| *604103 | ||||||||||||||||||||||||
| TITIN IMMUNOGLOBULIN DOMAIN PROTEIN; TTID | ||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||
| MYOTILIN; MYOT | ||||||||||||||||||||||||
| HGNC Approved Gene Symbol: MYOT | ||||||||||||||||||||||||
| Cytogenetic location: 5q31.2 Genomic coordinates (GRCh37): 5:137,203,544 - 137,223,539 (from NCBI) | ||||||||||||||||||||||||
| Gene Phenotype Relationships | ||||||||||||||||||||||||
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| TEXT | ||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||
| Cloning | ||||||||||||||||||||||||
| 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. They found that myotilin is expressed in skeletal and cardiac muscle, colocalizes with alpha-actinin in sarcomeric I bands, and directly interacts with alpha-actinin. | ||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||
| By radiation hybrid mapping, Salmikangas et al. (1999) located the myotilin gene on 5q31 between markers AFM350yB1 and D5S500. The locus of a dominantly inherited limb-girdle muscular dystrophy, LGMD1A (159000), resides in an overlapping narrow segment, and a form of distal myopathy with vocal cord and pharyngeal weakness (158580) maps to the same region. Muscle specificity and apparent role as a sarcomeric structural protein raised the possibility that defects in the myotilin gene may cause muscular dystrophy. | ||||||||||||||||||||||||
| Gene Function | ||||||||||||||||||||||||
| 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. | ||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||
| Hauser et al. (2000) identified a mutation in the myotilin gene (T57I; 604103.0001) in a large North American family of German descent segregating LGMD1A. 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. Selcen and Engel (2004) identified mutations in the TTID 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 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 spheroid body myopathy (182920) originally reported by Goebel et al. (1978), Foroud et al. (2005) identified a heterozygous mutation in the TTID gene (S39F; 604103.0006). Although patients with spheroid body myopathy showed some overlapping clinical features with LGMD1A and myotilinopathy, Foroud et al. (2005) nevertheless concluded that there were enough clinical and pathologic differences to consider it a distinct disorder. | ||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | ||||||||||||||||||||||||
| Table View | ||||||||||||||||||||||||
| .0001 MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1A | ||||||||||||||||||||||||
| TTID, THR57ILE [dbSNP:rs28937597] | ||||||||||||||||||||||||
| In a large North American family of German descent segregating LGMD1A (159000), 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. | ||||||||||||||||||||||||
| .0002 MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1A | ||||||||||||||||||||||||
| MYOTILINOPATHY, INCLUDED | ||||||||||||||||||||||||
| TTID, SER55PHE [dbSNP:rs121908457] | ||||||||||||||||||||||||
| Hauser et al. (2002) performed a mutation screening of 86 families with a variety of neuromuscular disorders. In an Argentinian family with LGMD1A (159000), they identified a new 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 myotilinopathy (609200), a form of myofibrillar myopathy. 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. | ||||||||||||||||||||||||
| .0003 MYOTILINOPATHY | ||||||||||||||||||||||||
| TTID, SER60CYS [dbSNP:rs121908458] | ||||||||||||||||||||||||
| In 3 unrelated patients with myotilinopathy (609200), a form of myofibrillar myopathy, 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). | ||||||||||||||||||||||||
| .0004 MYOTILINOPATHY | ||||||||||||||||||||||||
| TTID, SER60PHE [dbSNP:rs121908458] | ||||||||||||||||||||||||
| In a patient with myotilinopathy (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). | ||||||||||||||||||||||||
| .0005 MYOTILINOPATHY | ||||||||||||||||||||||||
| TTID, SER95ILE [dbSNP:rs121908460] | ||||||||||||||||||||||||
| In a patient with myotilinopathy (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. | ||||||||||||||||||||||||
| .0006 MYOPATHY, SPHEROID BODY | ||||||||||||||||||||||||
| TTID, SER39PHE [dbSNP:rs121908461] | ||||||||||||||||||||||||
| In 21 affected members of a large kindred with spheroid body myopathy (182920) originally reported 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. | ||||||||||||||||||||||||
| .0007 MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 1A | ||||||||||||||||||||||||
| TTID, ARG6HIS | ||||||||||||||||||||||||
| In a Turkish woman with LGMD1A (159000), 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. | ||||||||||||||||||||||||
| REFERENCES | ||||||||||||||||||||||||
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