Gene: SMAD4

Alternate names for this Gene: DPC4|JIP|MADH4|MYHRS

Gene Summary: This gene encodes a member of the Smad family of signal transduction proteins. Smad proteins are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to transforming growth factor (TGF)-beta signaling. The product of this gene forms homomeric complexes and heteromeric complexes with other activated Smad proteins, which then accumulate in the nucleus and regulate the transcription of target genes. This protein binds to DNA and recognizes an 8-bp palindromic sequence (GTCTAGAC) called the Smad-binding element (SBE). The protein acts as a tumor suppressor and inhibits epithelial cell proliferation. It may also have an inhibitory effect on tumors by reducing angiogenesis and increasng blood vessel hyperpermeability. The encoded protein is a crucial component of the bone morphogenetic protein signaling pathway. The Smad proteins are subject to complex regulation by post-translational modifications. Mutations or deletions in this gene have been shown to result in pancreatic cancer, juvenile polyposis syndrome, and hereditary hemorrhagic telangiectasia syndrome.

Gene is located in Chromosome: 18

Location in Chromosome : 18q21.2

Description of this Gene: SMAD family member 4

Type of Gene: protein-coding

rs1057519962 in SMAD4 gene and Adenocarcinoma of lung (disorder) PMID 26619011 2016 Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.

rs1057519962 in SMAD4 gene and Adenocarcinoma of pancreas PMID 26619011 2016 Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.

rs1057519962 in SMAD4 gene and Adenocarcinoma of prostate PMID 26619011 2016 Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.

rs1057519739 in SMAD4 gene and Colorectal Neoplasms PMID 8898652 1996 Somatic alterations of the DPC4 gene in human colorectal cancers in vivo.

PMID 17994767 2007 Novel mutations in Smad proteins that inhibit signaling by the transforming growth factor beta in mammalian cells.

PMID 12821112 2003 Role of Smad4 (DPC4) inactivation in human cancer.

PMID 9679244 1998 TGF-beta signaling and cancer: structural and functional consequences of mutations in Smads.

PMID 14715079 2004 Molecular and functional consequences of Smad4 C-terminal missense mutations in colorectal tumour cells.

PMID 10775259 2000 Transcriptional control by the TGF-beta/Smad signaling system.

PMID 10479724 1999 Inactivation of both alleles of the DPC4/SMAD4 gene in advanced colorectal cancers: identification of seven novel somatic mutations in tumors from Japanese patients.

PMID 26619011 2016 Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.

rs397518413 in SMAD4 gene and Dysmorphic features PMID 24398790 2014 SMAD4 mutations causing Myhre syndrome result in disorganization of extracellular matrix improved by losartan.

PMID 26420300 2015 Myhre syndrome: Clinical features and restrictive cardiopulmonary complications.

PMID 24424121 2014 Myhre and LAPS syndromes: clinical and molecular review of 32 patients.

PMID 22585601 2012 Mutations of SMAD4 account for both LAPS and Myhre syndromes.

PMID 22243968 2012 A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome.

PMID 22581936 2012 Clinical application of exome sequencing in undiagnosed genetic conditions.

PMID 24715504 2014 Novel SMAD4 mutation causing Myhre syndrome.

PMID 27562837 2016 Natural history and life-threatening complications in Myhre syndrome and review of the literature.

PMID 22846733 2013 Genetic testing by cancer site: colon (polyposis syndromes).

PMID 22158539 2011 Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome.

PMID 15031030 2004 A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4).

PMID 16613914 2006 SMAD4 mutations found in unselected HHT patients.

PMID 17873119 2007 High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome.

rs12968012 in SMAD4 gene and Eczema PMID 30595370 2019 Leveraging Polygenic Functional Enrichment to Improve GWAS Power.

rs1057519962 in SMAD4 gene and Esophageal carcinoma PMID 26619011 2016 Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.

rs1057519962 in SMAD4 gene and Gastric Adenocarcinoma PMID 26619011 2016 Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.

rs11875522 in SMAD4 gene and High density lipoprotein measurement PMID 23063622 2012 Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci.

rs121912580 in SMAD4 gene and JUVENILE POLYPOSIS/HEREDITARY HEMORRHAGIC TELANGIECTASIA SYNDROME (disorder) PMID 15031030 2004 A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4).

rs1060500740 in SMAD4 gene and Juvenile polyposis syndrome PMID 16436638 2006 Mutation screening in juvenile polyposis syndrome.

PMID 21572342 2012 Juvenile polyposis syndrome, SMAD4 mutations, and hereditary hemorrhagic telangiectasia.

