TBX5 (gene): Difference between revisions

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{{DISPLAYTITLE:''TBX5'' (gene)}}
{{DISPLAYTITLE:''TBX5'' (gene)}}
{{Infobox gene}}
{{Infobox gene}}
'''T-box transcription factor TBX5''' is a [[protein]] that in humans is encoded by the ''TBX5'' [[gene]].<ref name="pmid8988165">{{cite journal | vauthors = Basson CT, Bachinsky DR, Lin RC, Levi T, Elkins JA, Soults J, Grayzel D, Kroumpouzou E, Traill TA, Leblanc-Straceski J, Renault B, Kucherlapati R, Seidman JG, Seidman CE | title = Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome | journal = Nat Genet | volume = 15 | issue = 1 | pages = 30–5 |date=January 1997 | pmid = 8988165 | pmc =  | doi = 10.1038/ng0197-30 }}</ref><ref name="pmid8054982">{{cite journal | vauthors = Terrett JA, Newbury-Ecob R, Cross GS, Fenton I, Raeburn JA, Young ID, Brook JD | title = Holt-Oram syndrome is a genetically heterogeneous disease with one locus mapping to human chromosome 12q | journal = Nat Genet | volume = 6 | issue = 4 | pages = 401–4 |date=September 1994 | pmid = 8054982 | pmc =  | doi = 10.1038/ng0494-401 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: TBX5 T-box 5| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6910| accessdate = }}</ref>
'''T-box transcription factor TBX5''' is a [[protein]] that in humans is encoded by the ''TBX5'' [[gene]].<ref name="pmid8988165">{{cite journal | vauthors = Basson CT, Bachinsky DR, Lin RC, Levi T, Elkins JA, Soults J, Grayzel D, Kroumpouzou E, Traill TA, Leblanc-Straceski J, Renault B, Kucherlapati R, Seidman JG, Seidman CE | title = Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome | journal = Nature Genetics | volume = 15 | issue = 1 | pages = 30–5 | date = January 1997 | pmid = 8988165 | pmc =  | doi = 10.1038/ng0197-30 }}</ref><ref name="pmid8054982">{{cite journal | vauthors = Terrett JA, Newbury-Ecob R, Cross GS, Fenton I, Raeburn JA, Young ID, Brook JD | title = Holt-Oram syndrome is a genetically heterogeneous disease with one locus mapping to human chromosome 12q | journal = Nature Genetics | volume = 6 | issue = 4 | pages = 401–4 | date = April 1994 | pmid = 8054982 | pmc =  | doi = 10.1038/ng0494-401 }}</ref><ref name="entrez">{{cite web | title = Entrez Gene: TBX5 T-box 5| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=6910| accessdate = }}</ref>


This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the [[T-box]]. T-box genes encode transcription factors involved in the regulation of developmental processes.  This gene is closely linked{{clarify|date=April 2013}} to related family member T-box 3 (ulnar mammary syndrome) on human chromosome 12.
This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the [[T-box]]. T-box genes encode transcription factors involved in the regulation of developmental processes.  This gene is closely linked{{clarify|date=April 2013}} to related family member T-box 3 (ulnar mammary syndrome) on human chromosome 12.
Tbx5 is a gene that is located on the long arm of chromosome 12.<ref>{{cite journal | vauthors = Patel C, Silcock L, McMullan D, Brueton L, Cox H | title = TBX5 intragenic duplication: a family with an atypical Holt-Oram syndrome phenotype | journal = European Journal of Human Genetics | volume = 20 | issue = 8 | pages = 863–9 | date = August 2012 | pmid = 22333898 | pmc = 3400730 | doi = 10.1038/ejhg.2012.16 }}</ref> Tbx5 produces a protein called T-box 5 that acts as a transcription factor.<ref>{{cite journal | vauthors = Jhang WK, Lee BH, Kim GH, Lee JO, Yoo HW | title = Clinical and molecular characterisation of Holt-Oram syndrome focusing on cardiac manifestations | journal = Cardiology in the Young | volume = 25 | issue = 6 | pages = 1093–8 | date = August 2015 | pmid = 25216260 | doi = 10.1017/s1047951114001656 }}</ref> The Tbx5 gene is involved with forelimb and heart development.<ref name="Steimle_2017" /> This gene impacts the early development of the forelimb by triggering [[fibroblast growth factor]], [[FGF10]].<ref>{{cite journal | vauthors = Nishimoto S, Wilde SM, Wood S, Logan MP | title = RA Acts in a Coherent Feed-Forward Mechanism with Tbx5 to Control Limb Bud Induction and Initiation | journal = Cell Reports | volume = 12 | issue = 5 | pages = 879–91 | date = August 2015 | pmid = 26212321 | pmc = 4553633 | doi = 10.1016/j.celrep.2015.06.068 }}</ref>


