Alternative titles; symbols
HGNC Approved Gene Symbol: MYOT
Cytogenetic location: 5q31.2 Genomic coordinates (GRCh38) : 5:137,867,860-137,887,851 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q31.2 | Myopathy, myofibrillar, 3 | 609200 | Autosomal dominant | 3 |
Striated muscle sarcomeres are highly organized structures composed of actin (thin) and myosin (thick) filaments that slide past each other during contraction. The integrity of sarcomeres is controlled by a set of structural proteins, among which are titin (TTN; 188840), a giant molecule that contains several immunoglobulin (Ig)-like domains and associates with thin and thick filaments, and alpha-actinin (ACTN1; 102575), an actin crosslinking protein. Mutations in several sarcomeric and sarcolemmal proteins have been shown to result in muscular dystrophy and cardiomyopathy.
Salmikangas et al. (1999) described a novel 57-kD cytoskeletal protein, myotilin. Its N-terminal sequence is unique, but the C-terminal half contains 2 Ig-like domains homologous to titin. Salmikangas et al. (1999) found that myotilin is expressed in skeletal and cardiac muscle, colocalizes with alpha-actinin in sarcomeric I bands, and directly interacts with alpha-actinin.
By radiation hybrid mapping, Salmikangas et al. (1999) located the myotilin gene on 5q31 between markers AFM350yB1 and D5S500. Muscle specificity and apparent role as a sarcomeric structural protein raised the possibility that defects in the myotilin gene may cause muscular dystrophy.
Salmikangas et al. (2003) demonstrated that myotilin directly binds F-actin (see 102610), efficiently crosslinks actin filaments alone or in concert with alpha-actinin, and prevents filament disassembly induced by latrunculin A. Myotilin formed dimers via its C-terminal half, which may be necessary for the actin-bundling activity. Overexpression of full-length myotilin (but not the C-terminal half) induced formation of thick actin cables in nonmuscle cells devoid of endogenous myotilin. The expression of myotilin in muscle cells was tightly regulated to the later stages of in vitro myofibrillogenesis, when preassembled myofibrils began to align. Expression of either N- or C-terminally truncated myotilin fragments (but not wildtype myotilin) in differentiating myocytes led to myofibril disarray. Salmikangas et al. (2003) concluded that myotilin plays an indispensable role in stabilization and anchorage of thin filaments, which may be a prerequisite for correct Z disc organization.
Myofibrillar Myopathy 3
Hauser et al. (2000) identified a heterozygous mutation in the myotilin gene (T57I; 604103.0001) in affected members of a large North American family of German descent diagnosed with limb-girdle muscular dystrophy (LGMD1A), later classified as myofibrillar myopathy-3 (MFM3; 609200) (Straub et al., 2018). The mutant allele was transcribed, and normal levels of correctly localized myotilin protein were seen in muscle. The mutation did not disrupt binding to alpha-actinin.
Selcen and Engel (2004) identified mutations in the MYOT gene (604103.0002-604103.0005) in 6 of 57 patients with myofibrillar myopathy. The authors termed the disorder 'myotilinopathy' to distinguish it from other forms of myofibrillar myopathy. One of the mutations, ser55 to phe (S55F; 604103.0002), had previously been identified in a patient diagnosed with LGMD1A. All of the mutations occurred in a serine residue in serine-rich exon 2 of the protein, suggesting it is a hotspot for mutation.
In 21 affected members of a large kindred with myofibrillar myopathy-3 (MFM3; 609200), originally reported by Goebel et al. (1978) as 'spheroid body myopathy,' Foroud et al. (2005) identified a heterozygous mutation in the TTID gene (S39F; 604103.0006).
Moza et al. (2007) obtained Myo -/- mice at a normal mendelian ratio. Myo -/- mice were indistinguishable from wildtype, with normal growth, fertility, and life span and normal skeletal and cardiac muscle appearance, strength, and performance. Light and transmission electron microscopy revealed complete integrity of Myo -/- sarcomeres and Z discs. However, telethonin (TCAP; 604488), a small Z disc protein, was upregulated in Myo -/- skeletal muscle, and more weakly in Myo -/- cardiac muscle, at both the mRNA and protein level. Moza et al. (2007) concluded that MYO is not required for striated muscle development or function.