PMID 18178612 2008 Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis.

PMID 9811934 1998 Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases.

PMID 12417513 2002 Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis.

PMID 16152648 2005 Vessels' morphology in SMAD4 and BMPR1A-related juvenile polyposis.

PMID 22810475 2012 The prevalence of hereditary hemorrhagic telangiectasia in juvenile polyposis syndrome.

PMID 19135894 2009 FAM/USP9x, a deubiquitinating enzyme essential for TGFbeta signaling, controls Smad4 monoubiquitination.

PMID 12821112 2003 Role of Smad4 (DPC4) inactivation in human cancer.

PMID 15031030 2004 A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4).

PMID 16287957 2005 Molecular classification of patients with unexplained hamartomatous and hyperplastic polyposis.

PMID 22243968 2012 A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome.

PMID 9389648 1997 Dual role of the Smad4/DPC4 tumor suppressor in TGFbeta-inducible transcriptional complexes.

PMID 27302097 2016 Gain-of-function mutations in SMAD4 cause a distinctive repertoire of cardiovascular phenotypes in patients with Myhre syndrome.

PMID 22158539 2011 Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome.

PMID 22683461 2012 Retinal involvement in two unrelated patients with Myhre syndrome.

PMID 24398790 2014 SMAD4 mutations causing Myhre syndrome result in disorganization of extracellular matrix improved by losartan.

PMID 26636501 2016 Severe constipation in a patient with Myhre syndrome: a case report.

PMID 22585601 2012 Mutations of SMAD4 account for both LAPS and Myhre syndromes.

PMID 17362581 2007 Development of a denaturing high-performance liquid chromatography screening method for SMAD4 in juvenile polyposis syndrome.

PMID 17873119 2007 High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome.

PMID 16613914 2006 SMAD4 mutations found in unselected HHT patients.

PMID 20101697 2010 Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome.

PMID 15014009 2004 Missense mutations of MADH4: characterization of the mutational hot spot and functional consequences in human tumors.

PMID 10764709 2000 Analysis of genetic and phenotypic heterogeneity in juvenile polyposis.

PMID 10797267 2000 Germline mutations of the dpc4 gene in Korean juvenile polyposis patients.

PMID 27595937 2016 Smad4 suppresses the tumorigenesis and aggressiveness of neuroblastoma through repressing the expression of heparanase.

PMID 24424121 2014 Myhre and LAPS syndromes: clinical and molecular review of 32 patients.

PMID 24715504 2014 Novel SMAD4 mutation causing Myhre syndrome.

PMID 18355998 2008 Gastric involvement in juvenile polyposis associated with germline SMAD4 mutations: an entity characterized by a mixed hypertrophic and polypoid gastropathy.

PMID 23399955 2013 Prevalence of germline PTEN, BMPR1A, SMAD4, STK11, and ENG mutations in patients with moderate-load colorectal polyps.

PMID 14526373 2003 From developmental disorder to heritable cancer: it's all in the BMP/TGF-beta family.

PMID 15235019 2004 The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations.

PMID 18823382 2009 The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis.

PMID 11583957 2001 Comprehensive analysis of SMAD4 mutations and protein expression in juvenile polyposis: evidence for a distinct genetic pathway and polyp morphology in SMAD4 mutation carriers.

PMID 22316667 2012 Germline mutations in SMAD4 disrupt bone morphogenetic protein signaling.

PMID 9214508 1997 A structural basis for mutational inactivation of the tumour suppressor Smad4.

PMID 23239472 2013 Thoracic aortic disease in two patients with juvenile polyposis syndrome and SMAD4 mutations.

PMID 9582123 1998 Mutations in the SMAD4/DPC4 gene in juvenile polyposis.

PMID 22748914 2012 A unifying working hypothesis for juvenile polyposis syndrome and Ménétrier's disease: specific localization or concomitant occurrence of a separate entity?

PMID 28944238 2017 Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes.

PMID 27375208 2016 A SMAD4 mutation indicative of juvenile polyposis syndrome in a family previously diagnosed with Menetrier's disease.

PMID 26681312 2016 Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.

rs377767347 in SMAD4 gene and Mammary Neoplasms PMID 26619011 2016 Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.

rs281875320 in SMAD4 gene and Myhre syndrome PMID 22243968 2012 A restricted spectrum of mutations in the SMAD4 tumor-suppressor gene underlies Myhre syndrome.

PMID 22158539 2011 Mutations at a single codon in Mad homology 2 domain of SMAD4 cause Myhre syndrome.

PMID 24715504 2014 Novel SMAD4 mutation causing Myhre syndrome.

