TTN

gene

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Also known as CMPD4FLJ32040TMDCMH9LGMD2JMYLK5

Summary

TTN (titin, HGNC:12403) is a protein-coding gene on chromosome 2q31.2, encoding Titin (Q8WZ42). Key component in the assembly and functioning of vertebrate striated muscles.

This gene encodes a large abundant protein of striated muscle. The product of this gene is divided into two regions, a N-terminal I-band and a C-terminal A-band. The I-band, which is the elastic part of the molecule, contains two regions of tandem immunoglobulin domains on either side of a PEVK region that is rich in proline, glutamate, valine and lysine. The A-band, which is thought to act as a protein-ruler, contains a mixture of immunoglobulin and fibronectin repeats, and possesses kinase activity. An N-terminal Z-disc region and a C-terminal M-line region bind to the Z-line and M-line of the sarcomere, respectively, so that a single titin molecule spans half the length of a sarcomere. Titin also contains binding sites for muscle associated proteins so it serves as an adhesion template for the assembly of contractile machinery in muscle cells. It has also been identified as a structural protein for chromosomes. Alternative splicing of this gene results in multiple transcript variants. Considerable variability exists in the I-band, the M-line and the Z-disc regions of titin. Variability in the I-band region contributes to the differences in elasticity of different titin isoforms and, therefore, to the differences in elasticity of different muscle types. Mutations in this gene are associated with familial hypertrophic cardiomyopathy 9, and autoantibodies to titin are produced in patients with the autoimmune disease scleroderma.

Source: NCBI Gene 7273 — RefSeq curated summary.

At a glance

Gene–disease (curated): dilated cardiomyopathy 1G (Definitive, ClinGen) — +13 more curated relationships
GWAS associations: 36
Clinical variants (ClinVar): 30,060 total — 221 pathogenic, 3580 likely-pathogenic
Phenotypes (HPO): 147
Druggable target: yes
Dosage sensitivity (ClinGen): haploinsufficiency emerging evidence, triplosensitivity no evidence
MANE Select transcript: NM_001267550

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:12403
Approved symbol	TTN
Name	titin
Location	2q31.2
Locus type	gene with protein product
Status	Approved
Aliases	CMPD4, FLJ32040, TMD, CMH9, LGMD2J, MYLK5
Ensembl gene	ENSG00000155657
Ensembl biotype	protein_coding
OMIM	188840
Entrez	7273

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 14 protein_coding, 1 retained_intron

ENST00000342175, ENST00000342992, ENST00000359218, ENST00000360870, ENST00000412264, ENST00000425332, ENST00000426232, ENST00000436599, ENST00000446966, ENST00000460472, ENST00000470257, ENST00000589042, ENST00000591111, ENST00000634225, ENST00000715174

RefSeq mRNA: 7 — MANE Select: NM_001267550 NM_001256850, NM_001267550, NM_003319, NM_133378, NM_133379, NM_133432, NM_133437