In affected members of a large North American family of German descent diagnosed with a form of limb-girdle muscular dystrophy (LGMD1A), later reclassified as myofibrillar myopathy-3 (MFM3; 609200) by Straub et al. (2018), Hauser et al. (2000) identified a 450C-T missense mutation in the TTID gene, resulting in the conversion of thr57 to ile (T57I). The mutation was not found in 396 control chromosomes. The mutant allele was transcribed, and normal levels of correctly localized myotilin protein were seen in LGMD1A muscle. The mutation did not disrupt binding to alpha-actinin.
Hauser et al. (2002) performed a mutation screening of 86 families with a variety of neuromuscular disorders. In an Argentinian family with a diagnosis of limb-girdle muscular dystrophy (LGMD1A), later reclassified as myofibrillar myopathy-3 (MFM3; 609200) by Straub et al. (2018), they identified a TTID mutation predicted to result in the conversion of serine-55 to phenylalanine (S55F). The mutation was located in the unique N-terminal domain of myotilin, only 2 residues from the thr57-to-ile mutation (604103.0001). Both mutations are located outside the alpha-actinin and gamma-filamin binding sites within myotilin.
Selcen and Engel (2004) identified the S55F mutation in a woman with MFM3. The patient had slowly progressive muscle weakness and wasting, distal greater than proximal, and peripheral neuropathy. She had an affected brother with cardiomyopathy and an affected son.
In 3 unrelated patients with myofibrillar myopathy (MFM3; 609200), Selcen and Engel (2004) identified a heterozygous 459C-G transversion in exon 2 of the TTID gene, resulting in a ser60-to-cys (S60C) substitution in the hydrophobic stretch of the protein. The patients had distal muscle weakness and peripheral neuropathy. One of the patients had cardiomyopathy and 2 had increased serum creatine kinase. The S60C mutation was not identified in 200 control chromosomes. Another unrelated patient had a different mutation in the same codon (S60F; 604103.0004).
In a patient with myofibrillar myopathy (MFM3; 609200), Selcen and Engel (2004) identified a heterozygous 459C-T transition in exon 2 of the TTID gene, resulting in a ser60-to-phe (S60F) substitution in the hydrophobic stretch of the protein. The patient had proximal muscle weakness, cardiomyopathy, and peripheral neuropathy. The mutation was not identified in 200 control chromosomes. Three other patients had a different mutation in the same codon (S60C; 604103.0003).
In a patient with myofibrillar myopathy (MFM3; 609200), Selcen and Engel (2004) identified a heterozygous 564G-T transversion in exon 2 of the TTID gene, resulting in a ser95-to-ile (S95I) substitution. The mutation lies in the alpha-actinin (102575)-binding domain of the protein.
In 21 affected members of a large kindred with myofibrillar myopathy-3 (MFM3; 609200), originally reported as 'spheroid body myopathy' by Goebel et al. (1978), Foroud et al. (2005) identified a heterozygous 116C-T transition in exon 2 of the TTID gene, resulting in a ser39-to-phe (S39F) substitution. The mutation was not identified in 135 control individuals.
In a Turkish woman diagnosed with a form of limb-girdle muscular dystrophy (LGMD1A), later reclassified as myofibrillar myopathy (MFM3; 609200) by Straub et al. (2018), Reilich et al. (2011) identified a heterozygous 17G-A transition in exon 2 of the TTID gene, resulting in an arg6-to-his (R6H) substitution in a highly conserved residue. The mutation was not found in 70 Turkish control chromosomes or in 140 European control chromosomes. The patient had a rapidly progressive disease course. She developed progressive proximal weakness of the lower limbs at age 40 years followed by proximal upper limb weakness, and subsequently developed mild distal muscle weakness. She was wheelchair-dependent at age 50. Within the next 3 years, she developed respiratory insufficiency and dysphagia, resulting in death from pneumonia at age 55. Muscle imaging showed fatty degeneration of most proximal muscles in both the upper and lower limbs, as well as in the thoracic and abdominal cavities. Muscle biopsy at age 40 showed a mild myopathic pattern with increased fiber size variability, some central nuclei, some autophagocytic vacuoles, and mild fibrosis; there were no signs of a myofibrillar myopathy. The patient's mother and 1 sister were reportedly less severely affected.