== Function ==
== Function ==
The encoded protein may play a role in heart development and specification of limb identity. Mutations in this gene have been associated with [[Holt-Oram syndrome]], a developmental disorder affecting the heart and upper limbs. Skeletally there may be abnormally bent fingers, sloping shoulders, and phocomelia. Cardiac defects include ventral and atrial septation and problems with the conduction system.<ref name="pmid12668595">{{cite journal | vauthors = Packham EA, Brook JD | title = T-box genes in human disorders | journal = Hum. Mol. Genet. | volume = 12 | issue = Spec No 1 | pages = R37–44 | year = 2003 | pmid = 12668595 | doi = 10.1093/hmg/ddg077}}</ref> Several transcript variants encoding different isoforms have been described for this gene.<ref name="entrez" />
 
Tbx5 is involved with the development of the four chambers in the heart, the electrical conducting system, and the septum separating the right and left sides of the heart.<ref>{{cite journal | vauthors = Boogerd CJ, Evans SM | title = TBX5 and NuRD Divide the Heart | journal = Developmental Cell | volume = 36 | issue = 3 | pages = 242–4 | date = February 2016 | pmid = 26859347 | doi = 10.1016/j.devcel.2016.01.015 }}</ref>


== Clinical significance ==
== Clinical significance ==
In studies done in mutant mice without the TBX5 gene it has been shown that the homozygous mice did not survive gestation due to the heart not developing past E9.5. Also the heterozygous mice were born with morphological problems such as enlarged hearts, atrial and ventral septum defects, and limb malformations similar to those found in the Holt-Oram Syndrome.<ref name="pmid14573514">{{cite journal | vauthors = Takeuchi JK, Ohgi M, Koshiba-Takeuchi K, Shiratori H, Sakaki I, Ogura K, Saijoh Y, Ogura T | title = Tbx5 specifies the left/right ventricles and ventricular septum position during cardiogenesis | journal = Development | volume = 130 | issue = 24 | pages = 5953–64 | year = 2003 | pmid = 14573514 | doi = 10.1242/dev.00797 }}</ref> Supporting the essential role of TBX5 in the heart development.


==Interactions==
The encoded protein may play a role in heart development and specification of limb identity. Mutations in this gene have been associated with [[Holt-Oram syndrome]], a developmental disorder affecting the heart and upper limbs.<ref name="Steimle_2017" /><ref name="Virdis_2016">{{cite journal | vauthors = Virdis G, Dessole M, Dessole S, Ambrosini G, Cosmi E, Cherchil PL, Capobianco G | title = Holt Oram syndrome: a case report and review of the literature | journal = Clinical and Experimental Obstetrics & Gynecology | volume = 43 | issue = 1 | pages = 137–9 | year = 2016 | pmid = 27048037 | doi =  }}</ref> Skeletally there may be abnormally bent fingers, sloping shoulders, and [[phocomelia]]. Cardiac defects include ventral and atrial septation and problems with the conduction system.<ref name="pmid12668595">{{cite journal | vauthors = Packham EA, Brook JD | title = T-box genes in human disorders | journal = Human Molecular Genetics | volume = 12 Spec No 1 | issue = Spec No 1 | pages = R37-44 | date = April 2003 | pmid = 12668595 | doi = 10.1093/hmg/ddg077 }}</ref> Several transcript variants encoding different isoforms have been described for this gene.<ref name="entrez" />
TBX5 (gene) has been shown to [[Protein-protein interaction|interact]] with:
 
* [[GATA4]]<ref name = pmid12845333>{{cite journal | date = July 2003 | vauthors = Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, Cohen JC, Srivastava D | title = GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5 | journal = Nature | volume = 424 | issue = 6947 | pages = 443–7 | pmid = 12845333 | doi = 10.1038/nature01827}}</ref> and
In studies done in mutant mice without the TBX5 gene it has been shown that the homozygous mice did not survive gestation due to the heart not developing past embryonic day ''E9.5''. Also the heterozygous mice were born with morphological problems such as enlarged hearts, atrial and ventral septum defects, and limb malformations similar to those found in the Holt-Oram Syndrome.<ref name="pmid14573514">{{cite journal | vauthors = Takeuchi JK, Ohgi M, Koshiba-Takeuchi K, Shiratori H, Sakaki I, Ogura K, Saijoh Y, Ogura T | title = Tbx5 specifies the left/right ventricles and ventricular septum position during cardiogenesis | journal = Development | volume = 130 | issue = 24 | pages = 5953–64 | date = December 2003 | pmid = 14573514 | doi = 10.1242/dev.00797 }}</ref> Supporting the essential role of TBX5 in the heart development.
* [[NKX2-5]].<ref name = pmid12845333/><ref name = pmid11431700>{{cite journal | date = July 2001 | vauthors = Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R, Komuro I | title = Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation | journal = Nat. Genet. | volume = 28 | issue = 3 | pages = 276–80 | pmid = 11431700 | doi = 10.1038/90123}}</ref>
 