CCDS: CCDS33337, CCDS54421, CCDS54422, CCDS54423, CCDS54424, CCDS59435

Canonical transcript exons

ENST00000589042 — 363 exons

Exon	Start	End
ENSE00001465556	178807212	178807423
ENSE00001725280	178667236	178667319
ENSE00003502146	178804552	178804655
ENSE00003801213	178546212	178546502
ENSE00003801249	178715493	178715774
ENSE00003801264	178685518	178685598
ENSE00003801306	178536938	178537243
ENSE00003801355	178758984	178759172
ENSE00003801382	178677621	178677917
ENSE00003801391	178599554	178599850
ENSE00003801476	178711062	178711349
ENSE00003801552	178674314	178674409
ENSE00003801625	178601882	178601914
ENSE00003801638	178528274	178528427
ENSE00003801641	178528528	178529219
ENSE00003801649	178706454	178706739
ENSE00003801659	178785848	178786141
ENSE00003801707	178585072	178585347
ENSE00003801753	178594344	178594646
ENSE00003801787	178598506	178598654
ENSE00003801788	178733239	178733517
ENSE00003801817	178593173	178593475
ENSE00003801894	178604708	178604898
ENSE00003801907	178633413	178633676
ENSE00003801954	178632147	178632413
ENSE00003802004	178597908	178598058
ENSE00003802009	178694829	178694906
ENSE00003802031	178633187	178633326
ENSE00003802090	178614847	178614968
ENSE00003802092	178764527	178764811
ENSE00003802112	178704877	178704966
ENSE00003802187	178689290	178689373
ENSE00003802254	178634723	178634849
ENSE00003802351	178713897	178714175
ENSE00003802353	178618584	178618853
ENSE00003802375	178625273	178625396
ENSE00003802386	178553914	178554216
ENSE00003802440	178714292	178714573
ENSE00003802442	178719164	178719451
ENSE00003802498	178679339	178679416
ENSE00003802505	178583607	178583906
ENSE00003802530	178621840	178622008
ENSE00003802540	178620715	178620993
ENSE00003802597	178558341	178558637
ENSE00003802603	178780000	178780205
ENSE00003802614	178777704	178777975
ENSE00003802637	178729288	178729566
ENSE00003802641	178542662	178542949
ENSE00003802643	178601658	178601787
ENSE00003802653	178621102	178621368
ENSE00003802745	178659172	178659255
ENSE00003802874	178620217	178620625
ENSE00003802941	178557648	178558235
ENSE00003802960	178774207	178774473
ENSE00003802968	178728500	178728778
ENSE00003803067	178684330	178684413
ENSE00003803086	178723046	178723324
ENSE00003803093	178695348	178695410
ENSE00003803112	178693922	178694008
ENSE00003803146	178720385	178720663
ENSE00003803170	178617779	178618081
ENSE00003803222	178546600	178546905
ENSE00003803385	178545388	178545693
ENSE00003803420	178605414	178605713
ENSE00003803442	178598748	178599062
ENSE00003803485	178701528	178701587
ENSE00003803639	178794399	178794551
ENSE00003803723	178612057	178612162
ENSE00003803811	178615641	178615788
ENSE00003803812	178701120	178701203
ENSE00003803896	178576923	178577510
ENSE00003803899	178792072	178792197
ENSE00003803910	178707526	178707813
ENSE00003803944	178615307	178615484
ENSE00003803996	178635963	178636241
ENSE00003804074	178731693	178731971
ENSE00003804106	178593568	178593867
ENSE00003804121	178607401	178607685
ENSE00003804130	178619988	178620112
ENSE00003804165	178781121	178781263
ENSE00003804186	178732834	178733121
ENSE00003804239	178601265	178601564
ENSE00003804241	178773838	178774110
ENSE00003804245	178706862	178706954
ENSE00003804290	178612277	178612576
ENSE00003804298	178723856	178724143
ENSE00003804328	178635165	178635304
ENSE00003804355	178549570	178549869
ENSE00003804385	178673633	178673710
ENSE00003804454	178607021	178607314
ENSE00003804455	178785620	178785742
ENSE00003804523	178770060	178770320
ENSE00003804589	178630804	178630943
ENSE00003804742	178587118	178587417
ENSE00003804802	178642237	178642317
ENSE00003804844	178698843	178698914
ENSE00003804845	178649817	178649894
ENSE00003804858	178636398	178636799
ENSE00003804875	178675039	178675113
ENSE00003804879	178614052	178614348
ENSE00003804884	178721847	178722134
ENSE00003804939	178712697	178712975
ENSE00003804962	178782212	178782427
ENSE00003804968	178773109	178773369
ENSE00003805050	178652096	178652179
ENSE00003805056	178609208	178609570
ENSE00003805059	178678125	178678208
ENSE00003805132	178609684	178609986
ENSE00003805135	178672635	178672703
ENSE00003805150	178633817	178634083
ENSE00003805178	178732440	178732718
ENSE00003805227	178738082	178738360
ENSE00003805240	178675921	178675995
ENSE00003805296	178783720	178783785
ENSE00003805330	178683211	178683291
ENSE00003805355	178722259	178722546
ENSE00003805371	178705174	178705357
ENSE00003805382	178527446	178527748
ENSE00003805410	178688111	178688224
ENSE00003805436	178578806	178579393
ENSE00003805486	178537342	178537917
ENSE00003805536	178727090	178727371
ENSE00003805599	178702454	178702663
ENSE00003805623	178789360	178789497
ENSE00003805661	178587516	178587800
ENSE00003805710	178777149	178777317
ENSE00003805733	178730093	178730371
ENSE00003805756	178685253	178685330
ENSE00003805779	178539382	178539966
ENSE00003805805	178720921	178721202
ENSE00003805819	178611758	178611954
ENSE00003805821	178702040	178702066
ENSE00003805836	178729664	178729945
ENSE00003805863	178794922	178795252
ENSE00003805894	178541282	178541584
ENSE00003805931	178630241	178630367
ENSE00003806016	178719983	178720264
ENSE00003806021	178599146	178599445
ENSE00003806122	178637369	178637419
ENSE00003806123	178782806	178783064
ENSE00003806136	178612773	178613072
ENSE00003806194	178542264	178542563
ENSE00003806229	178651243	178651320
ENSE00003806244	178681661	178681738
ENSE00003806278	178600854	178601171
ENSE00003806295	178617325	178617512
ENSE00003806356	178694599	178694676
ENSE00003806373	178652458	178652541
ENSE00003806388	178695865	178696269
ENSE00003806397	178582940	178583227
ENSE00003806423	178727585	178727863
ENSE00003806467	178611372	178611677
ENSE00003806479	178770412	178770675
ENSE00003806496	178679599	178679682
ENSE00003806587	178556848	178557144
ENSE00003806655	178722659	178722937
ENSE00003806702	178645920	178646030
ENSE00003806733	178624465	178624731
ENSE00003806747	178640048	178640110
ENSE00003806782	178607785	178608081
ENSE00003806831	178733614	178733892
ENSE00003806836	178538946	178539251
ENSE00003806856	178732066	178732347
ENSE00003806939	178577988	178578185
ENSE00003806988	178773462	178773725
ENSE00003807032	178730925	178731203
ENSE00003807039	178593961	178594242
ENSE00003807046	178547407	178549473
ENSE00003807057	178731305	178731583
ENSE00003807103	178764177	178764302
ENSE00003807140	178544201	178544506
ENSE00003807178	178717523	178717810
ENSE00003807203	178651666	178651749
ENSE00003807205	178640541	178640630
ENSE00003807271	178768673	178768933
ENSE00003807304	178662966	178663055
ENSE00003807363	178591978	178592277
ENSE00003807378	178769679	178769939
ENSE00003807405	178680254	178680331
ENSE00003807419	178576529	178576831
ENSE00003807476	178592379	178592660
ENSE00003807489	178652264	178652347
ENSE00003807496	178734328	178734606
ENSE00003807497	178622670	178622767
ENSE00003807542	178580322	178580609
ENSE00003807571	178671090	178671170
ENSE00003807606	178802138	178802341
ENSE00003807647	178619621	178619887
ENSE00003807681	178554865	178555152
ENSE00003807700	178723418	178723696
ENSE00003807762	178725768	178726046
ENSE00003807878	178682697	178682903
ENSE00003807889	178582296	178582592
ENSE00003807893	178650751	178650834
ENSE00003807896	178595507	178595809
ENSE00003807933	178713085	178713372
ENSE00003807963	178779229	178779462
ENSE00003807976	178635440	178635715
ENSE00003808021	178549986	178550273
ENSE00003808052	178684666	178684749
ENSE00003808061	178610993	178611271
ENSE00003808118	178670218	178670295
ENSE00003808123	178535982	178536575
ENSE00003808172	178768014	178768155
ENSE00003808212	178530241	178535849
ENSE00003808223	178767759	178767924
ENSE00003808243	178672407	178672481
ENSE00003808302	178719554	178719832
ENSE00003808334	178684906	178684989
ENSE00003808353	178671971	178672267
ENSE00003808430	178710635	178710922
ENSE00003808554	178782539	178782602
ENSE00003808579	178717095	178717382
ENSE00003808594	178602282	178602590
ENSE00003808619	178735511	178736074
ENSE00003808643	178540068	178540370
ENSE00003808716	178790708	178790845
ENSE00003808777	178578611	178578715
ENSE00003808789	178557253	178557555
ENSE00003808790	178597538	178597819
ENSE00003808806	178683999	178684082
ENSE00003808824	178651884	178651967
ENSE00003808827	178613161	178613276
ENSE00003808828	178616479	178616630
ENSE00003808853	178581499	178581804
ENSE00003808968	178778874	178779118
ENSE00003808993	178551630	178553396
ENSE00003808994	178591599	178591892
ENSE00003809007	178709566	178709856
ENSE00003809028	178604987	178605295
ENSE00003809128	178545820	178546116
ENSE00003809179	178644548	178644616
ENSE00003809195	178618189	178618491
ENSE00003809302	178692016	178692099
ENSE00003809346	178608178	178608477
ENSE00003809358	178775356	178777049
ENSE00003809388	178681079	178681171
ENSE00003809410	178613751	178613937
ENSE00003809440	178774921	178775202
ENSE00003809461	178702168	178702245
ENSE00003809504	178728891	178729169
ENSE00003809515	178650164	178650271
ENSE00003809522	178614466	178614753
ENSE00003809569	178659005	178659088
ENSE00003809650	178718322	178718600
ENSE00003809653	178678747	178678830
ENSE00003809662	178799825	178799910
ENSE00003809782	178799487	178799731
ENSE00003809802	178789978	178790115
ENSE00003809850	178771211	178771471
ENSE00003809851	178603876	178604305
ENSE00003809884	178525989	178527307
ENSE00003809887	178725368	178725649
ENSE00003809908	178553502	178553807
ENSE00003809946	178543834	178544115
ENSE00003809965	178718695	178718973
ENSE00003809985	178616729	178617013
ENSE00003809996	178631034	178631300
ENSE00003810010	178730505	178730792
ENSE00003810048	178692497	178692580
ENSE00003810081	178679894	178680055
ENSE00003810094	178712315	178712593
ENSE00003810121	178688677	178688778
ENSE00003810188	178588538	178591504
ENSE00003810204	178538540	178538839
ENSE00003810208	178714986	178715264
ENSE00003810306	178784070	178784351
ENSE00003810323	178704510	178704777
ENSE00003810357	178586505	178586807
ENSE00003810384	178543069	178543662
ENSE00003810399	178584669	178584968
ENSE00003810448	178584276	178584578
ENSE00003810473	178602002	178602150
ENSE00003810484	178689053	178689136
ENSE00003810498	178717943	178718221
ENSE00003810564	178592775	178593083
ENSE00003810594	178681376	178681450
ENSE00003810611	178547003	178547305
ENSE00003810612	178728110	178728397
ENSE00003810688	178697121	178697168
ENSE00003810732	178617120	178617234
ENSE00003810755	178639699	178639788
ENSE00003810775	178579939	178580229
ENSE00003810781	178704147	178704407
ENSE00003810791	178753124	178753180
ENSE00003810843	178793404	178793541
ENSE00003810851	178766381	178766612
ENSE00003810862	178678414	178678497
ENSE00003810976	178800395	178800682
ENSE00003811024	178577602	178577898
ENSE00003811102	178554453	178554752
ENSE00003811103	178711944	178712222
ENSE00003811115	178693609	178693689
ENSE00003811138	178608606	178608908
ENSE00003811164	178610090	178610389
ENSE00003811169	178689515	178689595
ENSE00003811193	178559311	178576416
ENSE00003811205	178550967	178551260
ENSE00003811210	178579561	178579848
ENSE00003811220	178529960	178530116
ENSE00003811260	178651453	178651536
ENSE00003811271	178689813	178689896
ENSE00003811290	178581906	178582208
ENSE00003811334	178734707	178734988
ENSE00003811344	178629301	178629443
ENSE00003811356	178724260	178724538
ENSE00003811384	178632526	178632792
ENSE00003811387	178621475	178621741
ENSE00003811401	178587899	178588219
ENSE00003811410	178634366	178634629
ENSE00003811443	178632918	178633044
ENSE00003811446	178777420	178777584
ENSE00003811452	178641241	178641315
ENSE00004024265	178739141	178741921
ENSE00004024272	178665377	178665460
ENSE00004024279	178664654	178664737
ENSE00004024280	178664852	178664926
ENSE00004024281	178757542	178757916
ENSE00004024285	178756222	178756797
ENSE00004024286	178664460	178664537
ENSE00004024294	178663627	178663710
ENSE00004024305	178663819	178663902
ENSE00004024308	178666824	178666901
ENSE00004024310	178664015	178664098
ENSE00004025966	178658272	178658355
ENSE00004025967	178663266	178663349
ENSE00004025968	178647381	178647464
ENSE00004025969	178661759	178661842
ENSE00004025970	178657498	178657581
ENSE00004025971	178667442	178667525
ENSE00004025972	178649248	178649331
ENSE00004025973	178658077	178658157
ENSE00004025974	178663433	178663516
ENSE00004025975	178654208	178654291
ENSE00004025976	178662142	178662222
ENSE00004025977	178652848	178652931
ENSE00004025978	178669592	178669675
ENSE00004025979	178657881	178657961
ENSE00004025980	178653817	178653897
ENSE00004025981	178657687	178657767
ENSE00004025982	178677201	178677287
ENSE00004025983	178662338	178662418
ENSE00004025984	178658705	178658794
ENSE00004025985	178647064	178647144
ENSE00004025986	178661948	178662028
ENSE00004025987	178654445	178654534
ENSE00004025988	178662533	178662616
ENSE00004025989	178654745	178654828
ENSE00004025990	178653238	178653321
ENSE00004025991	178652653	178652736
ENSE00004025992	178649554	178649631
ENSE00004025993	178654912	178654995
ENSE00004025994	178653621	178653701
ENSE00004025995	178665708	178665791
ENSE00004025996	178653427	178653507
ENSE00004025997	178675671	178675754
ENSE00004025998	178667638	178667721
ENSE00004025999	178646485	178646559
ENSE00004026000	178658468	178658551
ENSE00004026001	178662729	178662812
ENSE00004026002	178669373	178669447
ENSE00004026003	178654012	178654095
ENSE00004026004	178653041	178653124

