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FLASH GENE
Symbol TTN contributors: mct/npt/pgu - updated : 04-03-2015
HGNC name titin
HGNC id 12403
Corresponding disease
CMD1G cardiomyopathy, dilated 1G
CMH9 cardiomyopathy, familial, hypertrophic, 9
EOMFC early-onset myopathy with fatal cardiomyopathy
LGMD2J limb-girdle muscular dystrophy type 2J
MPRM myopathy, proximal, with early respiratory muscle involvement
RCM4 restrictive cardiomyopathy 4, familial
TMDT tibial muscular dystrophy, onset in the early 40 years
Location 2q31.2      Physical location : 179.390.719 - 179.672.150
Synonym name
  • connectin
  • rhabdomyosarcoma antigen MU-RMS-40.14
  • giant skeletal muscle protein
  • Synonym symbol(s) FLJ26020, FLJ26409, FLJ32040, FLJ34413, FLJ39564, FLJ43066, HMERF, CMPD4, CONNECTIN, TMD, CMD1G, CMH9, CMPD4, EOMFC, HMERF, LGMD2J, MYLK5
    EC.number 2.7.11.1
    DNA
    TYPE anonymous DNA segment
    SPECIAL FEATURE arranged in tandem
    STRUCTURE 281.44 kb     313 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    MAPPING cloned Y linked N status confirmed
    Map cen - D2S335 - TTN - D2S324 - D2S364 - D2S384 - D2S350 - D2S118 - D2S72 - qter
    Authors LDB (99)
    Physical map
    HOXD4 2q31 homeo box D4 HOXD3 2q31 homeo box D3 HOXD1 2q31-q37 homeo box D1 LOC150978 2q31.2 similar to 60S acidic ribosomal protein P1 LOC129841 2q31.2 similar to 40S ribosomal protein SA (P40) (34/67 kDa laminin receptor) (Colon carcinoma laminin-binding protein) (NEM/1CHD4) (Multidrug resistance-associated protein MGr1-Ag) MTX2 2q24.3-q31 metaxin 2 LOC375295 2q31.2 hypothetical gene supported by BC013438 FUCA1P 2q31-q32 fucosidase, alpha-L- 1, tissue pseudogene LOC391465 2 similar to STIP1 homology and U-Box containing protein 1; serologically defined colon cancer antigen 7; carboxy terminus of Hsp70p-interacting protein; heat shock protein A binding protein 2 (c-terminal) LOC150739 2q31.2 similar to keratin 8; cytokeratin 8; keratin, type II cytoskeletal 8 hnRNPA3 2q31.2 heterogeneous nuclear ribonucleoprotein A3 NFE2L2 2q31 nuclear factor (erythroid-derived 2)-like 2 DKFZp451M2119 2q31.2-q31.3 hypothetical protein DKFZp451M2119 AGPS 2q33 alkylglycerone phosphate synthase FLJ30990 2q31.3 hypothetical protein FLJ30990 FLJ13946 2q31.3 hypothetical protein FLJ13946 PDE11A 2q31 phosphodiesterase 11A HCP9 2q31.2 cytochrome c, somatic pseudogene DRB1 2q31.3 developmentally regulated RNA-binding protein 1 OSBPL6 2q31-q32.1 oxysterol binding protein-like 6 PRKRA 2q31.2 protein kinase, interferon-inducible double stranded RNA dependent activator NUDCP2 2q31 nuclear distribution gene C homolog (A. nidulans) pseudogene 2 FKBP7 2q31.2 FK506 binding protein 7 PLEKHA3 2q31.2 pleckstrin homology domain containing, family A (phosphoinositide binding specific) member 3 TTN 2q24.3-q31 titin FLJ39502 2q31.3 hypothetical protein FLJ39502 DKFZp434O0515 FLJ25270 LOC389065 2 similar to RIKEN cDNA B830010L13 gene LOC391466 2 similar to dim1 KIAA1604 2q32.1 KIAA1604 protein
    RNA
    TRANSCRIPTS type messenger
    text likely several (? or many) isoforms contributing to myofibrillar elastic diversity
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    312 - 101519 3800 33423 major in the muscle 2002 11812150
    also called TTN2A or N2-A
    191 splicing 82028 2970 26926 cardiac muscle 2002 11812150
  • also called TTN2B or N2-B
  • phosphorylation of the N2-B unique sequence (N2BUS) by cGMP-dependent protein kinase (PKG) or cAMP-dependent protein kinase (PKA) decreases titin stiffness (PMID: 23764881)
  • lacking some repeats of the PEVK region excluding 101 exons
  • FHL1 directly interferes with ERK2-mediated TTN-N2B phosphorylation (PMID: 22778266)
  • 192 - 82403 3025 27051 cardiac isoform 2002 11812150
    also called novex-1
    192 - 82604 3980 27118 cardiac and skeletal muscle 2002 11812150
    also called novex-2
    46 - 17306 616 5604 all striated muscle 2002 11812150
  • also called novex-3
  • lacking the PEVK region truncated
  • - - - 2000 - smooth muscles 2002 11812150
  • also called sm-titin or smitin
  • interacts with C-terminal EF hand region and central rod R2-R3 spectrin-like repeat region sites in ACTN1