The encoded protein plays a major role in [[limb development]], specifically during [[limb bud]] initiation.<ref name=”Tickle2015”>{{cite journal | vauthors = Tickle C | title = How the embryo makes a limb: determination, polarity and identity | journal = Journal of Anatomy | volume = 227 | issue = 4 | pages = 418–30 | date = October 2015 | pmid = 26249743 | doi = 10.1111/joa.12361 }}</ref> For instance, in chickens Tbx5 specifies forelimb status.<ref>{{cite journal | vauthors = Rodriguez-Esteban C, Tsukui T, Yonei S, Magallon J, Tamura K, Izpisua Belmonte JC | title = The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity | journal = Nature | volume = 398 | issue = 6730 | pages = 814–8 | date = April 1999 | pmid = 10235264 | doi = 10.1038/19769 }}</ref> The activation of Tbx5 and other [[T-box|T-box proteins]] by [[Hox genes]] activates signaling cascades that involve the [[Wnt signaling pathway]] and [[Fibroblast growth factor|FGF signals]] in limb buds.<ref name=”Tickle2015”></ref> Ultimately, Tbx5 leads to the development of [[Apical ectodermal ridge|apical ectodermal ridge (AER)]] and [[Zone of polarizing activity|zone of polarizing activity (ZPA)]] signaling centers in the developing limb bud, which specify the orientation growth of the developing limb.<ref name=”Tickle2015”></ref> Together with [[Tbx4]], Tbx5 plays a role in patterning the soft tissues (muscles and tendons) of the musculoskeletal system.<ref name=devcellmusc>{{cite journal | vauthors = Hasson P, DeLaurier A, Bennett M, Grigorieva E, Naiche LA, Papaioannou VE, Mohun TJ, Logan MP | title = Tbx4 and tbx5 acting in connective tissue are required for limb muscle and tendon patterning | journal = Developmental Cell | volume = 18 | issue = 1 | pages = 148–56 | date = January 2010 | pmid = 20152185 | pmc = 3034643 | doi = 10.1016/j.devcel.2009.11.013 }}</ref>
 
A mutation in this gene can cause [[Holt-Oram syndrome]] or [[Tetra-amelia syndrome|Amelia syndrome]].<ref name="Steimle_2017">{{cite journal | vauthors = Steimle JD, Moskowitz IP | title = TBX5: A Key Regulator of Heart Development | journal = Current Topics in Developmental Biology | volume = 122 | issue = | pages = 195–221 | year = 2017 | pmid = 28057264 | pmc = 5371404 | doi = 10.1016/bs.ctdb.2016.08.008 }}</ref> Holt-Oram syndrome can cause several different defects. One effect of Holt-Oram syndrome is a hole in the septum.<ref>{{cite journal | vauthors = Jhang WK, Lee BH, Kim GH, Lee JO, Yoo HW | title = Clinical and molecular characterisation of Holt-Oram syndrome focusing on cardiac manifestations | journal = Cardiology in the Young | volume = 25 | issue = 6 | pages = 1093–8 | date = August 2015 | pmid = 25216260 | doi = 10.1017/s1047951114001656 }}</ref> Another symptom of this syndrome is bone abnormalities in the fingers, wrists, or arms.<ref>{{cite journal | vauthors = Pizard A, Burgon PG, Paul DL, Bruneau BG, Seidman CE, Seidman JG | title = Connexin 40, a target of transcription factor Tbx5, patterns wrist, digits, and sternum | journal = Molecular and Cellular Biology | volume = 25 | issue = 12 | pages = 5073–83 | date = June 2005 | pmid = 15923624 | pmc = 1140596 | doi = 10.1128/mcb.25.12.5073-5083.2005 }}</ref> An additional defect that Holt-Oram syndrome can cause is a conduction disease leading to abnormal heart rates and arrhythmias.<ref>{{cite journal | vauthors = Patel C, Silcock L, McMullan D, Brueton L, Cox H | title = TBX5 intragenic duplication: a family with an atypical Holt-Oram syndrome phenotype | journal = European Journal of Human Genetics | volume = 20 | issue = 8 | pages = 863–9 | date = August 2012 | pmid = 22333898 | pmc = 3400730 | doi = 10.1038/ejhg.2012.16 }}</ref> Amelia syndrome is a condition where forelimb malformation occurs because FGF-10 is not triggered due to Tbx5 mutations.<ref>{{cite journal | vauthors =  | title = Tetra-Amelia Syndrome | journal = Gene Reviews | date = 28 August 2007 | pmid = 20301453 }}</ref> This condition can lead to the absence of one or both forelimbs.