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 99.98.

FANTOM5 (CAGE): breadth broad, TPM avg 80.5598 / max 20297.7038, expressed in 416 samples.

FANTOM5 promoters (107 alternative TSS)

Promoter ID	TPM avg	Samples expressed
32654	67.1604	248
32616	1.1228	73
32612	0.5640	56
32482	0.5005	47
32488	0.4774	38
32487	0.4548	44
32380	0.4348	39
32614	0.4248	42
32489	0.4171	35
32496	0.3379	44

Top tissues by expression

279 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
biceps brachii	UBERON:0001507	99.98	gold quality
gluteal muscle	UBERON:0002000	99.98	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	99.98	gold quality
triceps brachii	UBERON:0001509	99.97	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	99.97	gold quality
heart right ventricle	UBERON:0002080	99.96	gold quality
diaphragm	UBERON:0001103	99.93	gold quality
vastus lateralis	UBERON:0001379	99.92	gold quality
body of tongue	UBERON:0011876	99.92	gold quality
quadriceps femoris	UBERON:0001377	99.87	gold quality
deltoid	UBERON:0001476	99.81	gold quality
left ventricle myocardium	UBERON:0006566	99.76	gold quality
skeletal muscle tissue	UBERON:0001134	99.75	gold quality
tibialis anterior	UBERON:0001385	99.75	gold quality
myocardium	UBERON:0002349	99.54	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.51	gold quality
vena cava	UBERON:0004087	99.49	gold quality
gastrocnemius	UBERON:0001388	99.39	gold quality
cardiac muscle of right atrium	UBERON:0003379	99.26	gold quality
muscle organ	UBERON:0001630	99.15	gold quality
muscle of leg	UBERON:0001383	98.85	gold quality
cardiac ventricle	UBERON:0002082	98.02	gold quality
heart left ventricle	UBERON:0002084	97.95	gold quality
apex of heart	UBERON:0002098	97.92	gold quality
cardiac atrium	UBERON:0002081	97.77	gold quality
right atrium auricular region	UBERON:0006631	97.53	gold quality
muscle tissue	UBERON:0002385	96.68	gold quality
tendon of biceps brachii	UBERON:0008188	95.71	gold quality
heart	UBERON:0000948	94.76	gold quality
pharyngeal mucosa	UBERON:0000355	94.40	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	10522.33
E-GEOD-124472	yes	1828.15
E-MTAB-11268	no	79475.13
E-CURD-112	no	3.11
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
IGF1	Activation

Upstream regulators (CollecTRI, top): EN1

miRNA regulators (miRDB)

45 targeting TTN, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-4658	99.77	64.94	514
HSA-MIR-6790-5P	99.77	65.24	505
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-548O-3P	99.74	69.30	2228
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-3659	99.70	67.97	694
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-514B-5P	99.50	68.19	1766
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-7849-3P	99.47	68.17	1224
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-4762-3P	99.43	69.72	2363
HSA-MIR-150-3P	99.43	70.51	920
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-505-3P	99.19	69.71	896
HSA-MIR-224-3P	98.91	68.42	1815
HSA-MIR-522-3P	98.91	68.56	1817
HSA-MIR-1304-5P	98.90	68.58	1054
HSA-MIR-513B-3P	98.76	68.12	1577
HSA-MIR-222-5P	98.75	69.17	1242
HSA-MIR-12114	98.70	63.45	730
HSA-MIR-4709-5P	98.51	67.25	1335
HSA-MIR-4490	98.51	68.47	943

Functional genomics

ClinGen dosage: haploinsufficiency 2 (emerging evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

