SMAD family member 4
Last updated 2 May 2023
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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.
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 tumour suppressor. Transcription factors help control the activity of particular genes, and tumour suppressors keep cells from growing and dividing too fast or in an uncontrolled way.
Conditions referring to this gene or chromosome
Other names
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)
SMAD4_HUMAN
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Further reading and references
- SMAD family member 4; MedlinePlus, National Library of Medicine.
- 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. doi: 10.1136/jmg.2007.052506. 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.
- 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.
- 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. doi: 10.1111/j.1440-1746.2005.03865.x.
- 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.
- 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.
- 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.
- 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.
- 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.
- Lin AE, Brunetti-Pierri N, Lindsay ME, Schimmenti LA, Starr LJ. Myhre Syndrome. 2017 Apr 13 [updated 2024 Dec 12]. In: Adam MP, Bick S, Mirzaa GM, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Available from http://www.ncbi.nlm.nih.gov/books/NBK425723/
- 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.
- 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.
- 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.
- 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.
- 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.
- 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. doi: 10.1016/S0002-9440(10)62516-3.
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