==Other information==
== Interactions ==
Tbx5 is a gene that is located on the long arm of chromosome 12.<ref>{{cite journal|author=Patel, C.|author2=Silcock, L.|author3=Mcmullan, D.|author4=Brueton, L.|author5=Cox, H|last-author-amp=yes|title=TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype|journal=European Journal of Human Genetics|date=15 February 2012|volume=20|issue=8|pages=863–869|doi=10.1038/ejhg.2012.16|pmid=22333898|pmc=3400730}}<!--|accessdate=10 April 2016--></ref> Tbx5 produces a protein called T-box 5 that acts as a transcription factor.<ref>{{cite journal|author=Jhang, W. K.|author2=Lee, B. H.|author3=Kim, G.|author4=Lee, J.|author5=Yoo, H|last-author-amp=yes|title=Clinical and molecular characterisation of Holt–Oram syndrome focusing on cardiac manifestations|journal=Cardiology in the Young|volume=25|issue=6|pages=1093–1098|doi=10.1017/s1047951114001656}}<!--|accessdate=10 April 2016--></ref> The Tbx5 gene is involved with forelimb and heart development. This gene impacts the early development of the forelimb by triggering FGF-10 (Fibroblast Growth Factor 10).<ref>{{cite journal|author=Nishimoto, S.|author2=Wilde, S.|author3=Wood, S.|author4=Logan, M.|last-author-amp=yes|title=RA Acts in a Coherent Feed-Forward Mechanism with Tbx5 to Control Limb Bud Induction and Initiation|journal=Cell Reports|date=2015|volume=12|issue=5|pages=879–891|doi=10.1016/j.celrep.2015.06.068|pmid=26212321|pmc=4553633}}</ref> Tbx5 is involved with the development of the four chambers in the heart, the electrical conducting system, and the septum separating the right and left sides of the heart.<ref>{{cite journal|vauthors=Boogerd CJ, Evans SM|title=TBX5 and NuRD Divide the Heart|journal=Developmental Cell|date=8 February 2016|volume=36|issue=3|pages=242–244|doi=10.1016/j.devcel.2016.01.015|pmid=26859347}}<!--|accessdate=10 April 2016--></ref> A mutation in this gene can cause Holt-Oram syndrome or Amelia syndrome. Holt-Oram syndrome can cause several different defects. One effect of Holt-Oram syndrome is a hole in the septum.<ref>{{cite journal|author=Jhang, W. K.|author2=Lee, B. H.|author3=Kim, G.|author4=Lee, J.|author5=Yoo, H|last-author-amp=yes|title=Clinical and molecular characterisation of Holt–Oram syndrome focusing on cardiac manifestations|journal=Cardiology in the Young|volume=25|issue=6|pages=1093–1098|doi=10.1017/s1047951114001656}}<!--|accessdate=10 April 2016--></ref> Another symptom of this syndrome is bone abnormalities in the fingers, wrists, or arms.<ref>{{cite journal|author=Pizard, A.|author2=Burgon, P. G.|author3=Paul, D. L.|author4=Bruneau, B. G.|author5=Seidman, C. E.|author6=Seidman, J. G.|last-author-amp=yes|title=Connexin 40, a Target of Transcription Factor Tbx5, Patterns Wrist, Digits, and Sternum|journal=Molecular and Cellular Biology|date=2005|volume=25|issue=12|pages=5073–5083|doi=10.1128/mcb.25.12.5073-5083.2005|pmid=15923624|pmc=1140596}}<!--|accessdate=10 April 2016--></ref> An additional defect that Holt-Oram syndrome can cause is a conduction disease leading to abnormal heart rates and arrhythmias.<ref>{{cite journal|author=Patel, C.|author2=Silcock, L.|author3=Mcmullan, D.|author4=Brueton, L.|author5=Cox, H|last-author-amp=yes|title=TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype|journal=European Journal of Human Genetics|date=15 February 2012|volume=20|issue=8|pages=863–869|doi=10.1038/ejhg.2012.16|pmid=22333898|pmc=3400730}}<!--|accessdate=10 April 2016--></ref> Amelia syndrome is a condition where forelimb malformation occurs because FGF-10 is not triggered due to Tbx5 mutations.<ref>{{cite journal|last1=Niemann|first1=Stephan, MD|title=Tetra-Amelia Syndrome|journal=Gene Reviews|date=28 August 2007|pmid=20301453}}<!--|accessdate=10 April 2016--></ref> This condition can lead to the absence of one or both forelimbs.


==References==
TBX5 (gene) has been shown to [[Protein-protein interaction|interact]] with:
* [[GATA4]]<ref name = pmid12845333>{{cite journal | vauthors = Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, Cohen JC, Srivastava D | title = GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5 | journal = Nature | volume = 424 | issue = 6947 | pages = 443–7 | date = July 2003 | pmid = 12845333 | doi = 10.1038/nature01827 }}</ref>  and
* [[NKX2-5]].<ref name = pmid12845333/><ref name = pmid11431700>{{cite journal | vauthors = Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R, Komuro I | title = Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation | journal = Nature Genetics | volume = 28 | issue = 3 | pages = 276–80 | date = July 2001 | pmid = 11431700 | doi = 10.1038/90123 }}</ref>
{{clear}}
== References ==
{{Reflist}}
{{Reflist}}


