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SMAD4 gene

SMAD family member 4

Normal Function

The SMAD4 gene provides instructions for making a protein involved in transmitting chemical signals from the cell surface to the nucleus. The SMAD4 protein is part of a signaling pathway, called the transforming growth factor beta (TGF-β) pathway, that allows the environment outside the cell to affect gene activity and protein production within the cell. The signaling process begins when a TGF-β protein attaches (binds) to a receptor protein on the cell surface, which turns on (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 these cellular processes, the SMAD4 protein is involved in the development of many body systems.

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.

Health Conditions Related to Genetic Changes

Hereditary hemorrhagic telangiectasia

At least 27 mutations in the SMAD4 gene have been found to cause a form of hereditary hemorrhagic telangiectasia, a disorder characterized by certain blood vessel abnormalities. In particular, some smaller arteries (arterioles) abnormally flow directly into veins rather than into other vessels called capillaries. These abnormalities are called arteriovenous malformations. When they occur in vessels near the surface of the skin, where they are visible as red markings, they are known as telangiectases (the singular is telangiectasia).

The form of hereditary hemorrhagic telangiectasia caused by SMAD4 gene mutations is 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.

More About This Health Condition

Juvenile polyposis syndrome

At least 78 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.

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Myhre syndrome

At least four mutations in the SMAD4 gene have been identified in people with Myhre syndrome, a condition characterized by intellectual disability, a buildup of scar tissue (fibrosis) in the skin and internal organs, and other problems affecting multiple body systems and functions. These mutations affect the protein building block (amino acid) at protein position 496 or 500 by replacing it with a different amino acid. Studies suggest that these mutations result in an abnormally stable SMAD4 protein that remains active in the cell longer than it is needed. These mutations are classified as "gain-of-function" because they enhance the activity of the SMAD4 protein. Increased availability of active SMAD4 allows the protein more time to interact with other proteins and may result in abnormal TGF-β signaling in many cell types, which affects development of several body systems and leads to the signs and symptoms of Myhre syndrome.

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MedlinePlus Genetics provides information about Cholangiocarcinoma

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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

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 (described above). 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.

Other Names for This Gene

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

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Gene and Variant Databases


  • 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. Citation on PubMed
  • 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. doi: 10.1136/jmg.2007.052506. Epub 2007 Sep 14. Citation on PubMed or Free article on PubMed Central
  • 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. Citation on PubMed
  • Caputo V, Bocchinfuso G, Castori M, Traversa A, Pizzuti A, Stella L, Grammatico P, Tartaglia M. Novel SMAD4 mutation causing Myhre syndrome. Am J Med Genet A. 2014 Jul;164A(7):1835-40. doi: 10.1002/ajmg.a.36544. Epub 2014 Apr 8. Citation on PubMed
  • 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. Citation on PubMed or Free article on PubMed Central
  • Chow E, Macrae F. A review of juvenile polyposis syndrome. J Gastroenterol Hepatol. 2005 Nov;20(11):1634-40. doi: 10.1111/j.1440-1746.2005.03865.x. Citation on PubMed
  • 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. doi: 10.1016/S0140-6736(04)15732-2. Citation on PubMed
  • 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. doi: 10.1136/jmg.2004.018598. Citation on PubMed or Free article on PubMed Central
  • 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. doi: 10.1086/340258. Epub 2002 Mar 27. Citation on PubMed or Free article on PubMed Central
  • Le Goff C, Mahaut C, Abhyankar A, Le Goff W, Serre V, Afenjar A, Destree A, di Rocco M, Heron 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. Citation on PubMed
  • Lin AE, Alali A, Starr LJ, Shah N, Beavis A, Pereira EM, Lindsay ME, Klugman S. Gain-of-function pathogenic variants in SMAD4 are associated with neoplasia in Myhre syndrome. Am J Med Genet A. 2020 Feb;182(2):328-337. doi: 10.1002/ajmg.a.61430. Epub 2019 Dec 14. Erratum In: Am J Med Genet A. 2024 Jan 18;: Citation on PubMed
  • Lin AE, Brunetti-Pierri N, Lindsay ME, Schimmenti LA, Starr LJ. Myhre Syndrome. 2017 Apr 13 [updated 2022 Nov 24]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from Citation on PubMed
  • Lin AE, Michot C, Cormier-Daire V, L'Ecuyer TJ, Matherne GP, Barnes BH, Humberson JB, Edmondson AC, Zackai E, O'Connor MJ, Kaplan JD, Ebeid MR, Krier J, Krieg E, Ghoshhajra B, Lindsay ME. Gain-of-function mutations in SMAD4 cause a distinctive repertoire of cardiovascular phenotypes in patients with Myhre syndrome. Am J Med Genet A. 2016 Oct;170(10):2617-31. doi: 10.1002/ajmg.a.37739. Epub 2016 Jun 14. Citation on PubMed
  • 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. No abstract available. Citation on PubMed
  • Meerschaut I, Beyens A, Steyaert W, De Rycke R, Bonte K, De Backer T, Janssens S, Panzer J, Plasschaert F, De Wolf D, Callewaert B. Myhre syndrome: A first familial recurrence and broadening of the phenotypic spectrum. Am J Med Genet A. 2019 Dec;179(12):2494-2499. doi: 10.1002/ajmg.a.61377. Epub 2019 Oct 9. Citation on PubMed
  • 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. doi: 10.1002/ajmg.c.30020. Citation on PubMed
  • Pyatt RE, Pilarski R, Prior TW. Mutation screening in juvenile polyposis syndrome. J Mol Diagn. 2006 Feb;8(1):84-8. doi: 10.2353/jmoldx.2006.050072. Citation on PubMed or Free article on PubMed Central
  • 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. Citation on PubMed or Free article on PubMed Central
  • 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. doi: 10.1016/S0002-9440(10)62516-3. Citation on PubMed or Free article on PubMed Central

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