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; MIM 188840), a giant molecule that contains several immunoglobulin (Ig)-like domains and associates with thin and thick filaments, and alpha-actinin (ACTN1; MIM 102575), an actin cross-linking protein. Mutations in several sarcomeric and sarcolemmal proteins have been shown to result in muscular dystrophy and cardiomyopathy.[supplied by OMIM]
Myotilin (myofibrillar titin-like protein) also known as TTID (TiTin Immunoglobulin Domain) is a skeletal muscle protein that is found within the Z-disc of sarcomeres. It is mutated in various forms of muscular dystrophy:
- Limb-Girdle Muscular Dystrophy type 1A (LGMD1A)
- Myofibrillar Myopathy (MFM)
- Spheroid Body Myopathy
- Distal Myopathy
Myotilin was originally identified as a novel alpha-actinin binding partner with two Ig-like domains, that localised to the Z-disc. The C2-type Ig-like domains reside at the C-terminal half, and are most homologous to Ig domains 2-3 of palladin and Ig domains 4-5 of myopalladin and more distantly related to Z-disc Ig domains 7 and 8 of titin. By contrast, the N-terminal part of myotilin is unique, consisting of a serine-rich region with no homology to known proteins. Several disease-associated mutations involve serine residues within the serine-rich domain. Myotilin expression in human tissues is mainly restricted to striated muscles and nerves. In muscles, myotilin is predominantly found within the Z-discs. Myotilin forms homodimers and binds alpha-actinin, actin, Filamin C, FATZ-1 and ZASP. Myotilin induces the formation of actin bundles in vitro and in non-muscle cells. A ternary complex myotilin/actin/alpha-actinin can be observed in vitro and actin bundles formed in this conditions appear more tightly packed than those induced by alpha-actinin alone. It was demonstrated that myotilin stabilises F-actin by slowing down the disassembly rate. Ectopic overexpression of truncated myotilin causes the disruption of nascent myofibrils and the co-accumulation of myotilin and titin in amorphous cytoplasmic precipitates. In mature sarcomeres, wild-type myotilin co-localises with alpha-actinin and Z-disc titin, showing the striated pattern typical of sarcomeric proteins. Targeted disruption of myotilin gene in mice does not cause significant alteration in muscle function. On the other hand, transgenic mice with mutated myotilin develop muscle dystrophy.
^Godley LA, Lai F, Liu J, Zhao N, Le Beau MM (Nov 1999). "TTID: A novel gene at 5q31 encoding a protein with titin-like features". Genomics60 (2): 226–33. doi:10.1006/geno.1999.5912. PMID10486214.
^Salmikangas P, Mykkanen OM, Gronholm M, Heiska L, Kere J, Carpen O (Aug 1999). "Myotilin, a novel sarcomeric protein with two Ig-like domains, is encoded by a candidate gene for limb-girdle muscular dystrophy". Hum Mol Genet8 (7): 1329–36. doi:10.1093/hmg/8.7.1329. PMID10369880.
Speer MC, Yamaoka LH, Gilchrist JH, et al. (1992). "Confirmation of genetic heterogeneity in limb-girdle muscular dystrophy: linkage of an autosomal dominant form to chromosome 5q.". Am. J. Hum. Genet.50 (6): 1211–7. PMC1682558. PMID1598902.
Dixon MJ, Read AP, Donnai D, et al. (1991). "The gene for Treacher Collins syndrome maps to the long arm of chromosome 5.". Am. J. Hum. Genet.49 (1): 17–22. PMC1683211. PMID1676560.
Bartoloni L, Horrigan SK, Viles KD, et al. (1999). "Use of a CEPH meiotic breakpoint panel to refine the locus of limb-girdle muscular dystrophy type 1A (LGMD1A) to a 2-Mb interval on 5q31.". Genomics54 (2): 250–5. doi:10.1006/geno.1998.5579. PMID9828127.
Hauser MA, Horrigan SK, Salmikangas P, et al. (2000). "Myotilin is mutated in limb girdle muscular dystrophy 1A.". Hum. Mol. Genet.9 (14): 2141–7. doi:10.1093/hmg/9.14.2141. PMID10958653.
van der Ven PF, Wiesner S, Salmikangas P, et al. (2000). "Indications for a novel muscular dystrophy pathway. gamma-filamin, the muscle-specific filamin isoform, interacts with myotilin.". J. Cell Biol.151 (2): 235–48. doi:10.1083/jcb.151.2.235. PMC2192634. PMID11038172.
Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.". Proc. Natl. Acad. Sci. U.S.A.99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC139241. PMID12477932.
Salmikangas P, van der Ven PF, Lalowski M, et al. (2003). "Myotilin, the limb-girdle muscular dystrophy 1A (LGMD1A) protein, cross-links actin filaments and controls sarcomere assembly.". Hum. Mol. Genet.12 (2): 189–203. doi:10.1093/hmg/ddg020. PMID12499399.
Battle MA, Maher VM, McCormick JJ (2003). "ST7 is a novel low-density lipoprotein receptor-related protein (LRP) with a cytoplasmic tail that interacts with proteins related to signal transduction pathways.". Biochemistry42 (24): 7270–82. doi:10.1021/bi034081y. PMID12809483.
Selcen D, Engel AG (2004). "Mutations in myotilin cause myofibrillar myopathy.". Neurology62 (8): 1363–71. PMID15111675.
Gerhard DS, Wagner L, Feingold EA, et al. (2004). "The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).". Genome Res.14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC528928. PMID15489334.
Witt SH, Granzier H, Witt CC, Labeit S (2005). "MURF-1 and MURF-2 target a specific subset of myofibrillar proteins redundantly: towards understanding MURF-dependent muscle ubiquitination.". J. Mol. Biol.350 (4): 713–22. doi:10.1016/j.jmb.2005.05.021. PMID15967462.
Gontier Y, Taivainen A, Fontao L, et al. (2006). "The Z-disc proteins myotilin and FATZ-1 interact with each other and are connected to the sarcolemma via muscle-specific filamins.". J. Cell. Sci.118 (Pt 16): 3739–49. doi:10.1242/jcs.02484. PMID16076904.
Garvey SM, Senderek J, Beckmann JS, et al. (2006). "Myotilin is not the causative gene for vocal cord and pharyngeal weakness with distal myopathy (VCPDM).". Ann. Hum. Genet.70 (Pt 3): 414–6. doi:10.1111/j.1529-8817.2005.00252.x. PMID16674563.