==Further reading==
== Further reading ==
{{Refbegin | 2}}
{{Refbegin | 2}}
*{{cite journal | author=Simon H |title=T-box genes and the formation of vertebrate forelimb- and hindlimb specific pattern |journal=Cell Tissue Res. |volume=296 |issue= 1 |pages= 57–66 |year= 1999 |pmid= 10199965 |doi=10.1007/s004410051266 }}
* {{cite journal | vauthors = Simon H | title = T-box genes and the formation of vertebrate forelimb- and hindlimb specific pattern | journal = Cell and Tissue Research | volume = 296 | issue = 1 | pages = 57–66 | date = April 1999 | pmid = 10199965 | doi = 10.1007/s004410051266 }}
*{{cite journal | vauthors=Packham EA, Brook JD |title=T-box genes in human disorders |journal=Hum. Mol. Genet. |volume=12 |issue= Spec No 1|pages= R37–44 |year= 2003 |pmid= 12668595 |doi=10.1093/hmg/ddg077 }}
* {{cite journal | vauthors = Packham EA, Brook JD | title = T-box genes in human disorders | journal = Human Molecular Genetics | volume = 12 Spec No 1 | issue = Spec No 1 | pages = R37-44 | date = April 2003 | pmid = 12668595 | doi = 10.1093/hmg/ddg077 }}
*{{cite journal   |vauthors=Li QY, Newbury-Ecob RA, Terrett JA, etal |title=Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family |journal=Nat. Genet. |volume=15 |issue= 1 |pages= 21–9 |year= 1997 |pmid= 8988164 |doi= 10.1038/ng0197-21 }}
* {{cite journal | vauthors = Li QY, Newbury-Ecob RA, Terrett JA, Wilson DI, Curtis AR, Yi CH, Gebuhr T, Bullen PJ, Robson SC, Strachan T, Bonnet D, Lyonnet S, Young ID, Raeburn JA, Buckler AJ, Law DJ, Brook JD | title = Holt-Oram syndrome is caused by mutations in TBX5, a member of the Brachyury (T) gene family | journal = Nature Genetics | volume = 15 | issue = 1 | pages = 21–9 | date = January 1997 | pmid = 8988164 | doi = 10.1038/ng0197-21 }}
*{{cite journal   |vauthors=Basson CT, Huang T, Lin RC, etal |title=Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=96 |issue= 6 |pages= 2919–24 |year= 1999 |pmid= 10077612 |doi=10.1073/pnas.96.6.2919 | pmc=15870  }}
* {{cite journal | vauthors = Basson CT, Huang T, Lin RC, Bachinsky DR, Weremowicz S, Vaglio A, Bruzzone R, Quadrelli R, Lerone M, Romeo G, Silengo M, Pereira A, Krieger J, Mesquita SF, Kamisago M, Morton CC, Pierpont ME, Müller CW, Seidman JG, Seidman CE | title = Different TBX5 interactions in heart and limb defined by Holt-Oram syndrome mutations | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 6 | pages = 2919–24 | date = March 1999 | pmid = 10077612 | pmc = 15870 | doi = 10.1073/pnas.96.6.2919 }}
*{{cite journal   |vauthors=Yang J, Hu D, Xia J, etal |title=Three novel TBX5 mutations in Chinese patients with Holt-Oram syndrome |journal=Am. J. Med. Genet. |volume=92 |issue= 4 |pages= 237–40 |year= 2000 |pmid= 10842287 |doi=10.1002/(SICI)1096-8628(20000605)92:4<237::AID-AJMG2>3.0.CO;2-G }}
* {{cite journal | vauthors = Yang J, Hu D, Xia J, Yang Y, Ying B, Hu J, Zhou X | title = Three novel TBX5 mutations in Chinese patients with Holt-Oram syndrome | journal = American Journal of Medical Genetics | volume = 92 | issue = 4 | pages = 237–40 | date = June 2000 | pmid = 10842287 | doi = 10.1002/(SICI)1096-8628(20000605)92:4<237::AID-AJMG2>3.0.CO;2-G }}
*{{cite journal   |vauthors=Hatcher CJ, Goldstein MM, Mah CS, etal |title=Identification and localization of TBX5 transcription factor during human cardiac morphogenesis |journal=Dev. Dyn. |volume=219 |issue= 1 |pages= 90–5 |year= 2000 |pmid= 10974675 |doi= 10.1002/1097-0177(200009)219:1<90::AID-DVDY1033>3.0.CO;2-L }}
* {{cite journal | vauthors = Hatcher CJ, Goldstein MM, Mah CS, Delia CS, Basson CT | title = Identification and localization of TBX5 transcription factor during human cardiac morphogenesis | journal = Developmental Dynamics | volume = 219 | issue = 1 | pages = 90–5 | date = September 2000 | pmid = 10974675 | doi = 10.1002/1097-0177(200009)219:1<90::AID-DVDY1033>3.0.CO;2-L }}
*{{cite journal   |vauthors=Hatcher CJ, Kim MS, Mah CS, etal |title=TBX5 transcription factor regulates cell proliferation during cardiogenesis |journal=Dev. Biol. |volume=230 |issue= 2 |pages= 177–88 |year= 2001 |pmid= 11161571 |doi= 10.1006/dbio.2000.0134 }}
* {{cite journal | vauthors = Hatcher CJ, Kim MS, Mah CS, Goldstein MM, Wong B, Mikawa T, Basson CT | title = TBX5 transcription factor regulates cell proliferation during cardiogenesis | journal = Developmental Biology | volume = 230 | issue = 2 | pages = 177–88 | date = February 2001 | pmid = 11161571 | doi = 10.1006/dbio.2000.0134 }}
*{{cite journal   |vauthors=Cross SJ, Ching YH, Li QY, etal |title=The mutation spectrum in Holt-Oram syndrome |journal=J. Med. Genet. |volume=37 |issue= 10 |pages= 785–7 |year= 2001 |pmid= 11183182 |doi=10.1136/jmg.37.10.785 | pmc=1757164  }}
