Selected-GenAtlas references	SOURCE	GeneCards	NCBI Gene	Swiss-Prot	Orphanet	Ensembl
	HGNC	UniGene	Nucleotide	OMIM		UCSC

Home Page

FLASH GENE

Symbol

TBX5

contributors: mct - updated : 05-03-2017

HGNC name	T-box 5
HGNC id	11604

FLASH GENE DNA RNA EXPRESSION PROTEIN DISORDER ANIMAL & CELL MODELS

Corresponding disease	HOS1 Holt-Oram syndrome 1
Location	12q24.21      Physical location : 114.791.735 - 114.846.247
Synonym name	T-box transcription factor TBX5
	T-box protein 5
Synonym symbol(s)	HOS

DNA

TYPE	functioning gene
STRUCTURE	54.51 kb     9 Exon(s)

10 Kb 5' upstream gene genomic sequence study

regulatory sequence	Promoter
	cytosine-phosphate-guanine/HTF
	Binding site   transcription factor
text structure	one GC box, three potential T-box-like binding elements (TBE-A, -B, and -C), and one NKX2.5 binding site necessary for the promoter activity and its regulation
	three elements (CREs 2, 9, 16) with patterns of enhancer activity overlapping the endogenous expression pattern of TBX5, and strong expression in ventricles, the interventricular septum (IVS), and in both atria, atrial septum or AVC

MAPPING

cloned

Y

linked

status

confirmed

Map

cen - (D12S1344 ,D12S1333 ) - D12S2309 - D12S2310 - PTPN11 - D12S821 - D12S2311 - D12S1857 - D12S861 - D12S1616 - D12S1340 - D12S2300 - OAS1 - D12S1895 - D12S809 - D12S129 - TBX3 - D12S1646 - TBX5 - D12S184 - D12S1984 - (D12S1341 ,D12S1319 ) - D12S354 - (D12S1023 - D12S839 ) - D12S369 - D12S1602 - D12S1665 - D12S79 - qter

RNA

TRANSCRIPTS	type	messenger

identification nb exons type bp product Protein kDa AA specific expression Year Pubmed NM_000192 9 - 3921 NP_000183 57.6 518 more prominent in embryonic hearts 2015 25623069 TBX5a has a stronger binding affinity for GATA4 and is the only isoform to interact with NKX2–5, resulting in isoform-specific activation of NPPA roles in regulating cardiomyocyte growth NM_080718 7 splicing 1050 NP_542449 39.1 349 - 1999 10199965 truncated NM_080717 8 splicing 3736 NP_542448 52.5 468 predominant isoform in skeletal myoblasts 2015 25623069 TBX5c lacking exon 2 different N terminus antagonizes TBX5a regulation of pro-proliferative signals such as IGF1, FGF10 and BMP4. NM_181486 9 - 3749 NP_852259 57.6 518 - 1999 10199965 TBX5B - - - - 255 more prominent in adult hearts 2011 21856288 role in regulating cardiomyocyte growth arrest

EXPRESSION

Type	restricted

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 Digestive esophagus         Reproductive female system placenta       Respiratory lung       predominantly   respiratory tract larynx         respiratory tract trachea       Skeleton appendicular skeleton upper limb

tissue

System Tissue Tissue level 1 Tissue level 2 Level Pubmed Species Stage Rna symbol Connective bone

cell lineage

cell lines

fluid/secretion

at STAGE

physiological period

embryo

Text	involved in the initiation of limb outgrow (upper limb bud) and heart (atrial walls, septa and valves), developing retina

PROTEIN

PHYSICAL PROPERTIES

STRUCTURE

motifs/domains	a large N terminal DNA binding domain (T-box)
	a C-terminal transactivation/repression domain (C-terminal region is a transcriptional activator), involved in antagonizing the splicing activity of SFRS2

mono polymer

homomer , dimer

HOMOLOGY

interspecies	homolog to murine T-box gene Tbx5 (T,brachyury)
	homolog to Drosophila optomotor-blind gene (omb)

intraspecies

homolog to highly in TBX4

Homologene

FAMILY

T box family

CATEGORY

DNA associated , transcription factor

SUBCELLULAR LOCALIZATION	intracellular
	intracellular,cytoplasm
	intracellular,nucleus,nucleoplasm
	intracellular,nucleus,chromatin/chromosome

