familial thoracic aortic aneurysm and dissection Genetics Home Reference provides information about familial thoracic aortic aneurysm and dissection. Loeys-Dietz syndrome At least 11 mutations in the SMAD3 gene have been found to cause Loeys-Dietz syndrome type III. This disorder affects connective tissue, which gives structure and support to blood vessels, the skeleton, and many other parts of the body. Loeys-Dietz syndrome type III is characterized by abnormal blood vessels and skeletal and joint deformities. Some of the mutations that cause this disorder insert or delete small amounts of genetic material in the SMAD3 gene, while other mutations result in a change to single protein building blocks (amino acids) in the SMAD3 protein. These mutations lead to the production of a nonfunctional SMAD3 protein. Despite a reduction in SMAD3 function, the TGF-β pathway is overactive. Researchers speculate that the activity of proteins in this signaling pathway is increased to compensate for the lack of SMAD3 activity; however the exact mechanism responsible for the increase in signaling is unclear. The overactive signaling pathway leads to dysregulated cell proliferation and gene activation, specifically affecting blood vessel and cartilage development. These changes lead to the abnormalities typical of Loeys-Dietz syndrome type III.

     The SMAD3 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 cell function, including 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 (including the SMAD3 protein). These SMAD proteins bind together to form a protein complex, which then moves to the cell nucleus. In the nucleus, the SMAD protein complex binds to specific areas of DNA to control the activity of particular genes and regulate cell proliferation. By controlling gene activity and regulating cell proliferation, the SMAD3 protein serves both as a transcription factor and as a tumor suppressor. Transcription factors help control when particular genes are turned on or off, and tumor suppressors keep cells from growing and dividing too fast or in an uncontrolled way.

The following transcription factors affect gene expression:

• ER-alpha
• C/EBPbeta
• C/EBPalpha
• STAT5A
• Zic1
• c-Myc
• Sp1
• Sox9

Molecular Function:

• Rna Polymerase Ii Core Promoter Proximal Region Sequence-Specific Dna Binding
• Transcription Factor Activity, Rna Polymerase Ii Core Promoter Sequence-Specific
• Core Promoter Proximal Region Sequence-Specific Dna Binding
• Rna Polymerase Ii Activating Transcription Factor Binding
• Transcription Factor Activity, Sequence-Specific Dna Binding
• Transforming Growth Factor Beta Receptor Binding
• Transcription Factor Binding
• Zinc Ion Binding
• Protein Kinase Binding
• Phosphatase Binding
• Transforming Growth Factor Beta Receptor, Pathway-Specific Cytoplasmic Mediator Activity
• Chromatin Dna Binding
• Ubiquitin Protein Ligase Binding
• Enhancer Binding
• Identical Protein Binding
• Protein Homodimerization Activity
• Ubiquitin Binding
• Bhlh Transcription Factor Binding
• Sequence-Specific Dna Binding
• Transcription Regulatory Region Dna Binding
• Co-Smad Binding
• R-Smad Binding

Biological Processes:

• Negative Regulation Of Transcription From Rna Polymerase Ii Promoter
• Ureteric Bud Development
• Response To Hypoxia
• In Utero Embryonic Development
• Mesoderm Formation
• Somitogenesis
• Liver Development
• Heart Looping
• Osteoblast Development
• Immune System Development
• Transcription, Dna-Templated
• Regulation Of Transcription From Rna Polymerase Ii Promoter
• Transport
• Activation Of Cysteine-Type Endopeptidase Activity Involved In Apoptotic Process
• Immune Response
• Smad Protein Complex Assembly
• Cell Cycle Arrest
• Transforming Growth Factor Beta Receptor Signaling Pathway
• Endoderm Development
• Embryonic Pattern Specification
• Positive Regulation Of Gene Expression
• Positive Regulation Of Alkaline Phosphatase Activity
• Positive Regulation Of Epithelial To Mesenchymal Transition
• Regulation Of Striated Muscle Tissue Development
• Regulation Of Transforming Growth Factor Beta Receptor Signaling Pathway
• Evasion Or Tolerance Of Host Defenses By Virus
• Signal Transduction Involved In Regulation Of Gene Expression
• Negative Regulation Of Cell Growth
• Positive Regulation Of Cell Migration
• Positive Regulation Of Bone Mineralization
• Negative Regulation Of Transforming Growth Factor Beta Receptor Signaling Pathway
• Thyroid Gland Development
• Primary Mirna Processing
• Positive Regulation Of Chondrocyte Differentiation
• Positive Regulation Of Interleukin-1 Beta Production
• Regulation Of Transforming Growth Factor Beta2 Production
• Positive Regulation Of Transforming Growth Factor Beta3 Production
• Activin Receptor Signaling Pathway
• Negative Regulation Of Osteoblast Proliferation
• Positive Regulation Of Catenin Import Into Nucleus
• Nodal Signaling Pathway
• Wound Healing
• T Cell Activation
• Negative Regulation Of Protein Catabolic Process
• Positive Regulation Of Transcription Factor Import Into Nucleus
• Negative Regulation Of Apoptotic Process
• Cell-Cell Junction Organization
• Positive Regulation Of Nitric Oxide Biosynthetic Process
• Negative Regulation Of Fat Cell Differentiation
• Negative Regulation Of Osteoblast Differentiation
• Positive Regulation Of Transcription, Dna-Templated
• Negative Regulation Of Mitotic Cell Cycle
• Positive Regulation Of Transcription From Rna Polymerase Ii Promoter
• Paraxial Mesoderm Morphogenesis
• Developmental Growth
• Embryonic Foregut Morphogenesis
• Embryonic Cranial Skeleton Morphogenesis
• Regulation Of Epithelial Cell Proliferation
• Negative Regulation Of Inflammatory Response
• Regulation Of Immune Response
• Protein Stabilization
• Positive Regulation Of Positive Chemotaxis
• Regulation Of Binding
• Negative Regulation Of Cytosolic Calcium Ion Concentration
• Positive Regulation Of Stress Fiber Assembly
• Positive Regulation Of Focal Adhesion Assembly
• Pericardium Development
• Canonical Wnt Signaling Pathway
• Transdifferentiation
• Smad Protein Signal Transduction
• Negative Regulation Of Wound Healing
• Lens Fiber Cell Differentiation
• Extrinsic Apoptotic Signaling Pathway
• Activation Of Cysteine-Type Endopeptidase Activity Involved In Apoptotic Signaling Pathway
• Positive Regulation Of Extracellular Matrix Assembly
• Positive Regulation Of Pri-Mirna Transcription From Rna Polymerase Ii Promoter