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FLASH GENE

Symbol

TTN

contributors: mct/npt/pgu - updated : 04-03-2015

HGNC name	titin
HGNC id	12403

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

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)

RNA

TRANSCRIPTS	type	messenger

text	likely several (? or many) isoforms contributing to myofibrillar elastic diversity

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_133378 312 - 101519 NP_596869 3800 33423 major in the muscle 2002 11812150 also called TTN2A or N2-A NM_003319 191 splicing 82028 NP_003310 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) NM_133432 192 - 82403 NP_597676 3025 27051 cardiac isoform 2002 11812150 also called novex-1 NM_133437 192 - 82604 NP_597681 3980 27118 cardiac and skeletal muscle 2002 11812150 also called novex-2 NM_133379 46 - 17306 NP_596870 616 5604 all striated muscle 2002 11812150 also called novex-3 lacking the PEVK region truncated variant 7 - - - isoform 7 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 RMMG6 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 NM_001267550 273 - 109224 NP_001254479 - 35991 - 2002 11812150 NM_001256850 313 - 104301 NP_001243779 - 34350 - 2002 11812150 variant N2BA cardiac titin-isoform

EXPRESSION

Type

widely

expressed in	(based on citations)
organ(s)	System Organ level 1 Organ level 2 Organ level 3 Organ level 4 Level Pubmed Species Stage Rna symbol Cardiovascular heart       highly Digestive pharynx       highly Respiratory respiratory tract larynx     highly

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Muscular striatum cardiac     Muscular striatum skeletal

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) to atrial fibrillation (AF)

Variant & Polymorphism other	specific reaction of ARMD patient sera with the titin domain portion of the fusion protein GST-RMMG6

Candidate gene	strong biological candidate gene at the 2q31 locus for atrial fibrillation because of its role in maintaining the structural integrity of the sarcomere and its involvement in muscle elasticity and force transmission
Marker
Therapy target

ANIMAL & CELL MODELS

Mdm mouse