SMAD4

SMAD family member 4, the group of SMAD family

Basic information

Region (hg38): 18:51028393-51085045

Previous symbols: [ "MADH4" ]

Links

ENSG00000141646 ∙ NCBI:4089 ∙ OMIM:600993 ∙ HGNC:6770 ∙ Uniprot:Q13485 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Myhre syndrome (Strong), mode of inheritance: AD
• Myhre syndrome (Definitive), mode of inheritance: AD
• juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (Strong), mode of inheritance: AD
• generalized juvenile polyposis/juvenile polyposis coli (Strong), mode of inheritance: AD
• juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (Strong), mode of inheritance: AD
• hereditary hemorrhagic telangiectasia (Supportive), mode of inheritance: AD
• Myhre syndrome (Supportive), mode of inheritance: AD
• familial thoracic aortic aneurysm and aortic dissection (Supportive), mode of inheritance: AD
• generalized juvenile polyposis/juvenile polyposis coli (Supportive), mode of inheritance: AD
• juvenile polyposis syndrome (Definitive), mode of inheritance: AD
• juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (Definitive), mode of inheritance: AD
• juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (Strong), mode of inheritance: AD
• juvenile polyposis syndrome (Strong), mode of inheritance: AD
• pulmonary arterial hypertension (Disputed Evidence), mode of inheritance: AD
• Myhre syndrome (Definitive), mode of inheritance: AD
• juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Hereditary hemorrhagic telangiectasia, type 1; Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome; Polyposis, juvenile intestinal; Myhre syndrome	AD	Audiologic/Otolaryngologic; Cardiovascular; Gastrointestinal; Hematologic; Oncologic	Individuals with HHT and JPS/HHT may have a variety of vascular complications, including arteriovenous malformations, aortic dilatation, and bleeding diatheses, and surveillance and early intervention related to manifestations (eg, related to thromboembolism or hepatic disease) may decrease morbidity and mortality; In JPS and JPS/HHT, surveillance and early diagnosis/treatment of malignancy (eg, colon cancer) may be beneficial; In Myhre syndrome, individuals may manifest with multisystemic features, including hearing impairment (for which appropriate interventions may be beneficial related to speech and language development) as well as cardiovascular anomalies, and appropriate surveillance may allow prompt diagnosis and treatment	Audiologic/Otolaryngologic; Cardiovascular; Gastrointestinal; Hematologic; Oncologic	7372073; 7296942; 9582123; 11568925; 12136244; 15031030; 15235019; 16152648; 15723310; 15754356; 16613914; 16690726; 17873119; 18824676; 20101697; 21465659; 21490502; 22158539; 22810475; 21835029; 22243968; 20301525

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the SMAD4 gene.

