Mutations of TGFß signaling molecules in human disease

The transforming growth factor β (TGFβ) signaling pathway regulates several biological processes including cellular proliferation, differentiation, apoptosis, migration, and extracellular matrix deposition. Ligand and receptor family members signal through two main Smad signaling branches, TGFβ/activin to Smad2/3 (Sma and MAD‐related proteins) and bone morphogenetic protein (BMP) to Smad1/5. At the molecular level, TGFβ acts by modifying cytoskeletal organization and ultimately regulating expression of specific target genes. Germline disruption of TGFβ signaling leads to several types of hereditary congenital malformation or dysfunction of the skeletal, muscular and/or cardiovascular systems, and to cancer predisposition syndromes. In this review, the molecular etiology of TGFβ‐associated disorders is examined, together with a discussion of clinical overlap between syndromes and possible biological explanations underlying the variable penetrance and expressivity of clinical characteristics. Increasing our...