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Genetics Home Reference: your guide to understanding genetic conditions
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SMAD3

Reviewed July 2014

What is the official name of the SMAD3 gene?

The official name of this gene is “SMAD family member 3.”

SMAD3 is the gene's official symbol. The SMAD3 gene is also known by other names, listed below.

What is the normal function of the SMAD3 gene?

The SMAD3 gene provides instructions for making a protein involved in transmitting chemical signals from the cell surface to the nucleus. This signaling pathway, called the transforming growth factor-beta (TGF-β) pathway, allows the environment outside the cell to affect cell function, including how the cell produces other proteins. The signaling process begins when a TGF-β protein attaches (binds) to a receptor on the cell surface, which activates a group of related SMAD proteins (including the SMAD3 protein). These SMAD proteins bind together to form a protein complex, which then moves to the cell nucleus. In the nucleus, the SMAD protein complex binds to specific areas of DNA to control the activity of particular genes and regulate cell proliferation.

By controlling gene activity and regulating cell proliferation, the SMAD3 protein serves both as a transcription factor and as a tumor suppressor. Transcription factors help control when particular genes are turned on or off, and tumor suppressors keep cells from growing and dividing too fast or in an uncontrolled way.

Does the SMAD3 gene share characteristics with other genes?

The SMAD3 gene belongs to a family of genes called SMAD (SMAD, mothers against DPP homologs).

A gene family is a group of genes that share important characteristics. Classifying individual genes into families helps researchers describe how genes are related to each other. For more information, see What are gene families? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genefamilies) in the Handbook.

How are changes in the SMAD3 gene related to health conditions?

Loeys-Dietz syndrome - caused by mutations in the SMAD3 gene

At least 11 mutations in the SMAD3 gene have been found to cause Loeys-Dietz syndrome type III. This disorder affects connective tissue, which gives structure and support to blood vessels, the skeleton, and many other parts of the body. Loeys-Dietz syndrome type III is characterized by abnormal blood vessels and skeletal and joint deformities. Some of the mutations that cause this disorder insert or delete small amounts of genetic material in the SMAD3 gene, while other mutations result in a change to single protein building blocks (amino acids) in the SMAD3 protein. These mutations lead to the production of a nonfunctional SMAD3 protein. Despite a reduction in SMAD3 function, the TGF-β pathway is overactive. Researchers speculate that the activity of proteins in this signaling pathway is increased to compensate for the lack of SMAD3 activity; however the exact mechanism responsible for the increase in signaling is unclear. The overactive signaling pathway leads to dysregulated cell proliferation and gene activation, specifically affecting blood vessel and cartilage development. These changes lead to the abnormalities typical of Loeys-Dietz syndrome type III.

Where is the SMAD3 gene located?

Cytogenetic Location: 15q22.33

Molecular Location on chromosome 15: base pairs 67,065,856 to 67,195,194

The SMAD3 gene is located on the long (q) arm of chromosome 15 at position 22.33.

The SMAD3 gene is located on the long (q) arm of chromosome 15 at position 22.33.

More precisely, the SMAD3 gene is located from base pair 67,065,856 to base pair 67,195,194 on chromosome 15.

See How do geneticists indicate the location of a gene? (http://ghr.nlm.nih.gov/handbook/howgeneswork/genelocation) in the Handbook.

Where can I find additional information about SMAD3?

You and your healthcare professional may find the following resources about SMAD3 helpful.

You may also be interested in these resources, which are designed for genetics professionals and researchers.

What other names do people use for the SMAD3 gene or gene products?

  • hMAD-3
  • hSMAD3
  • JV15-2
  • mad3
  • MADH3
  • MAD homolog 3
  • MAD, mothers against decapentaplegic homolog 3
  • mothers against decapentaplegic homolog 3
  • mothers against decapentaplegic homolog 3 isoform 3
  • SMAD3_HUMAN
  • SMAD, mothers against DPP homolog 3

See How are genetic conditions and genes named? (http://ghr.nlm.nih.gov/handbook/mutationsanddisorders/naming) in the Handbook.

