A schematic representation of the TGF-β signaling pathway. Endoglin (yellow) is needed for signalling. The ligand (blue) binds to the receptor complex; red indicates a type II receptor protein, which activates a type I receptor protein (turquoise) such as alk-1, which in turn phosphorylates a SMAD-based nuclear transcription factor (green and purple).<unk> s and arteriovenous malformations in<unk>  are thought to arise because of changes in angiogenesis, the development of blood vessels out of existing ones. The development of a new blood vessel requires the activation and migration of various types of cells, chiefly endothelium, smooth muscle and pericytes. The exact mechanism by which the<unk>  mutations influence this process is not yet clear, and it is likely that they disrupt a balance between pro- and antiangiogenic signals in blood vessels. The wall of<unk> s is unusually friable, which explains the tendency of these lesions to bleed. All genes known so far to be linked to<unk>  code for proteins in the TGF-β signaling pathway. This is a group of proteins that participates in signal transduction of hormones of the transforming growth factor beta superfamily (the transforming growth factor beta, bone morphogenetic protein and growth differentiation factor classes), specifically BMP9/GDF2 and BMP10. The hormones do not enter the cell but link to receptors on the cell membrane; these then activate other proteins, eventually influencing cellular behavior in a number of ways such as cellular survival, proliferation (increasing in number) and differentiation (becoming more specialized). For the hormone signal to be adequately transduced, a combination of proteins is needed: two each of two types of serine/threonine-specific kinase type membrane receptors and endoglin. When bound to the hormone, the type II receptor proteins phosphorylate (transfer phosphate) onto type I receptor proteins (of which Alk-1 is one), which in turn phosphorylate a complex of SMAD proteins (chiefly SMAD1, SMAD5 and SMAD8). These bind to SMAD4 and migrate to the cell nucleus where they act as transcription factors and participate in the transcription of particular genes. In addition to the SMAD pathway, the membrane receptors also act on the MAPK pathway, which has additional actions on the behavior of cells. Both Alk-1 and endoglin are expressed predominantly in endothelium, perhaps explaining why<unk> -causing mutations in these proteins lead predominantly to blood vessel problems. Both ENG and ACVRL1 mutations lead predominantly to underproduction of the related proteins, rather than misfunctioning of the proteins.
Hereditary hemorrhagic telangiectasia
Pedophilia
Patau syndrome
Ehlers–Danlos syndromes
Haemophilia
Bernard–Soulier syndrome
Ogden syndrome
Panayiotopoulos syndrome