* {{cite journal | vauthors = Cross SJ, Ching YH, Li QY, Armstrong-Buisseret L, Spranger S, Lyonnet S, Bonnet D, Penttinen M, Jonveaux P, Leheup B, Mortier G, Van Ravenswaaij C, Gardiner CA | title = The mutation spectrum in Holt-Oram syndrome | journal = Journal of Medical Genetics | volume = 37 | issue = 10 | pages = 785–7 | date = October 2000 | pmid = 11183182 | pmc = 1757164 | doi = 10.1136/jmg.37.10.785 }}
*{{cite journal   |vauthors=Hiroi Y, Kudoh S, Monzen K, etal |title=Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation |journal=Nat. Genet. |volume=28 |issue= 3 |pages= 276–80 |year= 2001 |pmid= 11431700 |doi= 10.1038/90123 }}
* {{cite journal | vauthors = Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R, Komuro I | title = Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation | journal = Nature Genetics | volume = 28 | issue = 3 | pages = 276–80 | date = July 2001 | pmid = 11431700 | doi = 10.1038/90123 }}
*{{cite journal | vauthors=Akrami SM, Winter RM, Brook JD, Armour JA |title=Detection of a large TBX5 deletion in a family with Holt-Oram syndrome |journal=J. Med. Genet. |volume=38 |issue= 12 |pages= E44 |year= 2002 |pmid= 11748310 |doi=10.1136/jmg.38.12.e44 | pmc=1734777  }}
* {{cite journal | vauthors = Akrami SM, Winter RM, Brook JD, Armour JA | title = Detection of a large TBX5 deletion in a family with Holt-Oram syndrome | journal = Journal of Medical Genetics | volume = 38 | issue = 12 | pages = E44 | date = December 2001 | pmid = 11748310 | pmc = 1734777 | doi = 10.1136/jmg.38.12.e44 }}
*{{cite journal   |vauthors=He ML, Chen Y, Peng Y, etal |title=Induction of apoptosis and inhibition of cell growth by developmental regulator hTBX5 |journal=Biochem. Biophys. Res. Commun. |volume=297 |issue= 2 |pages= 185–92 |year= 2002 |pmid= 12237100 |doi=10.1016/S0006-291X(02)02142-3 }}
* {{cite journal | vauthors = He ML, Chen Y, Peng Y, Jin D, Du D, Wu J, Lu P, Lin MC, Kung HF | title = Induction of apoptosis and inhibition of cell growth by developmental regulator hTBX5 | journal = Biochemical and Biophysical Research Communications | volume = 297 | issue = 2 | pages = 185–92 | date = September 2002 | pmid = 12237100 | doi = 10.1016/S0006-291X(02)02142-3 }}
*{{cite journal   |vauthors=Strausberg RL, Feingold EA, Grouse LH, etal |title=Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences |journal=Proc. Natl. Acad. Sci. U.S.A. |volume=99 |issue= 26 |pages= 16899–903 |year= 2003 |pmid= 12477932 |doi= 10.1073/pnas.242603899  | pmc=139241 }}
* {{cite journal | vauthors = Fan C, Liu M, Wang Q | title = Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome | journal = The Journal of Biological Chemistry | volume = 278 | issue = 10 | pages = 8780–5 | date = March 2003 | pmid = 12499378 | pmc = 1579789 | doi = 10.1074/jbc.M208120200 }}
*{{cite journal  | vauthors=Fan C, Liu M, Wang Q |title=Functional analysis of TBX5 missense mutations associated with Holt-Oram syndrome |journal=J. Biol. Chem. |volume=278 |issue= 10 |pages= 8780–5 |year= 2003 |pmid= 12499378 |doi= 10.1074/jbc.M208120200 | pmc=1579789 }}
* {{cite journal | vauthors = Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, Cohen JC, Srivastava D | title = GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5 | journal = Nature | volume = 424 | issue = 6947 | pages = 443–7 | date = July 2003 | pmid = 12845333 | doi = 10.1038/nature01827 }}
*{{cite journal   |vauthors=Garg V, Kathiriya IS, Barnes R, etal |title=GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5 |journal=Nature |volume=424 |issue= 6947 |pages= 443–7 |year= 2003 |pmid= 12845333 |doi= 10.1038/nature01827 }}
* {{cite journal | vauthors = Huang T, Lock JE, Marshall AC, Basson C, Seidman JG, Seidman CE | title = Causes of clinical diversity in human TBX5 mutations | journal = Cold Spring Harbor Symposia on Quantitative Biology | volume = 67 | issue =  | pages = 115–20 | year = 2003 | pmid = 12858531 | doi = 10.1101/sqb.2002.67.115 }}
*{{cite journal   |vauthors=Huang T, Lock JE, Marshall AC, etal |title=Causes of clinical diversity in human TBX5 mutations |journal=Cold Spring Harb. Symp. Quant. Biol. |volume=67 |issue=  |pages= 115–20 |year= 2003 |pmid= 12858531 |doi=10.1101/sqb.2002.67.115 }}
* {{cite journal | vauthors = Collavoli A, Hatcher CJ, He J, Okin D, Deo R, Basson CT | title = TBX5 nuclear localization is mediated by dual cooperative intramolecular signals | journal = Journal of Molecular and Cellular Cardiology | volume = 35 | issue = 10 | pages = 1191–5 | date = October 2003 | pmid = 14519429 | doi = 10.1016/S0022-2828(03)00231-1 }}
*{{cite journal   |vauthors=Collavoli A, Hatcher CJ, He J, etal |title=TBX5 nuclear localization is mediated by dual cooperative intramolecular signals |journal=J. Mol. Cell. Cardiol. |volume=35 |issue= 10 |pages= 1191–5 |year= 2004 |pmid= 14519429 |doi=10.1016/S0022-2828(03)00231-1 }}
{{Refend}}
{{Refend}}


