Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease

Model of diseases associated with ENG, ACVRL1, and MADH4 mutations. The type II (RII) and type I (RI) receptors are related serine/threonine kinases which form high affinity complexes upon ligand binding. In endothelial cells, TGFβ1 and TGFβ3 isoforms bind the RII receptor (TβRII), and an RI receptor is then recruited (ALK‐5 or ALK‐1, which phosphorylate Smad2/3 or Smad1/5, respectively). Endoglin interacts with either of these receptor complexes. In the case of BMP‐2, BMP‐4, or BMP‐6, the RI receptors (ALK‐3 and ALK‐6) first bind the ligand, engage BMPRII receptor and transit the signal through Smad1/5. Smad4 represents a common Smad through which signals from different receptors converge and translocate to the nucleus to regulate transcriptional responses. Mutations targeting different components (red) of the TGFβ signalling pathway contribute to several human disorders (in parentheses). Mutations in the endoglin gene are known to cause HHT1 and probably pulmonary arterial hypertension. ALK‐1 mutations are associated with HHT2 and PPH, the later being also caused by BMPRII mutations. Mutations in ALK‐3 also cause juvenile polyposis, while mutations in MADH4 coding for Smad4 lead to a combined syndrome of juvenile polyposis and HHT. BMP, bone morphogenetic protein; HHT, hereditary haemorrhagic telangiectasia; JPHT, syndrome of juvenile polyposis and hereditary haemorrhagic telangiectasia; PAH, pulmonary arterial hypertension; PPH, primary pulmonary hypertension; TGF, transforming growth factor

Publication

Hereditary haemorrhagic telangiectasia: current views on genetics and mechanisms of disease. (2006) S A Abdalla, et al. J Med Genet. 2006 Feb;43(2):97-110. Figure: F3. All organisms Danio rerio Homo sapiens

Disease mentions