• Juvenile polyposis syndrome (1205 variants)
• Hereditary cancer-predisposing syndrome (440 variants)
• Familial thoracic aortic aneurysm and aortic dissection;Hereditary cancer-predisposing syndrome (400 variants)
• not provided (289 variants)
• Hereditary cancer-predisposing syndrome;Familial thoracic aortic aneurysm and aortic dissection (287 variants)
• Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (253 variants)
• Generalized juvenile polyposis/juvenile polyposis coli (224 variants)
• Myhre syndrome (217 variants)
• not specified (184 variants)
• Juvenile Polyposis (36 variants)
• Telangiectasia, hereditary hemorrhagic, type 1 (36 variants)
• SMAD4-related condition (11 variants)
• Familial thoracic aortic aneurysm and aortic dissection (8 variants)
• Neoplasm of the large intestine (5 variants)
• Inborn genetic diseases (4 variants)
• Carcinoma of pancreas;Myhre syndrome;Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome;Juvenile polyposis syndrome (4 variants)
• Neoplasm of uterine cervix (3 variants)
• Lung adenocarcinoma (3 variants)
• Pancreatic adenocarcinoma (3 variants)
• Myhre syndrome;Generalized juvenile polyposis/juvenile polyposis coli;Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome;Carcinoma of pancreas (3 variants)
• Carcinoma of colon (3 variants)
• Carcinoma of esophagus (3 variants)
• Gastric adenocarcinoma (3 variants)
• Squamous cell carcinoma of the head and neck (3 variants)
• Myhre syndrome;Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome;Carcinoma of pancreas;Juvenile polyposis syndrome (3 variants)
• Heritable Thoracic Aortic Disease (3 variants)
• Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome;Carcinoma of pancreas;Juvenile polyposis syndrome;Myhre syndrome (3 variants)
• Breast neoplasm (3 variants)
• Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome;Juvenile polyposis syndrome;Myhre syndrome;Carcinoma of pancreas (2 variants)
• Myhre syndrome;Juvenile polyposis syndrome;Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome;Carcinoma of pancreas (2 variants)
• Early age onset of sporadic thoracic aortic dissections (2 variants)
• Myhre syndrome;Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome;Generalized juvenile polyposis/juvenile polyposis coli;Carcinoma of pancreas (2 variants)
• Pulmonary hypertension, primary, 1 (2 variants)
• Carcinoma of pancreas;Generalized juvenile polyposis/juvenile polyposis coli;Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome;Myhre syndrome (2 variants)
• Malignant tumor of breast (2 variants)
• Carcinoma of pancreas;Myhre syndrome;Generalized juvenile polyposis/juvenile polyposis coli;Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (2 variants)
• Heritable thoracic aortic disease without juvenile polyposis and hereditary hemorrhagic telangiectasia (1 variants)
• Lung cancer (1 variants)
• Juvenile polyposis of stomach (1 variants)
• Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome;Myhre syndrome;Carcinoma of pancreas;Juvenile polyposis syndrome (1 variants)
• Intellectual disability (1 variants)
• Vascular dementia (1 variants)
• Isolated thoracic aortic aneurysm (1 variants)
• Carcinoma of pancreas (1 variants)
• Colorectal cancer (1 variants)
• Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome;Carcinoma of pancreas;Myhre syndrome;Juvenile polyposis syndrome (1 variants)
• Neurodevelopmental delay (1 variants)
• Myhre syndrome;Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (1 variants)
• Pulmonary arterial hypertension (1 variants)
• Moyamoya angiopathy (1 variants)
• Gastrointestinal polyposis (1 variants)
• Juvenile polyposis syndrome;Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome;Carcinoma of pancreas;Myhre syndrome (1 variants)
• Generalized juvenile polyposis/juvenile polyposis coli;Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome;Myhre syndrome (1 variants)
• Gallbladder cancer (1 variants)
• Myhre syndrome;Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome;Juvenile polyposis syndrome;Carcinoma of pancreas (1 variants)
• Nephroblastoma (1 variants)
• Hereditary hemorrhagic telangiectasia;Generalized juvenile polyposis/juvenile polyposis coli (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the SMAD4 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			7	352		359
missense	5	17	645	5		672
nonsense	55	8	3			66
start loss			5			5
frameshift	93	15	3			111
inframe indel		1	7			8
splice donor/acceptor (+/-2bp)	4	18	3			25
splice region			44	48	2	94
non coding			155	212	46	413
Total	157	59	828	569	46

