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Genetics Home Reference: your guide to understanding genetic conditions     A service of the U.S. National Library of Medicine®


Reviewed January 2013

What is the official name of the SMAD4 gene?

The official name of this gene is “SMAD family member 4.”

SMAD4 is the gene's official symbol. The SMAD4 gene is also known by other names, listed below.

What is the normal function of the SMAD4 gene?

The SMAD4 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 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. The SMAD proteins bind to the SMAD4 protein and form a protein complex, which then moves to the cell nucleus. In the nucleus, the SMAD protein complex binds to specific areas of DNA where it controls the activity of particular genes and regulates cell growth and division (proliferation).

By controlling gene activity and regulating cell proliferation, the SMAD4 protein serves both as a transcription factor and as a tumor suppressor. Transcription factors help control the activity of particular genes, and tumor suppressors keep cells from growing and dividing too fast or in an uncontrolled way.

Does the SMAD4 gene share characteristics with other genes?

The SMAD4 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? ( in the Handbook.

How are changes in the SMAD4 gene related to health conditions?

hereditary hemorrhagic telangiectasia - caused by mutations in the SMAD4 gene

At least five mutations in the SMAD4 gene have been found to cause a form of hereditary hemorrhagic telangiectasia called juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome. People with this disorder have the blood vessel problems associated with hereditary hemorrhagic telangiectasia as well as an increased risk of developing intestinal growths (polyps) at an early age; the polyps may become cancerous.

SMAD4 gene mutations that cause this disorder affect the TGF-β signaling pathway. Disruption of this pathway may interfere with both the tumor suppressor function of the SMAD4 protein and the appropriate development of the boundaries between veins and arteries, resulting in the signs and symptoms of juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome.

juvenile polyposis syndrome - caused by mutations in the SMAD4 gene

More than 60 mutations in the SMAD4 gene have been found to cause juvenile polyposis syndrome, a disorder characterized by multiple noncancerous (benign) growths called juvenile polyps. Most SMAD4 gene mutations that cause juvenile polyposis syndrome result in the production of an abnormally short, nonfunctional protein. A lack of functional SMAD4 protein prevents binding to other SMAD proteins and interferes with the transmission of chemical signals from the cell surface to the nucleus. The SMAD protein complex is not activated and cannot be transported to the nucleus, where it is needed to regulate cell proliferation and the activity of certain genes. This unregulated cell growth can lead to polyp formation in people with juvenile polyposis syndrome.

Myhre syndrome - caused by mutations in the SMAD4 gene

At least three mutations in the SMAD4 gene have been identified in people with Myhre syndrome, a condition with features including intellectual disability, short stature, and hearing loss. Each of these mutations affects the protein building block (amino acid) isoleucine at protein position 500 by replacing it with a different amino acid. Some researchers believe that the SMAD4 gene mutations that cause Myhre syndrome impair the ability of the SMAD4 protein to bind properly with the other SMAD proteins and other proteins involved in the signaling pathway. Other studies have suggested that these mutations result in an abnormally stable SMAD4 protein that remains active in the cell longer. Changes in SMAD4 binding or availability may result in abnormal signaling in many cell types, which affects development of many body systems and leads to the signs and symptoms of Myhre syndrome.

cancers - increased risk from variations of the SMAD4 gene

People with mutations in the SMAD4 gene appear to have an increased risk of developing various cancers. Some of these gene mutations are inherited, while others are acquired during a person's lifetime. Such acquired (somatic) mutations are present only in certain cells. Cells with mutations in the SMAD4 gene, whether inherited or somatic, may proliferate out of control and result in a tumor, often in the colon or pancreas.

other disorders - caused by mutations in the SMAD4 gene

SMAD4 gene mutations have also been identified in a small number of individuals with juvenile polyposis and blood vessel abnormalities other than hereditary hemorrhagic telangiectasia. These abnormalities include weakening and stretching (dilation) of the aorta, which is the large blood vessel that distributes blood from the heart to the rest of the body. Aortic dilation may lead to a bulge in the blood vessel wall (an aneurysm), or may cause the aortic valve to leak, which can result in a sudden tearing of the layers in the aorta wall (aortic dissection). Aortic aneurysm and dissection can be life-threatening. Impaired functioning of the mitral valve, which connects two of the four chambers of the heart, has also been seen in combination with juvenile polyposis caused by SMAD4 gene mutations.

Where is the SMAD4 gene located?

Cytogenetic Location: 18q21.1

Molecular Location on chromosome 18: base pairs 51,030,213 to 51,085,042

(Homo sapiens Annotation Release 107, GRCh38.p2) (NCBI (

The SMAD4 gene is located on the long (q) arm of chromosome 18 at position 21.1.

The SMAD4 gene is located on the long (q) arm of chromosome 18 at position 21.1.

More precisely, the SMAD4 gene is located from base pair 51,030,213 to base pair 51,085,042 on chromosome 18.

See How do geneticists indicate the location of a gene? ( in the Handbook.

Where can I find additional information about SMAD4?

You and your healthcare professional may find the following resources about SMAD4 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 SMAD4 gene or gene products?

  • DPC4
  • JIP
  • MADH4
  • MAD (mothers against decapentaplegic, Drosophila) homolog 4
  • MAD, mothers against decapentaplegic homolog 4
  • MAD, mothers against decapentaplegic homolog 4 (Drosophila)
  • Mothers against decapentaplegic, Drosophila, homolog of, 4
  • SMAD, mothers against DPP homolog 4 (Drosophila)

See How are genetic conditions and genes named? ( in the Handbook.

