-bp duplication (c.40dupA, NM_005592.3) in exon 1 of the MUSK gene, resulting in a frameshift and premature termination (Thr14AsnfsTer9). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family; it was not found in relevant SNP databases, including the Exome Variant Server database, or in 953 in-house control exomes. Muscle biopsy from the carrier mother indicated that the mutation was not subject to nonsense-mediated mRNA decay. Haplotype analysis indicated a founder effect.
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Luo, Z. G., Wang, Q., Zhou, J. Z., Wang, J., Lou, Z., Liu, M., He, X., Wynshaw-Boris, A., Xiong, W. C., Lu, B., Mei, L. Regulation of AChR clustering by Dishevelled interacting with MuSK and PAK1. Neuron 35: 489-505, 2002. [PubMed: 12165471] [Full Text: https://doi.org/10.1016/s0896-6273(02)00783-3]
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Wilbe, M., Ekvall, S., Eurenius, K., Ericson, K., Casar-Borota, O., Klar, J., Dahl, N., Ameur, A., Anneren, G., Bondeson, M.-L. MuSK: a new target for lethal fetal akinesia deformation sequence (FADS). J. Med. Genet. 52: 195-202, 2015. [PubMed: 25612909] [Full Text: https://doi.org/10.1136/jmedgenet-2014-102730]