Mitotic spindle staining with antititin antibodies is due to the association of titin or a titin-like molecule with this structure. (PMID:11746675)
molecular mechanics of PEVK and N2B spring elements (PMID:11799131)
structural and functional studies of titin’s fn3 modules reveal conserved surface patterns and binding to myosin S1–a possible role in the Frank-Starling mechanism of the heart (PMID:11800567)
adjacent domains in the I-band have very different kinetic properties which undergo only small changes in the presence of neighbouring domains; titin I-band behaves as the sum of its parts (PMID:11812150)
Titin mutations as the molecular basis for dilated cardiomyopathy (PMID:11846417)
Tibial muscular dystrophy is a titinopathy caused by mutations in TTN, the gene encoding the giant skeletal-muscle protein titin. (PMID:12145747)
protein engineering and single-molecule AFM examination of mechanical components that form elastic region of human cardiac titin; when these mechanical elements are combined, they explain the macroscopic behaviour of titin in intact muscle (PMID:12198551)
expression of titin isoforms switch in ischemic human heart disease (PMID:12221049)
Association of titin and myosin with microtubules in nascent myofibrils directed by MURF2 (PMID:12414993)
interaction of two N-terminal immunoglobulin with hydrophilic domain of small ankyrin-1 (PMID:12444090)
Titin plays a signaling role in targeting and orienting nebulin during sarcomere assembly (PMID:12482578)
The cDNA sequence of cardiac TTN isoform was determined. No differences were found between the N2B PRVK lengths in heart muscle. New N2BA splicing pathways in the first tandem Ig region were found. PEVK exon expression was also different. (PMID:12785098)
Molecular modeling is used to characterize the reversible unfolding of titin immunoglobulin domains I27 and I1. (PMID:12785101)
Titin PEVK conformation is malleable and responds to subtle environmental changes without co-operativity; this gradual conformational transition may represent a regulatory mechanism for fine-tuning protein interactions and elasticity. (PMID:12816538)
titin is a good candidate gene on chromosome 2q31.1 for the SV50 training response in white HERITAGE families (PMID:12865504)
the PEVK segment contains E-rich motifs that render titin a calcium-dependent molecular spring that adapts to the physiological state of the cell (PMID:14593205)
alphaB-crystallin bound in the position of the N2B region of titin, but not to PEVK region (PMID:14676215)
The behavior of the I27 domain of titin and its serial repeats is contrasted to that of simple secondary structures at various temperatures. (PMID:15211512)
The more compliant titin N2BA isoform predominates in hearts with dilated cardiomyopathy. Changes in titin isoform expression impact diastolic filling by lowering myocardial stiffness. Altered titin expression may affect cell signaling & gene expression. (PMID:15238456)
summary of the Ig and Fn3 domains of titin [review] (PMID:15322090)
Both control & dilated cardiomyopathy hearts coexpressed smaller (~ 3 MDa) N2B-isoform & longer (3.20 to 3.35 MDa) N2BA-isoforms. The average N2BA:N2B-ratio shifted from ~ 30:70 in controls to 42:58 in DCM, due to more N2BA-isoforms >3.30 MDa. (PMID:15345656)
analysis of actin binding along the PEVK domain of skeletal muscle titin (PMID:15507486)
PEVK exons encode polypeptides of similar elastic properties, unrelated to their total PEVK contents and hence, alternative splicing solely adjusts the length of the PEVK domain of titin. (PMID:15632200)
mutation in the titin kinase domain disrupts nbr1 binding and leads to hereditary muscle disease (PMID:15802564)
biophysical analysis of the PEVK domain of skeletal-muscle titin (PMID:15849252)
Results suggest that the C-terminus of nuclear titin binds lamins A and B in vivo and might contribute to nuclear organization during interphase. (PMID:16410549)
The PEVK segment of titin is not a simple entropic spring as is commonly assumed, but a highly evolved, gel-like enthalpic spring with its elasticity dominated by the sequence-specific charge interactions. (PMID:16465472)
Cardiomyopathy-associated point mutations in titin affect its binding to FHL2 protein. Altered recruitment of metabolic enzymes to the sarcomere via FHL2 may play a role in the pathogenesis of cardiomyopathies. (PMID:16465475)
The titin Z1Z2-telethonin complex resist considerable mechanical force through beta strand crosslinking, suggesting that telethonin is an important component of the N-terminal titin anchor. (PMID:16531234)
the importance of p94-connectin interaction in the control of p94 functions by regulating autolytic decay of p94 (PMID:16627476)
A dimer of two titin/telethonin complexes is formed within the crystal environment, potentially indicating the formation of higher oligomers. (PMID:16713295)
Mutations in titin may account for a significant portion of the genetic etiology in familial DCM. (PMID:16733766)
Titin is a giant scaffold for integrating stress and Src homology domain 3-mediated signaling pathways (PMID:16766517)
This suggests that the titin Z2-Zis1 domain can link filamins and alpha-actinin together in the periphery of the Z-line/dense bodies in a fashion that is conserved in smooth and striated muscles. (PMID:16949617)
biophysical analysis of the end-to-end length of the transition state before unfolding and the measured contour length per amino acid of human titin (PMID:17028145)
These results suggest that differential expression of titin gene exons in nonmuscle cells yields multiple novel isoforms of the protein c-titin that are associated with the actin stress fiber structures. (PMID:17366640)
C-terminal titin deletions cause a novel early-onset myopathy with fatal cardiomyopaty. (PMID:17444505)
biophysical analysis of the elasticity of titin Z1Z2 and a titin chain model (PMID:17496052)
titin splice diversity regulates structure and biomechanics of the sarcomere (PMID:17522126)
the molecular structure of a tandem arrangement of two immunoglobulin-like domains, A168 and A169, located within the A-band segment of titin (PMID:17574571)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ttn.2	ENSDARG00000028213
mus_musculus	Ttn	ENSMUSG00000051747
rattus_norvegicus	Ttn	ENSRNOG00000069271

Protein

Protein identifiers

Titin — Q8WZ42 (reviewed: Q8WZ42)

Alternative names: Connectin, Rhabdomyosarcoma antigen MU-RMS-40.14

All UniProt accessions (9): Q8WZ42, A0A0A0MRA3, A0A0C4DG59, A0A0U1RRH3, A0A1B0GXE3, A0AAQ5BIC8, C9JQJ2, H0Y4J7, H7C0U7

UniProt curated annotations — full annotation on UniProt →

Function. 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.

Subunit / interactions. Interacts with MYOM1, MYOM2, tropomyosin and myosin. Interacts with actin, primarily via the PEVK domains and with MYPN. Interacts with FHL2, NEB, CRYAB, LMNA/lamin-A and LMNB/lamin-B. Interacts with TCAP/telethonin and/or ANK1 isoform Mu17/ank1.5, via the first two N-terminal immunoglobulin domains. Interacts with TRIM63 and TRIM55, through several domains including immunoglobulin domains 141 and 142. Interacts with ANKRD1, ANKRD2 and ANKRD23, via the region between immunoglobulin domains 77 and 78 and interacts with CAPN3, via immunoglobulin domain 79. Interacts with NBR1 through the protein kinase domain. Interacts with CALM/calmodulin. Isoform 6 interacts with OBSCN isoform 3. Interacts with CMYA5.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Isoforms 3, 7 and 8 are expressed in cardiac muscle. Isoform 4 is expressed in vertebrate skeletal muscle. Isoform 6 is expressed in skeletal muscle (at protein level).

Post-translational modifications. Autophosphorylated.

Disease relevance. Myopathy, myofibrillar, 9, with early respiratory failure (MFM9) [MIM:603689] An autosomal dominant myopathy characterized by adulthood onset of weakness in proximal, distal, axial and respiratory muscles. Pelvic girdle weakness, foot drop and neck weakness are the main symptoms at onset, but ultimately the weakness usually involves the proximal compartment of both upper and lower limbs. Additional features include variable degrees of Achilles tendon contractures, spinal rigidity and muscle hypertrophy. Respiratory involvement often leads to requirement for non-invasive ventilation support. The disease is caused by variants affecting the gene represented in this entry. Cardiomyopathy, familial hypertrophic, 9 (CMH9) [MIM:613765] 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. The disease is caused by variants affecting the gene represented in this entry. Cardiomyopathy, dilated, 1G (CMD1G) [MIM:604145] A disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death. The disease is caused by variants affecting the gene represented in this entry. Tardive tibial muscular dystrophy (TMD) [MIM:600334] 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. The disease is caused by variants affecting the gene represented in this entry. Muscular dystrophy, limb-girdle, autosomal recessive 10 (LGMDR10) [MIM:608807] 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. The disease is caused by variants affecting the gene represented in this entry. Congenital myopathy 5 with cardiomyopathy (CMYO5) [MIM:611705] An autosomal recessive, early-onset muscular disorder characterized by dilated cardiomyopathy, delayed motor development with generalized muscle weakness predominantly affecting proximal and distal lower limbs. Skeletal muscle biopsies show minicore-like lesions with mitochondrial depletion and sarcomere disorganization, centralized nuclei, and type 1 fiber predominance. Dystrophic changes become apparent in the second decade. Cardiac muscle biopsies show disruption of myocardial architecture, nuclear hypertrophy, and endomysial fibrosis. Sudden death may occurr due to cardiomyopathy. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Full activation of the protein kinase domain requires both phosphorylation of Tyr-32341, preventing it from blocking the catalytic aspartate residue, and binding of Ca/CALM to the C-terminal regulatory tail of the molecule which results in ATP binding to the kinase.

Domain organisation. ZIS1 and ZIS5 regions contain multiple SPXR consensus sites for ERK- and CDK-like protein kinases as well as multiple SP motifs. ZIS1 could adopt a closed conformation which would block the TCAP-binding site. The PEVK region may serve as an entropic spring of a chain of structural folds and may also be an interaction site to other myofilament proteins to form interfilament connectivity in the sarcomere.

Miscellaneous. In some isoforms, after the PEVK repeat region there is a long PEVK duplicated region. On account of this region, it has been very difficult to sequence the whole protein. The length of this region (ranging from 183 to 2174 residues), may be a key elastic element of titin.

Similarity. Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family.