Foroud, T., Pankratz, N., Batchman, A. P., Pauciulo, M. W., Vidal, R., Miravalle, L., Goebel, H. H., Cushman, L. J., Azzarelli, B., Horak, H., Farlow, M., Nichols, W. C. A mutation in myotilin causes spheroid body myopathy. Neurology 65: 1936-1940, 2005. [PubMed: 16380616] [Full Text: https://doi.org/10.1212/01.wnl.0000188872.28149.9a]
Goebel, H. H., Muller, J., Gillen, H. W., Merritt, A. D. Autosomal dominant 'spheroid body myopathy'. Muscle Nerve 1: 14-26, 1978. [PubMed: 571956] [Full Text: https://doi.org/10.1002/mus.880010104]
Hauser, M. A., Conde, C. B., Kowaljow, V., Zeppa, G., Taratuto, A. L., Torian, U. M., Vance, J., Pericak-Vance, M. A., Speer, M. C., Rosa, A. L. Myotilin mutation found in second pedigree with LGMD1A. Am. J. Hum. Genet. 71: 1428-1432, 2002. [PubMed: 12428213] [Full Text: https://doi.org/10.1086/344532]
Hauser, M. A., Horrigan, S. K., Salmikangas, P., Torian, U. M., Viles, K. D., Dancel, R., Tim, R. W., Taivainen, A., Bartoloni, L., Gilchrist, J. M., Stajich, J. M., Gaskell, P. C., Gilbert, J. R., Vance, J. M., Pericak-Vance, M. A., Carpen, O., Westbrook, C. A., Speer, M. C. Myotilin is mutated in limb girdle muscular dystrophy 1A. Hum. Molec. Genet. 9: 2141-2147, 2000. [PubMed: 10958653] [Full Text: https://doi.org/10.1093/hmg/9.14.2141]
Moza, M., Mologni, L., Trokovic, R., Faulkner, G., Partanen, J., Carpen, O. Targeted deletion of the muscular dystrophy gene myotilin does not perturb muscle structure or function in mice. Molec. Cell. Biol. 27: 244-252, 2007. [PubMed: 17074808] [Full Text: https://doi.org/10.1128/MCB.00561-06]
Reilich, P., Krause, S., Schramm, N., Klutzny, U., Bulst, S., Zehetmayer, B., Schneiderat, P., Walter, M. C., Schoser, B., Lochmuller, H. A novel mutation in the myotilin gene (MYOT) causes a severe form of limb girdle muscular dystrophy 1A (LGMD1A). J. Neurol. 258: 1437-1444, 2011. [PubMed: 21336781] [Full Text: https://doi.org/10.1007/s00415-011-5953-9]
Salmikangas, P., Mykkanen, O.-M., Gronholm, M., Heiska, L., Kere, J., Carpen, O. Myotilin, a novel sarcomeric protein with two Ig-like domains, is encoded by a candidate gene for limb-girdle muscular dystrophy. Hum. Molec. Genet. 8: 1329-1336, 1999. [PubMed: 10369880] [Full Text: https://doi.org/10.1093/hmg/8.7.1329]
Salmikangas, P., van der Ven, P. F. M., Lalowski, M., Taivainen, A., Zhao, F., Suila, H., Schroder, R., Lappalainen, P., Furst, D. O., Carpen, O. Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly. Hum. Molec. Genet. 12: 189-203, 2003. [PubMed: 12499399] [Full Text: https://doi.org/10.1093/hmg/ddg020]
Selcen, D., Engel, A. G. Mutations in myotilin cause myofibrillar myopathy. Neurology 62: 1363-1371, 2004. Note: Erratum: Neurology 63: 405 only, 2004. [PubMed: 15111675] [Full Text: https://doi.org/10.1212/01.wnl.0000123576.74801.75]
Straub, V., Murphy, A., Udd, B. 229th ENMC international workshop: limb girdle muscular dystrophies--nomenclature and reformed classification, Naarden, the Netherlands, 17-19 March 2017. Neuromusc. Disord. 28: 702-710, 2018. [PubMed: 30055862] [Full Text: https://doi.org/10.1016/j.nmd.2018.05.007]