Variants in SMAD4

This is a list of pathogenic ClinVar variants found in the SMAD4 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
18-51030220-G-C		Myhre syndrome • Generalized juvenile polyposis/juvenile polyposis coli • Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	Uncertain significance (Jan 13, 2018)
18-51030242-GCAA-G		Myhre syndrome • Juvenile Polyposis • Telangiectasia, hereditary hemorrhagic, type 1	Uncertain significance (Jun 14, 2016)
18-51030247-A-G		Generalized juvenile polyposis/juvenile polyposis coli • Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome • Myhre syndrome	Uncertain significance (Jan 13, 2018)
18-51030256-C-G		Myhre syndrome • Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome • Generalized juvenile polyposis/juvenile polyposis coli	Uncertain significance (Jan 12, 2018)
18-51030275-C-A		Myhre syndrome • Generalized juvenile polyposis/juvenile polyposis coli • Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	Uncertain significance (Jan 12, 2018)
18-51030350-C-T		Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome • Myhre syndrome • Generalized juvenile polyposis/juvenile polyposis coli	Benign/Likely benign (Jan 13, 2018)
18-51030351-C-A		Generalized juvenile polyposis/juvenile polyposis coli • Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome • Myhre syndrome	Uncertain significance (Jan 13, 2018)
18-51030418-C-A		Generalized juvenile polyposis/juvenile polyposis coli • Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome • Myhre syndrome	Uncertain significance (Jan 13, 2018)
18-51030438-C-A		Myhre syndrome • Generalized juvenile polyposis/juvenile polyposis coli • Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome	Uncertain significance (Jan 12, 2018)
18-51030518-G-C		Myhre syndrome • Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome • Generalized juvenile polyposis/juvenile polyposis coli	Uncertain significance (Jan 13, 2018)
18-51030603-C-T		not specified	Benign (Mar 10, 2015)
18-51030616-G-A		not specified	Likely benign (Jan 13, 2017)
18-51030618-G-A		not specified	Likely benign (Aug 18, 2016)
18-51030629-C-T		Hereditary cancer-predisposing syndrome	Uncertain significance (Aug 07, 2021)
18-51030630-G-T		Hereditary cancer-predisposing syndrome	Likely benign (Oct 26, 2020)
18-51030629-C-CCTTGCAACGTTA		Hereditary cancer-predisposing syndrome	Uncertain significance (Oct 25, 2021)
18-51030635-A-G		Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome • Myhre syndrome • Generalized juvenile polyposis/juvenile polyposis coli • not specified	Conflicting classifications of pathogenicity (Jan 12, 2018)
18-51030638-TC-T		not specified	Likely benign (Jan 09, 2018)
18-51030639-CCC-TT		not specified	Likely benign (Dec 31, 2015)
18-51030642-C-T			Uncertain significance (Jan 03, 2018)
18-51030711-A-ACGG			Benign (Aug 19, 2019)
18-51030886-G-C		Hereditary cancer-predisposing syndrome	Likely benign (Dec 01, 2015)
18-51031163-A-G		Hereditary cancer-predisposing syndrome	Likely benign (Dec 01, 2015)
18-51031382-G-A		Hereditary cancer-predisposing syndrome	Likely benign (Dec 01, 2015)
18-51032618-A-G		Hereditary cancer-predisposing syndrome	Likely benign (Dec 01, 2015)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
SMAD4	protein_coding	protein_coding	ENST00000342988	11	117006

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.999	0.00119	125743	0	4	125747	0.0000159

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	4.13	107	312	0.342	0.0000164	3624
Missense in Polyphen		20	121.97	0.16398		1446
Synonymous	0.579	103	111	0.930	0.00000623	1069
Loss of Function	4.59	2	28.4	0.0705	0.00000138	334

