1ya5

Structural highlights

Disease

[TITIN_HUMAN] Defects in TTN are the cause of hereditary myopathy with early respiratory failure (HMERF) [MIM:603689]; also known as Edstrom myopathy. HMERF is an autosomal dominant, adult-onset myopathy with early respiratory muscle involvement.^[1] Defects in TTN are the cause of familial hypertrophic cardiomyopathy type 9 (CMH9) [MIM:613765]. Familial hypertrophic cardiomyopathy is a hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.^[2] Defects in TTN are the cause of cardiomyopathy dilated type 1G (CMD1G) [MIM:604145]. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.^{[3] [4] [5]} Defects in TTN are the cause of tardive tibial muscular dystrophy (TMD) [MIM:600334]; also known as Udd myopathy. TMD is an autosomal dominant, late-onset distal myopathy. Muscle weakness and atrophy are usually confined to the anterior compartment of the lower leg, in particular the tibialis anterior muscle. Clinical symptoms usually occur at age 35-45 years or much later.^{[6] [7]} Defects in TTN are the cause of limb-girdle muscular dystrophy type 2J (LGMD2J) [MIM:608807]. LGMD2J is an autosomal recessive degenerative myopathy characterized by progressive weakness of the pelvic and shoulder girdle muscles. Severe disability is observed within 20 years of onset. Defects in TTN are the cause of early-onset myopathy with fatal cardiomyopathy (EOMFC) [MIM:611705]. Early-onset myopathies are inherited muscle disorders that manifest typically from birth or infancy with hypotonia, muscle weakness, and delayed motor development. EOMFC is a titinopathy that, in contrast with the previously described examples, involves both heart and skeletal muscle, has a congenital onset, and is purely recessive. This phenotype is due to homozygous out-of-frame TTN deletions, which lead to a total absence of titin's C-terminal end from striated muscles and to secondary CAPN3 depletion.^[8] [TELT_HUMAN] Defects in TCAP are a cause of familial hypertrophic cardiomyopathy (CMH) [MIM:192600]; also designated FHC or HCM. Familial hypertrophic cardiomyopathy is a hereditary heart disorder characterized by ventricular hypertrophy, which is usually asymmetric and often involves the interventricular septum. The symptoms include dyspnea, syncope, collapse, palpitations, and chest pain. They can be readily provoked by exercise. The disorder has inter- and intrafamilial variability ranging from benign to malignant forms with high risk of cardiac failure and sudden cardiac death.^[9] Defects in TCAP are a cause of limb-girdle muscular dystrophy type 2G (LGMD2G) [MIM:601954]. LGMD2G is an autosomal recessive degenerative myopathy characterized by proximal and distal muscle weakness and atrophy in the limbs, dystrophic changes on muscle biopsy, and absence of telethonin. Cardiac muscle is involved in a subset of patients.^[10] Defects in TCAP are the cause of cardiomyopathy dilated type 1N (CMD1N) [MIM:607487]. Dilated cardiomyopathy is a disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.^{[11] [12] [13]}

Function

[TITIN_HUMAN] Key component in the assembly and functioning of vertebrate striated muscles. By providing connections at the level of individual microfilaments, it contributes to the fine balance of forces between the two halves of the sarcomere. The size and extensibility of the cross-links are the main determinants of sarcomere extensibility properties of muscle. In non-muscle cells, seems to play a role in chromosome condensation and chromosome segregation during mitosis. Might link the lamina network to chromatin or nuclear actin, or both during interphase.^[14] [TELT_HUMAN] Muscle assembly regulating factor. Mediates the antiparallel assembly of titin (TTN) molecules at the sarcomeric Z-disk.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