Isoforms (13)

UniProt ID	Names	Canonical?
Q8WZ42-1	1	yes
Q8WZ42-2	2
Q8WZ42-3	3, Small cardiac N2-B
Q8WZ42-4	4, Soleus
Q8WZ42-5	5
Q8WZ42-6	6, Small cardiac novex-3
Q8WZ42-7	7, Cardiac novex-2
Q8WZ42-8	8, Cardiac novex-1
Q8WZ42-9	9
Q8WZ42-10	10
Q8WZ42-11	11
Q8WZ42-12	12
Q8WZ42-13	13

RefSeq proteins (7): NP_001243779, NP_001254479, NP_003310, NP_596869, NP_596870, NP_597676, NP_597681 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR003961	FN3_dom	Domain
IPR004168	PPAK_motif	Repeat
IPR007110	Ig-like_dom	Domain
IPR008266	Tyr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR013098	Ig_I-set	Domain
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR015129	Titin_Z_rpt	Repeat
IPR036116	FN3_sf	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR040849	MyBP-C_THB	Domain

Pfam: PF00041, PF00069, PF02818, PF07679, PF09042, PF18362

Enzyme classification (BRENDA):

EC 2.7.11.1 — non-specific serine/threonine protein kinase (BRENDA: 71 organisms, 682 substrates, 228 inhibitors, 23 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

8 substrates with measured Km, best-characterized 8. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
ATP	0.0007–0.64	11
KKRAARATSNVFA	0.013–0.045	3
PAH1 PHOSPHATIDATE PHOSPHATASE	0.0002	2
RRRLSSLRA	0.0036–0.0037	2
GTP	0.46	1
KKRAARASSNVFA	0.02	1
LYS-LYS-PHE-ASN-ARG-THR-LEU-SER-VAL-ALA	0.0093	1
MYELIN BASIC PROTEIN	0.145	1

Catalyzed reactions (Rhea), 2 shown:

L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (1289 total): strand 353, sequence variant 297, domain 285, sequence conflict 71, compositionally biased region 53, helix 52, disulfide bond 46, repeat 38, region of interest 33, splice variant 24, modified residue 15, turn 12, coiled-coil region 4, binding site 2, mutagenesis site 2, chain 1, active site 1

Structure

Experimental structures (PDB)

64 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3PUC	X-RAY DIFFRACTION	0.96
8OMW	X-RAY DIFFRACTION	1.05
3KNB	X-RAY DIFFRACTION	1.4
8ORL	X-RAY DIFFRACTION	1.43
2WP3	X-RAY DIFFRACTION	1.48
5JDD	X-RAY DIFFRACTION	1.53
8OT5	X-RAY DIFFRACTION	1.56
6H4L	X-RAY DIFFRACTION	1.6
3LPW	X-RAY DIFFRACTION	1.65
8OQ9	X-RAY DIFFRACTION	1.65
8OS3	X-RAY DIFFRACTION	1.68
2BK8	X-RAY DIFFRACTION	1.69
2WWK	X-RAY DIFFRACTION	1.7
8OSD	X-RAY DIFFRACTION	1.7
5JDJ	X-RAY DIFFRACTION	1.74
1WAA	X-RAY DIFFRACTION	1.8
4O00	X-RAY DIFFRACTION	1.85
2Y9R	X-RAY DIFFRACTION	1.9
5JDE	X-RAY DIFFRACTION	1.9
8OTY	X-RAY DIFFRACTION	1.9
4C4K	X-RAY DIFFRACTION	1.95
8BW6	X-RAY DIFFRACTION	1.95
8OVU	X-RAY DIFFRACTION	1.95
2J8H	X-RAY DIFFRACTION	1.99
3QP3	X-RAY DIFFRACTION	2
1TKI	X-RAY DIFFRACTION	2
2A38	X-RAY DIFFRACTION	2
4QEG	X-RAY DIFFRACTION	2
5JOE	X-RAY DIFFRACTION	2
3Q5O	X-RAY DIFFRACTION	2.05

Predicted structure (AlphaFold)

No AlphaFold model available for Q8WZ42 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 32298 (proton acceptor)

Ligand- & substrate-binding residues (2): 32184–32192; 32207

Post-translational modifications (15): 263, 265, 267, 6920, 9122, 11503, 12007, 12009, 12022, 30443, 32341, 33245, 33247, 33602, 33614

Disulfide bonds (46): 964–1015, 1724–1777, 2109–2134, 2196–2246, 3259–3311, 4404–4455, 4499–4550, 4592–4643, 4686–4737, 4779–4830, 5061–5112, 5248–5299, 5623–5674, 5810–5861, 5903–5954, 6185–6236, 6372–6423, 6465–6516, 6748–6799, 7027–7078 …

Mutagenesis-validated functional residues (2):

Position	Phenotype
32207	disrupts catalytic activity.
32341	no phosphorylation on tyrosine.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-114608	Platelet degranulation
R-HSA-390522	Striated Muscle Contraction

MSigDB gene sets: 564 (showing top): GOBP_CHROMOSOME_ORGANIZATION, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_RESPONSE_TO_MUSCLE_STRETCH, GOBP_CIRCULATORY_SYSTEM_PROCESS, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GOBP_STRIATED_MUSCLE_CELL_DIFFERENTIATION, GOBP_CARDIAC_MYOFIBRIL_ASSEMBLY, GOBP_MULTICELLULAR_ORGANISMAL_MOVEMENT, TAL1ALPHAE47_01, DARWICHE_PAPILLOMA_PROGRESSION_RISK, GOBP_SARCOMERE_ORGANIZATION, GGGTGGRR_PAX4_03, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, GOBP_CHROMOSOME_CONDENSATION, GOBP_SKELETAL_MUSCLE_CONTRACTION

GO Biological Process (23): skeletal muscle contraction (GO:0003009), cardiac muscle hypertrophy (GO:0003300), muscle contraction (GO:0006936), striated muscle contraction (GO:0006941), mitotic chromosome condensation (GO:0007076), positive regulation of gene expression (GO:0010628), obsolete protein kinase A signaling (GO:0010737), muscle filament sliding (GO:0030049), skeletal muscle thin filament assembly (GO:0030240), skeletal muscle myosin thick filament assembly (GO:0030241), detection of muscle stretch (GO:0035995), sarcomere organization (GO:0045214), sarcomerogenesis (GO:0048769), positive regulation of protein secretion (GO:0050714), response to calcium ion (GO:0051592), cardiac myofibril assembly (GO:0055003), cardiac muscle tissue morphogenesis (GO:0055008), cardiac muscle cell development (GO:0055013), cardiac muscle contraction (GO:0060048), heart morphogenesis (GO:0003007), protein phosphorylation (GO:0006468), positive regulation of striated muscle contraction (GO:0045989), positive regulation of sarcomere organization (GO:0060298)

GO Molecular Function (26): protease binding (GO:0002020), protein serine/threonine kinase activity (GO:0004674), protein tyrosine kinase activity (GO:0004713), calcium ion binding (GO:0005509), calmodulin binding (GO:0005516), ATP binding (GO:0005524), structural constituent of muscle (GO:0008307), protein kinase regulator activity (GO:0019887), enzyme binding (GO:0019899), protein kinase binding (GO:0019901), telethonin binding (GO:0031433), identical protein binding (GO:0042802), protein homodimerization activity (GO:0042803), actinin binding (GO:0042805), actin filament binding (GO:0051015), muscle alpha-actinin binding (GO:0051371), structural molecule activity conferring elasticity (GO:0097493), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), structural molecule activity (GO:0005198), protein binding (GO:0005515), cytoskeletal protein binding (GO:0008092), kinase activity (GO:0016301), transferase activity (GO:0016740), metal ion binding (GO:0046872)

GO Cellular Component (13): condensed nuclear chromosome (GO:0000794), extracellular region (GO:0005576), cytosol (GO:0005829), striated muscle thin filament (GO:0005865), actin cytoskeleton (GO:0015629), Z disc (GO:0030018), M band (GO:0031430), I band (GO:0031674), extracellular exosome (GO:0070062), titin-telethonin complex (GO:1990733), nucleus (GO:0005634), cytoplasm (GO:0005737), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Response to elevated platelet cytosolic Ca2+	1
Muscle contraction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
protein kinase activity	4
myofibril assembly	3
protein binding	3
striated muscle contraction	2
muscle contraction	2
skeletal myofibril assembly	2
actomyosin structure organization	2
structural molecule activity	2
cytoskeletal protein binding	2
sarcomere	2
musculoskeletal movement	1
striated muscle hypertrophy	1
muscle system process	1
mitotic sister chromatid segregation	1
mitotic cell cycle	1
chromosome condensation	1
mitotic cell cycle process	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
actin-myosin filament sliding	1
actin filament organization	1
striated muscle myosin thick filament assembly	1
response to muscle stretch	1
detection of mechanical stimulus	1
protein secretion	1
regulation of protein secretion	1
positive regulation of protein transport	1
positive regulation of secretion by cell	1
response to metal ion	1
cardiac muscle cell development	1
heart morphogenesis	1
cardiac muscle tissue development	1
muscle tissue morphogenesis	1
striated muscle cell development	1
cardiac cell development	1
cardiac muscle cell differentiation	1
heart contraction	1
heart development	1