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000578	0.0000578
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.00000880	0.00000879
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: In muscle physiology, plays a central role in the balance between atrophy and hypertrophy. When recruited by MSTN, promotes atrophy response via phosphorylated SMAD2/4. MSTN decrease causes SMAD4 release and subsequent recruitment by the BMP pathway to promote hypertrophy via phosphorylated SMAD1/5/8. Acts synergistically with SMAD1 and YY1 in bone morphogenetic protein (BMP)-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within BMP response element (BMPRE) of cardiac activating regions (By similarity). Common SMAD (co-SMAD) is the coactivator and mediator of signal transduction by TGF-beta (transforming growth factor). Component of the heterotrimeric SMAD2/SMAD3-SMAD4 complex that forms in the nucleus and is required for the TGF-mediated signaling (PubMed:25514493). Promotes binding of the SMAD2/SMAD4/FAST-1 complex to DNA and provides an activation function required for SMAD1 or SMAD2 to stimulate transcription. Component of the multimeric SMAD3/SMAD4/JUN/FOS complex which forms at the AP1 promoter site; required for synergistic transcriptional activity in response to TGF-beta. May act as a tumor suppressor. Positively regulates PDPK1 kinase activity by stimulating its dissociation from the 14-3-3 protein YWHAQ which acts as a negative regulator. {ECO:0000250, ECO:0000269|PubMed:17327236, ECO:0000269|PubMed:25514493, ECO:0000269|PubMed:9389648}.
• Disease: DISEASE: Pancreatic cancer (PNCA) [MIM:260350]: A malignant neoplasm of the pancreas. Tumors can arise from both the exocrine and endocrine portions of the pancreas, but 95% of them develop from the exocrine portion, including the ductal epithelium, acinar cells, connective tissue, and lymphatic tissue. {ECO:0000269|PubMed:8553070}. Note=The gene represented in this entry may be involved in disease pathogenesis.; DISEASE: Juvenile polyposis syndrome (JPS) [MIM:174900]: Autosomal dominant gastrointestinal hamartomatous polyposis syndrome in which patients are at risk for developing gastrointestinal cancers. The lesions are typified by a smooth histological appearance, predominant stroma, cystic spaces and lack of a smooth muscle core. Multiple juvenile polyps usually occur in a number of Mendelian disorders. Sometimes, these polyps occur without associated features as in JPS; here, polyps tend to occur in the large bowel and are associated with an increased risk of colon and other gastrointestinal cancers. {ECO:0000269|PubMed:12417513, ECO:0000269|PubMed:9811934}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome (JP/HHT) [MIM:175050]: JP/HHT syndrome phenotype consists of the coexistence of juvenile polyposis (JIP) and hereditary hemorrhagic telangiectasia (HHT) [MIM:187300] in a single individual. JIP and HHT are autosomal dominant disorders with distinct and non-overlapping clinical features. The former, an inherited gastrointestinal malignancy predisposition, is caused by mutations in SMAD4 or BMPR1A, and the latter is a vascular malformation disorder caused by mutations in ENG or ACVRL1. All four genes encode proteins involved in the transforming-growth- factor-signaling pathway. Although there are reports of patients and families with phenotypes of both disorders combined, the genetic etiology of this association is unknown. {ECO:0000269|PubMed:15031030}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Colorectal cancer (CRC) [MIM:114500]: A complex disease characterized by malignant lesions arising from the inner wall of the large intestine (the colon) and the rectum. Genetic alterations are often associated with progression from premalignant lesion (adenoma) to invasive adenocarcinoma. Risk factors for cancer of the colon and rectum include colon polyps, long-standing ulcerative colitis, and genetic family history. {ECO:0000269|PubMed:16959974}. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: Note=SMAD4 variants may be associated with susceptibility to pulmonary hypertension, a disorder characterized by plexiform lesions of proliferating endothelial cells in pulmonary arterioles. The lesions lead to elevated pulmonary arterial pression, right ventricular failure, and death. The disease can occur from infancy throughout life and it has a mean age at onset of 36 years. Penetrance is reduced. Although familial pulmonary hypertension is rare, cases secondary to known etiologies are more common and include those associated with the appetite-suppressant drugs. {ECO:0000269|PubMed:21898662}.; DISEASE: Myhre syndrome (MYHRS) [MIM:139210]: A syndrome characterized by pre- and postnatal growth deficiency, mental retardation, generalized muscle hypertrophy and striking muscular build, decreased joint mobility, cryptorchidism, and unusual facies. Dysmorphic facial features include microcephaly, midface hypoplasia, prognathism, and blepharophimosis. Typical skeletal anomalies are short stature, square body shape, broad ribs, iliac hypoplasia, brachydactyly, flattened vertebrae, and thickened calvaria. Other features, such as congenital heart disease, may also occur. {ECO:0000269|PubMed:22158539, ECO:0000269|PubMed:22243968}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Chronic myeloid leukemia - Homo sapiens (human);Gastric cancer - Homo sapiens (human);TGF-beta signaling pathway - Homo sapiens (human);Adherens junction - Homo sapiens (human);AGE-RAGE signaling pathway in diabetic complications - Homo sapiens (human);Cell cycle - Homo sapiens (human);FoxO signaling pathway - Homo sapiens (human);HTLV-I infection - Homo sapiens (human);Signaling pathways regulating pluripotency of stem cells - Homo sapiens (human);Hepatocellular carcinoma - Homo sapiens (human);Hippo signaling pathway - Homo sapiens (human);Apelin signaling pathway - Homo sapiens (human);Th17 cell differentiation - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Hepatitis B - Homo sapiens (human);Wnt signaling pathway - Homo sapiens (human);Pancreatic cancer - Homo sapiens (human);Colorectal cancer - Homo sapiens (human);EGF-Core;TGF-Core;Cell Cycle;Androgen receptor signaling pathway;Bone Morphogenic Protein (BMP) Signalling and Regulation;Heart Development;Endoderm Differentiation;Mesodermal Commitment Pathway;Ectoderm Differentiation;Extracellular vesicle-mediated signaling in recipient cells;Hepatitis C and Hepatocellular Carcinoma;Hematopoietic Stem Cell Gene Regulation by GABP alpha-beta Complex;TGF-beta Signaling Pathway;Hypothesized Pathways in Pathogenesis of Cardiovascular Disease;TGF-B Signaling in Thyroid Cells for Epithelial-Mesenchymal Transition;Canonical and Non-Canonical TGF-B signaling;BMP Signaling Pathway in Eyelid Development;ESC Pluripotency Pathways;Chromosomal and microsatellite instability in colorectal cancer;EMT transition in Colorectal Cancer;TGF-beta Receptor Signaling;Senescence and Autophagy in Cancer;DNA Damage Response (only ATM dependent);Developmental Biology;RUNX2 regulates bone development;Transcriptional regulation by RUNX2;RUNX3 regulates CDKN1A transcription;Signal Transduction;Gene expression (Transcription);RUNX3 regulates BCL2L11 (BIM) transcription;Transcriptional regulation by RUNX3;wnt signaling pathway;cell cycle: g1/s check point;alk in cardiac myocytes;nfkb activation by nontypeable hemophilus influenzae;ctcf: first multivalent nuclear factor;Generic Transcription Pathway;Signaling by Activin;Post-translational protein modification;Metabolism of proteins;RNA Polymerase II Transcription;SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription;Downregulation of SMAD2/3:SMAD4 transcriptional activity;TGF-beta super family signaling pathway canonical;Signaling by NODAL;TGF_beta_Receptor;Transcriptional activity of SMAD2/SMAD3:SMAD4 heterotrimer;BMP receptor signaling;tgf beta signaling pathway;BMP Signalling Pathway;Ub-specific processing proteases;LIF signaling;Deubiquitination;Transcriptional regulation of pluripotent stem cells;Signaling by TGF-beta Receptor Complex;BMP2 signaling TGF-beta MV;Signaling by BMP;Signaling by TGF-beta family members;BMP signaling Dro;TGF-beta receptor signaling activates SMADs;Wnt Canonical;ALK1 signaling events;Validated nuclear estrogen receptor alpha network;Validated targets of C-MYC transcriptional repression;Validated targets of C-MYC transcriptional activation;Regulation of cytoplasmic and nuclear SMAD2/3 signaling;HIF-1-alpha transcription factor network;Wnt Mammals;Regulation of nuclear SMAD2/3 signaling;ALK2 signaling events;TGF-beta receptor signaling;LKB1 signaling events (Consensus)