What glossary definitions help with understanding SMAD4?

amino acid ; aneurysm ; aorta ; aortic dissection ; arteries ; benign ; cell ; cell nucleus ; cell proliferation ; colon ; dilation ; disability ; DNA ; gene ; growth factor ; hereditary ; inherited ; isoleucine ; juvenile ; mitral valve ; nucleus ; pancreas ; polyp ; polyposis ; proliferate ; proliferation ; protein ; receptor ; short stature ; stature ; syndrome ; telangiectasia ; transcription ; transcription factor ; tumor ; veins

You may find definitions for these and many other terms in the Genetics Home Reference Glossary.


  • Andrabi S, Bekheirnia MR, Robbins-Furman P, Lewis RA, Prior TW, Potocki L. SMAD4 mutation segregating in a family with juvenile polyposis, aortopathy, and mitral valve dysfunction. Am J Med Genet A. 2011 May;155A(5):1165-9. doi: 10.1002/ajmg.a.33968. Epub 2011 Apr 4. (
  • Aretz S, Stienen D, Uhlhaas S, Stolte M, Entius MM, Loff S, Back W, Kaufmann A, Keller KM, Blaas SH, Siebert R, Vogt S, Spranger S, Holinski-Feder E, Sunde L, Propping P, Friedl W. High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet. 2007 Nov;44(11):702-9. Epub 2007 Sep 14. (
  • Calva-Cerqueira D, Chinnathambi S, Pechman B, Bair J, Larsen-Haidle J, Howe JR. The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis. Clin Genet. 2009 Jan;75(1):79-85. doi: 10.1111/j.1399-0004.2008.01091.x. Epub 2008 Sep 24. (
  • Cancer Genome Anatomy Project (
  • Caputo V, Cianetti L, Niceta M, Carta C, Ciolfi A, Bocchinfuso G, Carrani E, Dentici ML, Biamino E, Belligni E, Garavelli L, Boccone L, Melis D, Andria G, Gelb BD, Stella L, Silengo M, Dallapiccola B, Tartaglia M. A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome. Am J Hum Genet. 2012 Jan 13;90(1):161-9. doi: 10.1016/j.ajhg.2011.12.011. (
  • Chow E, Macrae F. A review of juvenile polyposis syndrome. J Gastroenterol Hepatol. 2005 Nov;20(11):1634-40. Review. (
  • Gallione CJ, Repetto GM, Legius E, Rustgi AK, Schelley SL, Tejpar S, Mitchell G, Drouin E, Westermann CJ, Marchuk DA. A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4). Lancet. 2004 Mar 13;363(9412):852-9. (
  • Howe JR, Sayed MG, Ahmed AF, Ringold J, Larsen-Haidle J, Merg A, Mitros FA, Vaccaro CA, Petersen GM, Giardiello FM, Tinley ST, Aaltonen LA, Lynch HT. The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations. J Med Genet. 2004 Jul;41(7):484-91. (
  • Howe JR, Shellnut J, Wagner B, Ringold JC, Sayed MG, Ahmed AF, Lynch PM, Amos CI, Sistonen P, Aaltonen LA. Common deletion of SMAD4 in juvenile polyposis is a mutational hotspot. Am J Hum Genet. 2002 May;70(5):1357-62. Epub 2002 Mar 27. (
  • Le Goff C, Mahaut C, Abhyankar A, Le Goff W, Serre V, Afenjar A, Destrée A, di Rocco M, Héron D, Jacquemont S, Marlin S, Simon M, Tolmie J, Verloes A, Casanova JL, Munnich A, Cormier-Daire V. Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome. Nat Genet. 2011 Dec 11;44(1):85-8. doi: 10.1038/ng.1016. (
  • Lindor NM, Gunawardena SR, Thibodeau SN. Mutations of SMAD4 account for both LAPS and Myhre syndromes. Am J Med Genet A. 2012 Jun;158A(6):1520-1. doi: 10.1002/ajmg.a.35374. Epub 2012 May 14. (
  • Merg A, Howe JR. Genetic conditions associated with intestinal juvenile polyps. Am J Med Genet C Semin Med Genet. 2004 Aug 15;129C(1):44-55. Review. (
  • NCBI Gene (
  • Pyatt RE, Pilarski R, Prior TW. Mutation screening in juvenile polyposis syndrome. J Mol Diagn. 2006 Feb;8(1):84-8. (
  • Teekakirikul P, Milewicz DM, Miller DT, Lacro RV, Regalado ES, Rosales AM, Ryan DP, Toler TL, Lin AE. Thoracic aortic disease in two patients with juvenile polyposis syndrome and SMAD4 mutations. Am J Med Genet A. 2013 Jan;161A(1):185-91. doi: 10.1002/ajmg.a.35659. Epub 2012 Dec 13. (
  • Woodford-Richens KL, Rowan AJ, Poulsom R, Bevan S, Salovaara R, Aaltonen LA, Houlston RS, Wright NA, Tomlinson IP. Comprehensive analysis of SMAD4 mutations and protein expression in juvenile polyposis: evidence for a distinct genetic pathway and polyp morphology in SMAD4 mutation carriers. Am J Pathol. 2001 Oct;159(4):1293-300. (


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? ( in the Handbook.

Reviewed: January 2013
Published: February 8, 2016