The SMAD4 gene codes for the 552 amino acid zinc containing mothers against decapentaplegic homolog 4. This forms complexes with other SMAD transcription regulators such as the mothers against decapentaplegic homolog 1/mothers against decapentaplegic homolog 4/transcriptional repressor protein YY1 complex in bone morphogenetic protein-mediated cardiac-specific gene expression. Binds to SMAD binding elements (SBEs) (5'-GTCT/AGAC-3') within the BMP response element (BMPRE). The mothers against decapentaplegic homolog 3/mothers against decapentaplegic homolog 4 (SMAD3/SMAD4) complex is a key transcription regulator. It can also forms a SMAD3/SMAD4/JUN/FOS complex at the AP-1/SMAD site to regulate TGF-beta-mediated transcription. In muscle physiology, it plays a central role in the balance between atrophy and hypertrophy as when recruited by growth/differentiation factor 8, it promotes atrophy response via the phosphorylated mothers against decapentaplegic homolog 2/mothers against decapentaplegic homolog 4 complex. Mothers against decapentaplegic homolog 4 is the component of the mothers against decapentaplegic homolog 2/mothers against decapentaplegic homolog 4/forkhead box protein H1 complex that promotes binding to DNA and provides an activation function required for mothers against decapentaplegic homolog 1 or mothers against decapentaplegic homolog 2 to stimulate transcription.
Mutations of SMAD4 lead to:
- Juvenile polyposis syndrome (JPS, OMIM:174900)
- Autosomal dominant gastrointestinal hamartomatous polyposis syndrome increasing risk for gastrointestinal cancer.
- Juvenile polyposis/hereditary haemorrhagic telangiectasia syndrome (JP/HHT,OMIM:175050)
- A rare combination of juvenile polyposis and hereditary haemorrhagic telangiectasia
- Pancreatic cancer (OMIM:260350)
- Colorectal cancer (OMIM:114500)
- Myhre syndrome (MYHRS, OMIM:139210)
- Characterised by mental retardation, generalized muscle hypertrophy and striking muscular build, decreased joint mobility, cryptorchidism, and udysmorphic facial features. These include microcephaly, midface hypoplasia, prognathism, and blepharophimosis. Typical skeletal anomalies include short stature, square body shape, broad ribs, iliac hypoplasia, brachydactyly, flattened vertebrae, and thickened calvaria. Congenital heart disease is possible.