PMID 24424121 2014 Myhre and LAPS syndromes: clinical and molecular review of 32 patients.

rs1060500733 in SMAD4 gene and Neoplastic Syndromes, Hereditary PMID 24525918 2014 Appreciating the broad clinical features of SMAD4 mutation carriers: a multicenter chart review.

PMID 20685751 2010 SMAD4 mutation and the combined syndrome of juvenile polyposis syndrome and hereditary haemorrhagic telangiectasia.

PMID 20101697 2010 Overlapping spectra of SMAD4 mutations in juvenile polyposis (JP) and JP-HHT syndrome.

PMID 12417513 2002 Germline SMAD4 or BMPR1A mutations and phenotype of juvenile polyposis.

PMID 22316667 2012 Germline mutations in SMAD4 disrupt bone morphogenetic protein signaling.

PMID 18178612 2008 Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis.

PMID 16436638 2006 Mutation screening in juvenile polyposis syndrome.

PMID 10441006 1999 SMAD genes in juvenile polyposis.

PMID 9582123 1998 Mutations in the SMAD4/DPC4 gene in juvenile polyposis.

PMID 10797267 2000 Germline mutations of the dpc4 gene in Korean juvenile polyposis patients.

PMID 17873119 2007 High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome.

PMID 11274206 2001 Formation of a stable heterodimer between Smad2 and Smad4.

PMID 9811934 1998 Mutations in DPC4 (SMAD4) cause juvenile polyposis syndrome, but only account for a minority of cases.

PMID 15235019 2004 The prevalence of MADH4 and BMPR1A mutations in juvenile polyposis and absence of BMPR2, BMPR1B, and ACVR1 mutations.

PMID 15031030 2004 A combined syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia associated with mutations in MADH4 (SMAD4).

PMID 23239472 2013 Thoracic aortic disease in two patients with juvenile polyposis syndrome and SMAD4 mutations.

PMID 16152648 2005 Vessels' morphology in SMAD4 and BMPR1A-related juvenile polyposis.

PMID 21465659 2011 SMAD4 mutation segregating in a family with juvenile polyposis, aortopathy, and mitral valve dysfunction.

PMID 10479724 1999 Inactivation of both alleles of the DPC4/SMAD4 gene in advanced colorectal cancers: identification of seven novel somatic mutations in tumors from Japanese patients.

PMID 10764709 2000 Analysis of genetic and phenotypic heterogeneity in juvenile polyposis.

PMID 25931195 2015 Prevalence of thoracic aortopathy in patients with juvenile Polyposis Syndrome-Hereditary Hemorrhagic Telangiectasia due to SMAD4.

PMID 24580733 2014 Myhre syndrome.

PMID 24715504 2014 Novel SMAD4 mutation causing Myhre syndrome.

PMID 24841914 2014 Bilateral otospongiosis and a unilateral vestibular schwannoma in a patient with Myhre syndrome.

PMID 24424121 2014 Myhre and LAPS syndromes: clinical and molecular review of 32 patients.

PMID 24398790 2014 SMAD4 mutations causing Myhre syndrome result in disorganization of extracellular matrix improved by losartan.

PMID 26900293 2016 Mutation analysis of 13 driver genes of colorectal cancer-related pathways in Taiwanese patients.

PMID 26572829 2016 JP-HHT phenotype in Danish patients with SMAD4 mutations.

PMID 28944238 2017 Targeted sequencing of 36 known or putative colorectal cancer susceptibility genes.

PMID 28152038 2017 Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels.

PMID 27375208 2016 A SMAD4 mutation indicative of juvenile polyposis syndrome in a family previously diagnosed with Menetrier's disease.

PMID 26681312 2016 Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing.

PMID 23399955 2013 Prevalence of germline PTEN, BMPR1A, SMAD4, STK11, and ENG mutations in patients with moderate-load colorectal polyps.

PMID 22748914 2012 A unifying working hypothesis for juvenile polyposis syndrome and Ménétrier's disease: specific localization or concomitant occurrence of a separate entity?

PMID 23139211 2013 SMAD2, SMAD3 and SMAD4 mutations in colorectal cancer.

rs11875522 in SMAD4 gene and Serum HDL cholesterol measurement PMID 23063622 2012 Large-scale gene-centric meta-analysis across 32 studies identifies multiple lipid loci.

rs377767347 in SMAD4 gene and Squamous cell carcinoma of the head and neck PMID 26619011 2016 Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.

rs377767347 in SMAD4 gene and Uterine Cervical Neoplasm PMID 26619011 2016 Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.