==External links==
== External links ==
*[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hos  GeneReviews/NCBI/NIH/UW entry on Holt-Oram Syndrome]
*[https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=hos  GeneReviews/NCBI/NIH/UW entry on Holt-Oram Syndrome]
* {{MeshName|TBX5+protein,+human}}
* {{MeshName|TBX5+protein,+human}}

Latest revision as of 22:19, 1 February 2018

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Orthologs
SpeciesHumanMouse
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View/Edit Human

T-box transcription factor TBX5 is a protein that in humans is encoded by the TBX5 gene.[1][2][3]

This gene is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes encode transcription factors involved in the regulation of developmental processes. This gene is closely linked[clarification needed] to related family member T-box 3 (ulnar mammary syndrome) on human chromosome 12.

Tbx5 is a gene that is located on the long arm of chromosome 12.[4] Tbx5 produces a protein called T-box 5 that acts as a transcription factor.[5] The Tbx5 gene is involved with forelimb and heart development.[6] This gene impacts the early development of the forelimb by triggering fibroblast growth factor, FGF10.[7]

Function

Tbx5 is involved with the development of the four chambers in the heart, the electrical conducting system, and the septum separating the right and left sides of the heart.[8]

Clinical significance

The encoded protein may play a role in heart development and specification of limb identity. Mutations in this gene have been associated with Holt-Oram syndrome, a developmental disorder affecting the heart and upper limbs.[6][9] Skeletally there may be abnormally bent fingers, sloping shoulders, and phocomelia. Cardiac defects include ventral and atrial septation and problems with the conduction system.[10] Several transcript variants encoding different isoforms have been described for this gene.[3]

In studies done in mutant mice without the TBX5 gene it has been shown that the homozygous mice did not survive gestation due to the heart not developing past embryonic day E9.5. Also the heterozygous mice were born with morphological problems such as enlarged hearts, atrial and ventral septum defects, and limb malformations similar to those found in the Holt-Oram Syndrome.[11] Supporting the essential role of TBX5 in the heart development.

The encoded protein plays a major role in limb development, specifically during limb bud initiation.[12] For instance, in chickens Tbx5 specifies forelimb status.[13] The activation of Tbx5 and other T-box proteins by Hox genes activates signaling cascades that involve the Wnt signaling pathway and FGF signals in limb buds.[12] Ultimately, Tbx5 leads to the development of apical ectodermal ridge (AER) and zone of polarizing activity (ZPA) signaling centers in the developing limb bud, which specify the orientation growth of the developing limb.[12] Together with Tbx4, Tbx5 plays a role in patterning the soft tissues (muscles and tendons) of the musculoskeletal system.[14]

A mutation in this gene can cause Holt-Oram syndrome or Amelia syndrome.[6] Holt-Oram syndrome can cause several different defects. One effect of Holt-Oram syndrome is a hole in the septum.[15] Another symptom of this syndrome is bone abnormalities in the fingers, wrists, or arms.[16] An additional defect that Holt-Oram syndrome can cause is a conduction disease leading to abnormal heart rates and arrhythmias.[17] Amelia syndrome is a condition where forelimb malformation occurs because FGF-10 is not triggered due to Tbx5 mutations.[18] This condition can lead to the absence of one or both forelimbs.

Interactions

TBX5 (gene) has been shown to interact with:

References

  1. ↑ Basson CT, Bachinsky DR, Lin RC, Levi T, Elkins JA, Soults J, Grayzel D, Kroumpouzou E, Traill TA, Leblanc-Straceski J, Renault B, Kucherlapati R, Seidman JG, Seidman CE (January 1997). "Mutations in human TBX5 [corrected] cause limb and cardiac malformation in Holt-Oram syndrome". Nature Genetics. 15 (1): 30–5. doi:10.1038/ng0197-30. PMID 8988165.
  2. ↑ Terrett JA, Newbury-Ecob R, Cross GS, Fenton I, Raeburn JA, Young ID, Brook JD (April 1994). "Holt-Oram syndrome is a genetically heterogeneous disease with one locus mapping to human chromosome 12q". Nature Genetics. 6 (4): 401–4. doi:10.1038/ng0494-401. PMID 8054982.
  3. ↑ 3.0 3.1 "Entrez Gene: TBX5 T-box 5".
  4. ↑ Patel C, Silcock L, McMullan D, Brueton L, Cox H (August 2012). "TBX5 intragenic duplication: a family with an atypical Holt-Oram syndrome phenotype". European Journal of Human Genetics. 20 (8): 863–9. doi:10.1038/ejhg.2012.16. PMC 3400730. PMID 22333898.
  5. ↑ Jhang WK, Lee BH, Kim GH, Lee JO, Yoo HW (August 2015). "Clinical and molecular characterisation of Holt-Oram syndrome focusing on cardiac manifestations". Cardiology in the Young. 25 (6): 1093–8. doi:10.1017/s1047951114001656. PMID 25216260.
  6. ↑ 6.0 6.1 6.2 Steimle JD, Moskowitz IP (2017). "TBX5: A Key Regulator of Heart Development". Current Topics in Developmental Biology. 122: 195–221. doi:10.1016/bs.ctdb.2016.08.008. PMC 5371404. PMID 28057264.
  7. ↑ Nishimoto S, Wilde SM, Wood S, Logan MP (August 2015). "RA Acts in a Coherent Feed-Forward Mechanism with Tbx5 to Control Limb Bud Induction and Initiation". Cell Reports. 12 (5): 879–91. doi:10.1016/j.celrep.2015.06.068. PMC 4553633. PMID 26212321.
  8. ↑ Boogerd CJ, Evans SM (February 2016). "TBX5 and NuRD Divide the Heart". Developmental Cell. 36 (3): 242–4. doi:10.1016/j.devcel.2016.01.015. PMID 26859347.
  9. ↑ Virdis G, Dessole M, Dessole S, Ambrosini G, Cosmi E, Cherchil PL, Capobianco G (2016). "Holt Oram syndrome: a case report and review of the literature". Clinical and Experimental Obstetrics & Gynecology. 43 (1): 137–9. PMID 27048037.
  10. ↑ Packham EA, Brook JD (April 2003). "T-box genes in human disorders". Human Molecular Genetics. 12 Spec No 1 (Spec No 1): R37–44. doi:10.1093/hmg/ddg077. PMID 12668595.
  11. ↑ Takeuchi JK, Ohgi M, Koshiba-Takeuchi K, Shiratori H, Sakaki I, Ogura K, Saijoh Y, Ogura T (December 2003). "Tbx5 specifies the left/right ventricles and ventricular septum position during cardiogenesis". Development. 130 (24): 5953–64. doi:10.1242/dev.00797. PMID 14573514.
  12. ↑ 12.0 12.1 12.2 Tickle C (October 2015). "How the embryo makes a limb: determination, polarity and identity". Journal of Anatomy. 227 (4): 418–30. doi:10.1111/joa.12361. PMID 26249743.
  13. ↑ Rodriguez-Esteban C, Tsukui T, Yonei S, Magallon J, Tamura K, Izpisua Belmonte JC (April 1999). "The T-box genes Tbx4 and Tbx5 regulate limb outgrowth and identity". Nature. 398 (6730): 814–8. doi:10.1038/19769. PMID 10235264.
  14. ↑ Hasson P, DeLaurier A, Bennett M, Grigorieva E, Naiche LA, Papaioannou VE, Mohun TJ, Logan MP (January 2010). "Tbx4 and tbx5 acting in connective tissue are required for limb muscle and tendon patterning". Developmental Cell. 18 (1): 148–56. doi:10.1016/j.devcel.2009.11.013. PMC 3034643. PMID 20152185.
  15. ↑ Jhang WK, Lee BH, Kim GH, Lee JO, Yoo HW (August 2015). "Clinical and molecular characterisation of Holt-Oram syndrome focusing on cardiac manifestations". Cardiology in the Young. 25 (6): 1093–8. doi:10.1017/s1047951114001656. PMID 25216260.
  16. ↑ Pizard A, Burgon PG, Paul DL, Bruneau BG, Seidman CE, Seidman JG (June 2005). "Connexin 40, a target of transcription factor Tbx5, patterns wrist, digits, and sternum". Molecular and Cellular Biology. 25 (12): 5073–83. doi:10.1128/mcb.25.12.5073-5083.2005. PMC 1140596. PMID 15923624.
  17. ↑ Patel C, Silcock L, McMullan D, Brueton L, Cox H (August 2012). "TBX5 intragenic duplication: a family with an atypical Holt-Oram syndrome phenotype". European Journal of Human Genetics. 20 (8): 863–9. doi:10.1038/ejhg.2012.16. PMC 3400730. PMID 22333898.
  18. ↑ "Tetra-Amelia Syndrome". Gene Reviews. 28 August 2007. PMID 20301453.
  19. ↑ 19.0 19.1 Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, Cohen JC, Srivastava D (July 2003). "GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5". Nature. 424 (6947): 443–7. doi:10.1038/nature01827. PMID 12845333.
  20. ↑ Hiroi Y, Kudoh S, Monzen K, Ikeda Y, Yazaki Y, Nagai R, Komuro I (July 2001). "Tbx5 associates with Nkx2-5 and synergistically promotes cardiomyocyte differentiation". Nature Genetics. 28 (3): 276–80. doi:10.1038/90123. PMID 11431700.

Further reading

External links

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