basic FUNCTION	playing a role in regulating limb development and specification of limb identity (especially in forelimb growth and patterning)
	functional cooperation of TBX5 and MEF2C links MEF2C to the higher-order protein complex regulating heart development
	regulates ventricular myocyte relaxation in a cell-autonomous manner by direct modulation of the expression of ATP2A2
	acting as a regulator of apoptosis and cell growth
	activating a cardiac-specific promoter (atrial natriuretic factor (NPPA) alone and synergistically with other transcription factors
	playing an important role in modulating migration of vascular progenitor cells in the developing heart
	having a function in pre-mRNA splicing, and this function is relevant to the pathogenesis of Holt-Oram syndrome
	having a dual role in both transcriptional activation and pre-mRNA splicing
	acts cooperatively with NKX2.5 to regulate the expression of SHOX2 and BMP4
	TBX5 function is critical for the expression of SHOX2 in cardiac tissues
	acts upstream of SHOX2, which, in turn, activates BMP4 in thei nflow trac of the heart
	regulates transcriptional networks required for mature CCS (Cardiac conduction system) function
	TBX4 and TBX5 play similar roles in the initiation of hindlimb and forelimb outgrowth, respectively
	YAP1, CTNNB1 and TBX5 form a complex that regulates the expression of genes that promote survival, including BIRC5 and BCL2L1
	TBX5 and TBX4, two genes expressed in forelimb and hindlimb-forming regions respectively, play crucial roles in the initiation of limb outgrowth
	essential role for the T-box transcription factor gene TBX5 in sternum and forelimb formation and both structures share an embryological origin within the lateral plate mesoderm
	crucial for proper cardiovascular development
	TBX2, TBX3, TBX4, TBX5 and three members of TBX1 (TBX1, TBX15, TBX18), Brachyury (T) and Eomes (TBR2) are expressed in the developing limb

CELLULAR PROCESS	cell life, cell death/apoptosis
	nucleotide, transcription

PHYSIOLOGICAL PROCESS

development

text	controlling fore limb identity, promoting cardiomyocyte differentiation in synergy with CSX
	anteroposterior axis

PATHWAY

metabolism

signaling

TBX5-dependent pathway for the transcriptional control of diastolic function

a component	pairing with TBX3
	can form a complex with splicing factor SFRS2 and plays an important role in constitutive pre-mRNA splicing, alternative splicing, and transcriptional activation
	having a role in the development of the heart

INTERACTION

DNA	binding to both major and minor grooves of their DNA targets (T-box)

RNA

small molecule

protein	binding to CSX (NKX2.5), lacking in Holt-Oram syndrome
	binding to GATA4
	co-expressed with TBX20 in the heart-forming region but then become differentially expressed as heart morphogenesis progresses
	interacting with HEY2
	interaction between TBX5 and MEF2C leading to a synergistic activation of the -cardiac myosin heavy chain (MYH6)
	physically associates with MEF2C and cooperatively activates transcription from the MYH6 promoter
	Myocardin and TBX5 physically interact and their interaction domains were mapped to the basic domain and the coil domain of myocardin and TBX5, respectively
	direct molecular link between TBX5 and SCN5A, implicated in the function of the mature ventricular conduction system (VCS)
	TBX4 and TBX5 interact with FGF10 during the process of lung growth and branching but not during tracheal/bronchial cartilage development
	HDAC3 physically interacts with TBX5 and modulates its acetylation to repress TBX5-dependent activation of cardiomyocyte lineage-specific genes
	FBXO25 directly interacts with TBX5 and NKX2-5, and controls TBX5 and NKX2-5 transcriptional activity to regulate cardiomyocyte development
	while GATA4 and SMARCD3 are key inducers of myocardial differentiation, TBX5 is essential for the ability of cardiac cells to contract
	TBX2, TBX3, TBX4, TBX5 and three members of TBX1 (TBX1, TBX15, TBX18), Brachyury (T) and Eomes (TBR2) are expressed in the developing limb
	TBX4, TBX5 are both upstream regulators of FGF10 and RSPO2, which drive the outgrowth of all four limb buds

cell & other

REGULATION

Other

autoregulated as part of the mechanism of its transcription

ASSOCIATED DISORDERS

corresponding disease(s)

HOS1

Other morbid association(s)

Type Gene Modification Chromosome rearrangement Protein expression Protein Function constitutional germinal mutation     loss of function interacting with GATA4 in causing inherited heart septation defects (ASD)

Susceptibility

to development of retinopathy of prematurity (ROP) to familial dilated cardiomyopathy (DCM) to isolated congenital heart disease (CHD)

Variant & Polymorphism SNP	association between SNPs gene and the development of ROP
	low-frequency single-nucleotide polymorphism (SNP) that abrogates a cardiac-specific TBX5 enhancer, having the potential to lead to as many CHDs
	TBX5 loss-of-function mutation associated with enhanced susceptibility to DCM

Candidate gene

Marker

Therapy target

ANIMAL & CELL MODELS

deletion of Tbx5 from the mature murine ventricular conduction system (VCS), including the AV bundle and bundle branches, resulted in severe VCS functional consequences, including loss of fast conduction, arrhythmias, and sudden death