SMAD3 gene

SMAD family member 3

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.

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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.

Cytogenetic Location: 15q22.33, which is the long (q) arm of chromosome 15 at position 22.33

Molecular Location: base pairs 67,065,698 to 67,195,195 on chromosome 15 (Homo sapiens Annotation Release 108, GRCh38.p7) (NCBI)

Cytogenetic Location: 15q22.33, which is the long (q) arm of chromosome 15 at position 22.33
  • hMAD-3
  • hSMAD3
  • JV15-2
  • MAD homolog 3
  • MAD, mothers against decapentaplegic homolog 3
  • mad3
  • MADH3
  • mothers against decapentaplegic homolog 3
  • mothers against decapentaplegic homolog 3 isoform 3
  • SMAD, mothers against DPP homolog 3
  • SMAD3_HUMAN