Protein interactions and networks

STRING

3524 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TTN	TCAP	O15273	999
TTN	CAPN3	P20807	997
TTN	NEB	P20929	993
TTN	ACTN2	P35609	992
TTN	CSRP3	P50461	991
TTN	MYBPC3	Q14896	987
TTN	OBSCN	Q5VST9	987
TTN	TRIM63	Q969Q1	986
TTN	ANKRD1	Q15327	982
TTN	NBR1	Q14596	981
TTN	ANK1	P16157	966
TTN	FHL2	Q14192	958
TTN	ANKRD2	Q9GZV1	952
TTN	ANK2	Q01484	932
TTN	ANK3	Q12955	923

IntAct

313 interactions, top by confidence:

A	B	Type	Score
MED10	MED19	psi-mi:“MI:0914”(association)	0.910
MED29	MED19	psi-mi:“MI:0914”(association)	0.890
TTN	TCAP	psi-mi:“MI:0407”(direct interaction)	0.860
TTN	OBSCN	psi-mi:“MI:0915”(physical association)	0.850
TTN	OBSCN	psi-mi:“MI:0407”(direct interaction)	0.850
NFYC	NFYA	psi-mi:“MI:0914”(association)	0.850
TTN	OBSL1	psi-mi:“MI:0915”(physical association)	0.780
TTN	OBSL1	psi-mi:“MI:0407”(direct interaction)	0.780
MED19	MED19	psi-mi:“MI:0914”(association)	0.730
MED26	MED19	psi-mi:“MI:0914”(association)	0.730
SUN2	LMNA	psi-mi:“MI:0914”(association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
MAP1LC3B	TTN	psi-mi:“MI:0407”(direct interaction)	0.590
HSPB8	VWA8	psi-mi:“MI:0914”(association)	0.530
SYNM	TTN	psi-mi:“MI:0915”(physical association)	0.510
TTN	DYSF	psi-mi:“MI:2364”(proximity)	0.450
TTN	OPTN	psi-mi:“MI:2364”(proximity)	0.450
MAP1LC3A	TTN	psi-mi:“MI:0407”(direct interaction)	0.440
OXSR1	TTN	psi-mi:“MI:0407”(direct interaction)	0.440
MSN	TTN	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (400): TTN (Two-hybrid), TTN (Two-hybrid), TTN (Affinity Capture-MS), TTN (Biochemical Activity), TTN (Two-hybrid), FHL1 (Two-hybrid), TTN (Affinity Capture-MS), TTN (Affinity Capture-MS), TTN (Affinity Capture-MS), TTN (Affinity Capture-MS), TTN (Co-fractionation), TTN (Two-hybrid), TTN (Proximity Label-MS), TTN (Affinity Capture-MS), TTN (Affinity Capture-MS)

ESM2 similar proteins: A2ASS6, A8DYP0, E9QMW4, G4SLH0, J7M799, M9MRD1, O15061, O43491, O55103, O70318, O75952, O77788, P07197, P08553, P08855, P11799, P12839, P16053, P27321, P51125, P54938, P57786, P82179, P83741, Q06637, Q13061, Q23551, Q28820, Q4R3X7, Q63425, Q66H38, Q696W0, Q6TS35, Q70IV5, Q7Z589, Q7ZUV7, Q86TC9, Q8BMB0, Q8TC56, Q8WZ42

Diamond homologs: A0JN74, A1L4K1, A2ABU4, A2ASS6, B1H278, H0UZ81, O00478, P18892, P82456, Q02084, Q13410, Q1XHU0, Q495X7, Q5BN31, Q5D7I0, Q5R7W8, Q5R996, Q5VTT5, Q6MFZ5, Q6UX41, Q6UXE8, Q70KF4, Q7YRV4, Q8BVW3, Q8BZ52, Q8N3K9, Q8VI40, Q8WVV5, Q8WZ42, Q91431, Q96F44, Q96KV6, Q96PL5, Q99PQ2, Q9ESN2, Q9HCM9, Q9JLN5, A2CG49, A4IFM7, A8C984

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
“cyclosporin A”	up-regulates	TTN
TCAP	“up-regulates activity”	TTN	binding
TTN	“up-regulates quantity”	OBSCN	relocalization
PRKCA	“up-regulates activity”	TTN	phosphorylation
MAPK1	“up-regulates quantity”	TTN	phosphorylation
TTN	unknown	TCAP	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 161 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
sarcomere organization	7	18.0×	1e-04
muscle organ development	7	7.8×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

30060 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	221
Likely pathogenic	3580
Uncertain significance	6100
Likely benign	6100
Benign	417

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1011266	NM_001267550.2(TTN):c.6825del (p.Asp2275fs)	Pathogenic
1012335	NM_001267550.2(TTN):c.81274C>T (p.Gln27092Ter)	Pathogenic
1012351	NM_001267550.2(TTN):c.49669A>T (p.Lys16557Ter)	Pathogenic
1012357	NM_001267550.2(TTN):c.3073dup (p.Ser1025fs)	Pathogenic
1012358	NM_001267550.2(TTN):c.58240_58244del (p.Pro19414fs)	Pathogenic
1015906	NM_001267550.2(TTN):c.26287G>T (p.Glu8763Ter)	Pathogenic
1016464	NM_001267550.2(TTN):c.32312-1G>C	Pathogenic
1027852	NM_001267550.2(TTN):c.35678_35685delinsA (p.Thr11893fs)	Pathogenic
1035316	NM_001267550.2(TTN):c.6570dup (p.Met2191fs)	Pathogenic
1057336	NM_001267550.2(TTN):c.3344G>A (p.Trp1115Ter)	Pathogenic
1064523	NM_001267550.2(TTN):c.106541del (p.Asp35514fs)	Pathogenic
1065188	NM_001267550.2(TTN):c.83497G>T (p.Gly27833Ter)	Pathogenic
1065189	NM_001267550.2(TTN):c.69522T>G (p.Tyr23174Ter)	Pathogenic
1065191	NM_001267550.2(TTN):c.13592C>G (p.Ser4531Ter)	Pathogenic
1065192	NM_001267550.2(TTN):c.80514del (p.Val26839fs)	Pathogenic
1066283	NM_001267550.2(TTN):c.93088del (p.Arg31030fs)	Pathogenic
1069899	NM_001267550.2(TTN):c.77646del (p.Ile25883fs)	Pathogenic
1071779	NM_001267550.2(TTN):c.88462dup (p.Cys29488fs)	Pathogenic
1074124	NM_001267550.2(TTN):c.67348C>T (p.Gln22450Ter)	Pathogenic
1076903	NM_001267550.2(TTN):c.85011_85014del (p.Glu28338fs)	Pathogenic
1120210	NM_001267550.2(TTN):c.10115-1G>A	Pathogenic
1120211	NM_001267550.2(TTN):c.46455del (p.Pro15486fs)	Pathogenic
1175109	NM_001267550.2(TTN):c.77452G>T (p.Glu25818Ter)	Pathogenic
1175980	NM_001267550.2(TTN):c.32662del (p.Thr10888fs)	Pathogenic
1177408	NM_001267550.2(TTN):c.40238dup (p.Tyr13414fs)	Pathogenic
1200363	NM_001267550.2(TTN):c.78241_78247del (p.Glu26081fs)	Pathogenic
1203936	NM_001267550.2(TTN):c.97440del (p.Phe32480fs)	Pathogenic
1211111	NM_001267550.2(TTN):c.68383_68387del (p.Lys22795fs)	Pathogenic
12649	NM_001267550.2(TTN):c.2219G>T (p.Arg740Leu)	Pathogenic
12652	NM_001267550.2(TTN):c.107780_107790delinsTGAAAGAAAAA (p.Glu35927_Trp35930delinsValLysGluLys)	Pathogenic