What glossary definitions help with understanding SMAD3?

acids ; aneurysm ; cartilage ; cell ; cell nucleus ; cell proliferation ; connective tissue ; DNA ; familial ; gene ; growth factor ; joint ; nucleus ; proliferation ; protein ; receptor ; syndrome ; tissue ; transcription ; transcription factor ; tumor

You may find definitions for these and many other terms in the Genetics Home Reference Glossary (http://www.ghr.nlm.nih.gov/glossary).

References

  • OMIM: MOTHERS AGAINST DECAPENTAPLEGIC, DROSOPHILA, HOMOLOG OF, 3 (http://omim.org/entry/603109)
  • NCBI Gene (http://www.ncbi.nlm.nih.gov/gene/4088)
  • Regalado ES, Guo DC, Villamizar C, Avidan N, Gilchrist D, McGillivray B, Clarke L, Bernier F, Santos-Cortez RL, Leal SM, Bertoli-Avella AM, Shendure J, Rieder MJ, Nickerson DA; NHLBI GO Exome Sequencing Project, Milewicz DM. Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms. Circ Res. 2011 Sep 2;109(6):680-6. doi: 10.1161/CIRCRESAHA.111.248161. Epub 2011 Jul 21. (http://www.ncbi.nlm.nih.gov/pubmed/21778426?dopt=Abstract)
  • van de Laar IM, Oldenburg RA, Pals G, Roos-Hesselink JW, de Graaf BM, Verhagen JM, Hoedemaekers YM, Willemsen R, Severijnen LA, Venselaar H, Vriend G, Pattynama PM, Collée M, Majoor-Krakauer D, Poldermans D, Frohn-Mulder IM, Micha D, Timmermans J, Hilhorst-Hofstee Y, Bierma-Zeinstra SM, Willems PJ, Kros JM, Oei EH, Oostra BA, Wessels MW, Bertoli-Avella AM. Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis. Nat Genet. 2011 Feb;43(2):121-6. doi: 10.1038/ng.744. Epub 2011 Jan 9. (http://www.ncbi.nlm.nih.gov/pubmed/21217753?dopt=Abstract)
  • van de Laar IM, van der Linde D, Oei EH, Bos PK, Bessems JH, Bierma-Zeinstra SM, van Meer BL, Pals G, Oldenburg RA, Bekkers JA, Moelker A, de Graaf BM, Matyas G, Frohn-Mulder IM, Timmermans J, Hilhorst-Hofstee Y, Cobben JM, Bruggenwirth HT, van Laer L, Loeys B, De Backer J, Coucke PJ, Dietz HC, Willems PJ, Oostra BA, De Paepe A, Roos-Hesselink JW, Bertoli-Avella AM, Wessels MW. Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome. J Med Genet. 2012 Jan;49(1):47-57. doi: 10.1136/jmedgenet-2011-100382. (http://www.ncbi.nlm.nih.gov/pubmed/22167769?dopt=Abstract)
  • Wischmeijer A, Van Laer L, Tortora G, Bolar NA, Van Camp G, Fransen E, Peeters N, di Bartolomeo R, Pacini D, Gargiulo G, Turci S, Bonvicini M, Mariucci E, Lovato L, Brusori S, Ritelli M, Colombi M, Garavelli L, Seri M, Loeys BL. Thoracic aortic aneurysm in infancy in aneurysms-osteoarthritis syndrome due to a novel SMAD3 mutation: further delineation of the phenotype. Am J Med Genet A. 2013 May;161A(5):1028-35. doi: 10.1002/ajmg.a.35852. Epub 2013 Mar 29. (http://www.ncbi.nlm.nih.gov/pubmed/23554019?dopt=Abstract)

 

The resources on this site should not be used as a substitute for professional medical care or advice. Users seeking information about a personal genetic disease, syndrome, or condition should consult with a qualified healthcare professional. See How can I find a genetics professional in my area? (http://ghr.nlm.nih.gov/handbook/consult/findingprofessional) in the Handbook.

 
Reviewed: July 2014
Published: December 16, 2014