  • having a Zq domain that may bind to the ACTN1 R2-R3 central rod domain as well as Z-repeat domains that bind to the EF hand region
  • 3 - - 24.1 214 - 2002 11812150
  • encompassing 90p100 exon 248, 100p100 exon 249 and 23.4p100 exon 250
  • 100p100 identity with a region of titin N2-A
  • fused with GST to form glutathione-S-transferase fusion protein (GST-RMMG6) with a predicted size of 51.1 kDa
  • 273 - 109224 - 35991 - 2002 11812150
    313 - 104301 - 34350 - 2002 11812150
  • variant N2BA
  • cardiac titin-isoform
  • EXPRESSION
    Type widely
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly
    Digestivepharynx   highly
    Respiratoryrespiratory tractlarynx  highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularstriatumcardiac  
    Muscularstriatumskeletal  
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a N terminal I band forming the elastic part end
  • a PEVK (pro-Glu-Val-Lys) rich region
  • five regions of tandem repeats of the Ig type, binding to ACTA1
  • a N2A domain, putative binding site for CAPN3
  • the A band acting as a protein ruber containing a mixture of Ig and FBN repeats and possessing kinase activity
  • HOMOLOGY
    interspecies homolog to murine Ttn
    Homologene
    FAMILY
  • protein kinase superfamily
  • CAMK Ser/Thr protein kinase family
  • CATEGORY enzyme , structural protein
    SUBCELLULAR LOCALIZATION extracellular
        intracellular
    intracellular,cytoplasm,cytosolic
    intracellular,cytoplasm,cytoskeleton
    text giant sarcomeric protein, extending from the Z line to the M line of striated muscle sarcomere, myofibrils
    basic FUNCTION
  • essential in the temporal and spatial control of the assembly of the highly ordered sarcomeres of striated muscles
  • responsible for the elasticity of relaxed striated muscle
  • playing a CAPN3-dependent role through the N2A domain in the dynamics of muscle contraction
  • in striated muscle, titin provides elasticity and support functions for the sarcomere
  • titin filaments play important roles in sarcomere assembly, stability, and passive tension, as well as in stretch sensing, protein turnover, and gene regulation through interactions with other proteins including ACTN1
  • transient TTN-calcium interaction may serve a protective function in muscle, which could preclude costly unfolding of select domains when muscles elongate to great lengths
  • determinant of a resting tension of the sarcomere and crucial role in diastolic function
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS development
    text muscular
    PATHWAY
    metabolism
    signaling
    a component
  • complex between the muscle proteins titin and telethonin forms a highly directed molecular bond
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • calmodulin binding
  • obscurin
  • interacting with CAPN3, through N2A domain
  • interacting with ACTN1 (through N-terminal domains of titin to provide a structural linkage crucial for the integrity of the sarcomere)
  • interacting with TCAP (anchored in the Z-disk by telethonin, TCAP)
  • head-to-tail interaction of the C-terminus of titin and the N-terminus of obscurin-like-1(OBSL1)
  • RBM20, a gene for hereditary cardiomyopathy, regulates titin splicing
  • FHL1 as a novel negative regulator of titin N2B levels and phosphorylation-mediated mechanics
  • titin can be phosphoryalated by CAMK2D, and titin molecular spring region that determines diastolic stiffness is a target of CAMK2D
  • cell & other
    REGULATION
    Phosphorylated by CAMK2D, and titin molecular spring region that determines diastolic stiffness is a target of CAMK2D
    ASSOCIATED DISORDERS
    corresponding disease(s) CMD1G , CMH9 , TMDT , LGMD2J , MPRM , EOMFC , RCM4
    related resource FHC Mutation Database
    Susceptibility
  • to autoimmune scleroderma (antibodies in patients)
  • to autoimmune form of rippling muscle disease with myasthenia gravis (ARMD)
  • Variant & Polymorphism other
  • specific reaction of ARMD patient sera with the titin domain portion of the fusion protein GST-RMMG6
  • Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
    Mdm mouse