SpliceAI

37896 predictions. Top by Δscore:

Variant	Effect	Δscore
2:178527307:CCTT:C	acceptor_gain	1.0000
2:178527312:A:C	acceptor_gain	1.0000
2:178528266:ATACT:A	donor_loss	1.0000
2:178528267:TACTT:T	donor_loss	1.0000
2:178528268:ACT:A	donor_loss	1.0000
2:178528269:CT:C	donor_loss	1.0000
2:178528270:TT:T	donor_loss	1.0000
2:178528271:TACG:T	donor_loss	1.0000
2:178528272:A:AC	donor_gain	1.0000
2:178528272:A:C	donor_loss	1.0000
2:178528273:C:CA	donor_gain	1.0000
2:178528273:CG:C	donor_gain	1.0000
2:178528273:CGA:C	donor_gain	1.0000
2:178528273:CGAA:C	donor_gain	1.0000
2:178528273:CGAAG:C	donor_gain	1.0000
2:178536576:C:CA	acceptor_loss	1.0000
2:178536576:C:CC	acceptor_gain	1.0000
2:178536932:ACT:A	donor_loss	1.0000
2:178536933:CTC:C	donor_loss	1.0000
2:178536934:TCACC:T	donor_loss	1.0000
2:178536935:CA:C	donor_loss	1.0000
2:178536936:A:AC	donor_gain	1.0000
2:178536936:A:AG	donor_loss	1.0000
2:178536936:AC:A	donor_gain	1.0000
2:178536937:C:CC	donor_gain	1.0000
2:178536937:CC:C	donor_gain	1.0000
2:178536937:CCA:C	donor_gain	1.0000
2:178536937:CCAA:C	donor_gain	1.0000
2:178536937:CCAAA:C	donor_gain	1.0000
2:178537927:A:AC	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000063560 (2:178771571 G>A,C), RS1000076477 (2:178615575 A>G), RS1000081019 (2:178681580 C>A), RS1000104975 (2:178676461 A>G), RS1000110389 (2:178625285 G>A,C), RS1000112949 (2:178701944 G>A), RS1000150217 (2:178538604 A>C,G), RS1000169842 (2:178808336 C>A), RS1000178925 (2:178588132 C>T), RS1000179098 (2:178709486 G>C), RS1000233170 (2:178541221 G>A), RS1000250632 (2:178548758 T>A), RS1000257341 (2:178806337 C>A), RS1000262712 (2:178646323 A>G), RS1000268203 (2:178759019 C>A,T)

Disease associations

OMIM: gene MIM:188840 | disease phenotypes: MIM:604145, MIM:608807, MIM:600334, MIM:603689, MIM:607569, MIM:611705, MIM:613765, MIM:609470, MIM:115200, MIM:115195, MIM:119530, MIM:192600, MIM:160150, MIM:601419, MIM:615325, MIM:160500, MIM:117000, MIM:181500, MIM:613426, MIM:105210, MIM:601144, MIM:107970, MIM:192500, MIM:609040, MIM:219700, MIM:604169, MIM:613254, MIM:614408, MIM:603829, MIM:194200, MIM:255200, MIM:300696, MIM:115210, MIM:115080

GenCC curated gene-disease

Disease	Classification	Inheritance
dilated cardiomyopathy 1G	Definitive	Autosomal dominant
early-onset myopathy with fatal cardiomyopathy	Definitive	Autosomal recessive
tibial muscular dystrophy	Strong	Autosomal dominant
myopathy, myofibrillar, 9, with early respiratory failure	Strong	Autosomal dominant
autosomal recessive limb-girdle muscular dystrophy type 2J	Strong	Autosomal recessive
familial isolated dilated cardiomyopathy	Supportive	Autosomal dominant
autosomal recessive centronuclear myopathy	Supportive	Autosomal recessive
childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome	Supportive	Autosomal recessive
congenital myopathy	Limited	Autosomal dominant
hereditary skeletal muscle disorder	Limited	Autosomal dominant
hypertrophic cardiomyopathy 9	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (6)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
dilated cardiomyopathy 1G	Definitive	AD
TTN-related myopathy	Definitive	AR
arrhythmogenic right ventricular cardiomyopathy	Disputed	AD
myopathy, myofibrillar, 9, with early respiratory failure	Definitive	AD
hypertrophic cardiomyopathy	Limited	AD
tibial muscular dystrophy	Moderate	AD

Mondo (68): dilated cardiomyopathy 1G (MONDO:0011400), autosomal recessive limb-girdle muscular dystrophy type 2J (MONDO:0012127), tibial muscular dystrophy (MONDO:0010870), myopathy, myofibrillar, 9, with early respiratory failure (MONDO:0011362), early-onset myopathy with fatal cardiomyopathy (MONDO:0012714), hypertrophic cardiomyopathy 9 (MONDO:0013412), cardiomyopathy (MONDO:0004994), TTN-related myopathy (MONDO:0100175), left ventricular noncompaction 2 (MONDO:0012285), dilated cardiomyopathy (MONDO:0005021), autosomal recessive centronuclear myopathy (MONDO:0015705), familial dilated cardiomyopathy (MONDO:0016333), cerebral palsy (MONDO:0006497), hypertrophic cardiomyopathy 2 (MONDO:0007266), autosomal recessive titinopathy (MONDO:0100493)

Orphanet (47): Titin-related limb-girdle muscular dystrophy R10 (Orphanet:140922), Familial isolated dilated cardiomyopathy (Orphanet:154), Hereditary myopathy with early respiratory failure (Orphanet:178464), Early-onset myopathy with fatal cardiomyopathy (Orphanet:289377), Distal myopathy with early respiratory muscle involvement (Orphanet:34521), Tibial muscular dystrophy (Orphanet:609), Rare cardiomyopathy (Orphanet:167848), Left ventricular noncompaction (Orphanet:54260), Autosomal recessive centronuclear myopathy (Orphanet:169186), Dilated cardiomyopathy (Orphanet:217604), Familial dilated cardiomyopathy (Orphanet:217607), Limb-girdle muscular dystrophy (Orphanet:263), Rare hypertrophic cardiomyopathy (Orphanet:217569), Inherited arrhythmogenic cardiomyopathy (Orphanet:247), Inclusion myopathy (Orphanet:206662)

HPO phenotypes

147 total (30 of 147 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000160	Narrow mouth
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000303	Mandibular prognathia
HP:0000308	Microretrognathia
HP:0000407	Sensorineural hearing impairment
HP:0000411	Protruding ear
HP:0000508	Ptosis
HP:0000597	Ophthalmoparesis
HP:0000602	Ophthalmoplegia
HP:0000750	Delayed speech and language development
HP:0000969	Edema
HP:0001256	Mild intellectual disability
HP:0001260	Dysarthria
HP:0001270	Motor delay
HP:0001279	Syncope
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001290	Generalized hypotonia
HP:0001349	Facial diplegia
HP:0001385	Hip dysplasia
HP:0001508	Failure to thrive
HP:0001618	Dysphonia
HP:0001620	Abnormally high-pitched voice
HP:0001634	Mitral valve prolapse
HP:0001635	Congestive heart failure

GWAS associations

36 associations (top):