• Telethonin
• Titin

References

1. ↑ Lange S, Xiang F, Yakovenko A, Vihola A, Hackman P, Rostkova E, Kristensen J, Brandmeier B, Franzen G, Hedberg B, Gunnarsson LG, Hughes SM, Marchand S, Sejersen T, Richard I, Edstrom L, Ehler E, Udd B, Gautel M. The kinase domain of titin controls muscle gene expression and protein turnover. Science. 2005 Jun 10;308(5728):1599-603. Epub 2005 Mar 31. PMID:15802564 doi:1110463
2. ↑ Satoh M, Takahashi M, Sakamoto T, Hiroe M, Marumo F, Kimura A. Structural analysis of the titin gene in hypertrophic cardiomyopathy: identification of a novel disease gene. Biochem Biophys Res Commun. 1999 Aug 27;262(2):411-7. PMID:10462489 doi:10.1006/bbrc.1999.1221
3. ↑ Itoh-Satoh M, Hayashi T, Nishi H, Koga Y, Arimura T, Koyanagi T, Takahashi M, Hohda S, Ueda K, Nouchi T, Hiroe M, Marumo F, Imaizumi T, Yasunami M, Kimura A. Titin mutations as the molecular basis for dilated cardiomyopathy. Biochem Biophys Res Commun. 2002 Feb 22;291(2):385-93. PMID:11846417 doi:10.1006/bbrc.2002.6448
4. ↑ Gerull B, Gramlich M, Atherton J, McNabb M, Trombitas K, Sasse-Klaassen S, Seidman JG, Seidman C, Granzier H, Labeit S, Frenneaux M, Thierfelder L. Mutations of TTN, encoding the giant muscle filament titin, cause familial dilated cardiomyopathy. Nat Genet. 2002 Feb;30(2):201-4. Epub 2002 Jan 14. PMID:11788824 doi:10.1038/ng815
5. ↑ Matsumoto Y, Hayashi T, Inagaki N, Takahashi M, Hiroi S, Nakamura T, Arimura T, Nakamura K, Ashizawa N, Yasunami M, Ohe T, Yano K, Kimura A. Functional analysis of titin/connectin N2-B mutations found in cardiomyopathy. J Muscle Res Cell Motil. 2005;26(6-8):367-74. PMID:16465475 doi:10.1007/s10974-005-9018-5
6. ↑ Hackman P, Vihola A, Haravuori H, Marchand S, Sarparanta J, De Seze J, Labeit S, Witt C, Peltonen L, Richard I, Udd B. Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. Am J Hum Genet. 2002 Sep;71(3):492-500. Epub 2002 Jul 26. PMID:12145747 doi:S0002-9297(07)60330-9
7. ↑ Van den Bergh PY, Bouquiaux O, Verellen C, Marchand S, Richard I, Hackman P, Udd B. Tibial muscular dystrophy in a Belgian family. Ann Neurol. 2003 Aug;54(2):248-51. PMID:12891679 doi:10.1002/ana.10647
8. ↑ Carmignac V, Salih MA, Quijano-Roy S, Marchand S, Al Rayess MM, Mukhtar MM, Urtizberea JA, Labeit S, Guicheney P, Leturcq F, Gautel M, Fardeau M, Campbell KP, Richard I, Estournet B, Ferreiro A. C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopathy. Ann Neurol. 2007 Apr;61(4):340-51. PMID:17444505 doi:10.1002/ana.21089
9. ↑ Hayashi T, Arimura T, Itoh-Satoh M, Ueda K, Hohda S, Inagaki N, Takahashi M, Hori H, Yasunami M, Nishi H, Koga Y, Nakamura H, Matsuzaki M, Choi BY, Bae SW, You CW, Han KH, Park JE, Knoll R, Hoshijima M, Chien KR, Kimura A. Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. J Am Coll Cardiol. 2004 Dec 7;44(11):2192-201. PMID:15582318 doi:S0735-1097(04)01749-8
10. ↑ Moreira ES, Wiltshire TJ, Faulkner G, Nilforoushan A, Vainzof M, Suzuki OT, Valle G, Reeves R, Zatz M, Passos-Bueno MR, Jenne DE. Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin. Nat Genet. 2000 Feb;24(2):163-6. PMID:10655062 doi:10.1038/72822
11. ↑ Hayashi T, Arimura T, Itoh-Satoh M, Ueda K, Hohda S, Inagaki N, Takahashi M, Hori H, Yasunami M, Nishi H, Koga Y, Nakamura H, Matsuzaki M, Choi BY, Bae SW, You CW, Han KH, Park JE, Knoll R, Hoshijima M, Chien KR, Kimura A. Tcap gene mutations in hypertrophic cardiomyopathy and dilated cardiomyopathy. J Am Coll Cardiol. 2004 Dec 7;44(11):2192-201. PMID:15582318 doi:S0735-1097(04)01749-8
12. ↑ Knoll R, Hoshijima M, Hoffman HM, Person V, Lorenzen-Schmidt I, Bang ML, Hayashi T, Shiga N, Yasukawa H, Schaper W, McKenna W, Yokoyama M, Schork NJ, Omens JH, McCulloch AD, Kimura A, Gregorio CC, Poller W, Schaper J, Schultheiss HP, Chien KR. The cardiac mechanical stretch sensor machinery involves a Z disc complex that is defective in a subset of human dilated cardiomyopathy. Cell. 2002 Dec 27;111(7):943-55. PMID:12507422
13. ↑ Bos JM, Poley RN, Ny M, Tester DJ, Xu X, Vatta M, Towbin JA, Gersh BJ, Ommen SR, Ackerman MJ. Genotype-phenotype relationships involving hypertrophic cardiomyopathy-associated mutations in titin, muscle LIM protein, and telethonin. Mol Genet Metab. 2006 May;88(1):78-85. Epub 2005 Dec 13. PMID:16352453 doi:S1096-7192(05)00342-2
14. ↑ Mayans O, van der Ven PF, Wilm M, Mues A, Young P, Furst DO, Wilmanns M, Gautel M. Structural basis for activation of the titin kinase domain during myofibrillogenesis. Nature. 1998 Oct 29;395(6705):863-9. PMID:9804419 doi:10.1038/27603
15. ↑ Zou P, Pinotsis N, Lange S, Song YH, Popov A, Mavridis I, Mayans OM, Gautel M, Wilmanns M. Palindromic assembly of the giant muscle protein titin in the sarcomeric Z-disk. Nature. 2006 Jan 12;439(7073):229-33. PMID:16407954 doi:10.1038/nature04343