Recessive Scores

• pRec: 0.796

Intolerance Scores

• loftool: 0.116
• rvis_EVS: -0.32
• rvis_percentile_EVS: 31.69

Haploinsufficiency Scores

• pHI: 1.00
• hipred: Y
• hipred_score: 0.831
• ghis: 0.650

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• gene_indispensability_pred: E
• gene_indispensability_score: 1.00

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Smad4
• Phenotype: muscle phenotype; craniofacial phenotype; homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); neoplasm; endocrine/exocrine gland phenotype; digestive/alimentary phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; immune system phenotype; skeleton phenotype; renal/urinary system phenotype; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; reproductive system phenotype

Zebrafish Information Network

• Gene name: smad4a
• Affected structure: neuroectoderm
• Phenotype tag: abnormal
• Phenotype quality: wholly dorsalized

Gene ontology

• Biological process: negative regulation of transcription by RNA polymerase II;ovarian follicle development;branching involved in ureteric bud morphogenesis;response to hypoxia;in utero embryonic development;gastrulation with mouth forming second;outflow tract septum morphogenesis;atrioventricular valve formation;epithelial to mesenchymal transition involved in endocardial cushion formation;left ventricular cardiac muscle tissue morphogenesis;positive regulation of cell proliferation involved in heart valve morphogenesis;brainstem development;cellular iron ion homeostasis;transforming growth factor beta receptor signaling pathway;SMAD protein complex assembly;spermatogenesis;single fertilization;axon guidance;endoderm development;mesoderm development;cell population proliferation;negative regulation of cell population proliferation;negative regulation of cardiac muscle hypertrophy;positive regulation of epithelial to mesenchymal transition;positive regulation of pathway-restricted SMAD protein phosphorylation;neural crest cell differentiation;protein deubiquitination;regulation of transforming growth factor beta receptor signaling pathway;negative regulation of cell growth;BMP signaling pathway;positive regulation of transforming growth factor beta receptor signaling pathway;positive regulation of BMP signaling pathway;somite rostral/caudal axis specification;regulation of transforming growth factor beta2 production;positive regulation of luteinizing hormone secretion;somatic stem cell population maintenance;intracellular signal transduction;atrioventricular canal development;endothelial cell activation;embryonic digit morphogenesis;negative regulation of transcription, DNA-templated;positive regulation of transcription, DNA-templated;positive regulation of transcription by RNA polymerase II;positive regulation of follicle-stimulating hormone secretion;developmental growth;neuron fate commitment;sebaceous gland development;formation of anatomical boundary;regulation of binding;positive regulation of histone H3-K4 methylation;regulation of hair follicle development;uterus development;positive regulation of SMAD protein signal transduction;SMAD protein signal transduction;ventricular septum morphogenesis;negative regulation of cell death;endocardial cell differentiation;female gonad morphogenesis;pri-miRNA transcription by RNA polymerase II;secondary palate development;interleukin-6-mediated signaling pathway;protein homotrimerization;negative regulation of ERK1 and ERK2 cascade;response to transforming growth factor beta;cellular response to BMP stimulus;metanephric mesenchyme morphogenesis;nephrogenic mesenchyme morphogenesis;seminiferous tubule development;positive regulation of transcription from RNA polymerase II promoter involved in cellular response to chemical stimulus;negative regulation of cardiac myofibril assembly;positive regulation of histone H3-K9 acetylation
• Cellular component: nuclear chromatin;nucleus;nucleoplasm;transcription factor complex;cytoplasm;centrosome;cytosol;activin responsive factor complex;SMAD protein complex
• Molecular function: RNA polymerase II proximal promoter sequence-specific DNA binding;DNA-binding transcription factor activity, RNA polymerase II-specific;proximal promoter sequence-specific DNA binding;RNA polymerase II transcription factor binding;DNA-binding transcription activator activity, RNA polymerase II-specific;DNA binding;chromatin binding;DNA-binding transcription factor activity;transcription coregulator activity;protein binding;collagen binding;transforming growth factor beta receptor, common-partner cytoplasmic mediator activity;identical protein binding;protein homodimerization activity;sulfate binding;sequence-specific DNA binding;transcription regulatory region DNA binding;metal ion binding;protein heterodimerization activity;I-SMAD binding;R-SMAD binding