Study	Trait	p-value
GCST000452_5	QT interval	2.000000e-06
GCST001585_7	Breast size	6.000000e-06
GCST002500_17	QT interval	7.000000e-09
GCST003332_1	Rapid functional decline in sporadic amyotrophic lateral sclerosis	2.000000e-08
GCST003818_27	Resting heart rate	8.000000e-75
GCST004735_21	Epstein-Barr virus copy number in lymphoblastoid cell lines	3.000000e-07
GCST005171_22	QT interval	2.000000e-10
GCST005306_2	Atrial fibrillation	9.000000e-10
GCST005306_5	Atrial fibrillation	7.000000e-18
GCST005846_3	Heart rate response to recovery post exercise (10 sec)	2.000000e-09
GCST005846_4	Heart rate response to recovery post exercise (10 sec)	7.000000e-13
GCST005847_4	Heart rate response to recovery post exercise (20 sec)	1.000000e-09
GCST005959_4	Waist-to-hip ratio adjusted for BMI x sex interaction	6.000000e-06
GCST006061_15	Atrial fibrillation	7.000000e-25
GCST006061_159	Atrial fibrillation	3.000000e-23
GCST006414_71	Atrial fibrillation	7.000000e-25
GCST006444_21	Bone mineral density (hip)	8.000000e-06
GCST007045_19	PR interval	2.000000e-11
GCST010002_405	Refractive error	1.000000e-70
GCST010125_2	Left ventricular ejection fraction	1.000000e-18
GCST010130_1	Left ventricular end-systolic volume	6.000000e-23
GCST010131_1	Left ventricular end-diastolic volume	2.000000e-14
GCST010321_108	PR interval	8.000000e-28
GCST010796_4659	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-13
GCST010796_4660	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-18
GCST010919_9	QT interval	3.000000e-09
GCST011010_18	Electrocardiographic traits (multivariate)	6.000000e-09
GCST011198_4	Left ventricular end-systolic volume	2.000000e-17
GCST011202_4	Dilated cardiomyopathy (MTAG)	1.000000e-13
GCST011206_2	Left ventricular end-diastolic volume	1.000000e-11

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval
EFO:0007784	functional decline measurement
EFO:0009185	heart rate response to recovery post exercise
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0008343	sex interaction measurement
EFO:0007702	hip bone mineral density
EFO:0004462	PR interval
EFO:0008373	left ventricular ejection fraction measurement
EFO:0008206	left ventricular systolic function measurement
EFO:0008204	left ventricular diastolic function measurement
EFO:0004327	electrocardiography
EFO:0009289	left ventricular mass

MeSH disease descriptors (35)

Descriptor	Name	Tree numbers
D019571	Arrhythmogenic Right Ventricular Dysplasia	C14.240.400.145; C14.280.238.028; C14.280.400.145; C16.131.240.400.145
D001281	Atrial Fibrillation	C14.280.067.198; C23.550.073.198
D053840	Brugada Syndrome	C14.280.067.322; C14.280.123.250; C16.320.100
D009202	Cardiomyopathies	C14.280.238
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D002313	Cardiomyopathy, Restrictive	C14.280.238.160
D002547	Cerebral Palsy	C10.228.140.140.254
D003550	Cystic Fibrosis	C06.689.202; C08.381.187; C16.320.190; C16.614.213
D006323	Heart Arrest	C14.280.383
D006333	Heart Failure	C14.280.434
D054143	Heart Failure, Systolic	C14.280.434.676
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
D009136	Muscular Dystrophies	C05.651.534.500; C10.668.491.175.500; C16.320.577
D049288	Muscular Dystrophies, Limb-Girdle	C05.651.534.500.280; C10.668.491.175.500.149; C16.320.577.280
D009205	Myocarditis	C14.280.238.625
D009468	Neuromuscular Diseases	C10.668
D017180	Tachycardia, Ventricular	C14.280.067.845.940; C14.280.123.875.940; C23.550.073.845.940
D014693	Ventricular Fibrillation	C14.280.067.922; C23.550.073.922
D014927	Wolff-Parkinson-White Syndrome	C14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980
C563808	Arrhythmogenic Right Ventricular Dysplasia, Familial, 9 (supp.)
C565824	Cardiomyopathy, Dilated, 1g (supp.)
C563538	Cardiomyopathy, Dilated, 1s (supp.)
C566171	Cardiomyopathy, Familial Hypertrophic, 2 (supp.)
C566044	Cardiomyopathy, Familial Hypertrophic, 9 (supp.)
C566343	Hereditary Myopathy with Early Respiratory Failure (supp.)
C563854	Muscular Dystrophy, Limb-Girdle, Type 2J (supp.)
C562934	Myopathy, Centronuclear, Autosomal Recessive (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067440 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Myosin Light Chain Kinase (MLCK) family

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.92	Kd	11.93	nM	CHEMBL5653589
7.90	ED50	12.56	nM	CHEMBL5653589
7.30	Kd	49.56	nM	CHEMBL3752910
7.28	ED50	52.2	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149673: Binding affinity to human TTN incubated for 45 mins by Kinobead based pull down assay	kd	0.0119	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149673: Binding affinity to human TTN incubated for 45 mins by Kinobead based pull down assay	kd	0.0496	uM

CTD chemical–gene interactions

45 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases reaction, decreases expression, increases expression, affects binding	4
Benzo(a)pyrene	affects methylation, decreases expression, increases mutagenesis	3
bisphenol A	decreases expression, increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
GSK-J4	decreases expression	1
aminomethylphosphonic acid (AMPA)	decreases expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
cinnamaldehyde	decreases expression	1
coumarin	increases phosphorylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
cyanoginosin LR	increases expression	1
di-n-butylphosphoric acid	affects expression	1
cylindrospermopsin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	decreases expression	1
quinocetone	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
incobotulinumtoxinA	decreases expression	1
Sunitinib	increases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Caffeine	affects phosphorylation	1
Dioxins	increases mutagenesis	1
Diuron	decreases expression	1
Doxorubicin	decreases expression	1
Hydrogen Peroxide	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment	1
Nickel	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652715	Binding	Binding affinity to human TTN incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

25 cell lines: 17 induced pluripotent stem cell, 7 transformed cell line, 1 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A0JS	YCMi004-A	Induced pluripotent stem cell	Male
CVCL_A2PY	GM27125	Transformed cell line	Female
CVCL_A2VF	GM26114	Transformed cell line	Male
CVCL_A2VL	GM26130	Transformed cell line	Male
CVCL_A4ZS	ZZUNEUi017-A	Induced pluripotent stem cell	Male
CVCL_B5ES	ZZUNEUi023-A	Induced pluripotent stem cell	Male
CVCL_BV66	GM23417	Transformed cell line	Male
CVCL_C1TY	KSCBi018-A-3	Induced pluripotent stem cell	Male
CVCL_C1TZ	KSCBi018-A-4	Induced pluripotent stem cell	Male
CVCL_C1U0	KSCBi018-A-5	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

314 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03522207	PHASE4	TERMINATED	Accuracy and Efficacy of Trazodone (Desyrel) on Sleep Quality and Pain Management of TMD Patient
NCT07401745	PHASE4	ACTIVE_NOT_RECRUITING	Occlusal Splint Combined With Granisetron Injection for Management of Myofascial Pain Related to Temporomandibular Disorders
NCT00348530	PHASE4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	PHASE4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	PHASE4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone
NCT00559338	PHASE4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00606775	PHASE4	UNKNOWN	The Preventive Efficacy of Carvedilol on Cardiac Dysfunction in Duchenne Muscular Dystrophy
NCT00658203	PHASE4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00701220	PHASE4	COMPLETED	Statin Therapy for Ischemic and Nonischemic Cardiomyopathy
NCT00800761	PHASE4	COMPLETED	Intensive Combined Chelation Therapy for Iron-Induced Cardiac Disease in Patients With Thalassemia Major
NCT00806390	PHASE4	TERMINATED	Prevention of Anthracycline or Trastuzumab Induced Cardiomyopathy by Metoprolol
NCT01006473	PHASE4	COMPLETED	Exercise Training in Chagas Cardiomyopathy
NCT01261065	PHASE4	COMPLETED	Mechanisms of Improvement With Beta-Blocker Treatment in Heart Failure
NCT01345188	PHASE4	COMPLETED	Ranolazine in Ischemic Cardiomyopathy
NCT01868841	PHASE4	COMPLETED	123-I mIBG (AdreView) Heart-to-Mediastinal (H/M) Ratio and SPECT Imaging on a Small Field of View-High Efficiency Cardiac SPECT System
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NCT07116473	PHASE3	NOT_YET_RECRUITING	To Evaluate the Long-term Safety and Tolerability of Acoramidis in Participants With Newly Diagnosed ATTR-CM (ACT-EARLY OLE)
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