Research ArticleVASCULAR BIOLOGY

Inactivating mutations in Drosha mediate vascular abnormalities similar to hereditary hemorrhagic telangiectasia

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Sci. Signal.  16 Jan 2018:
Vol. 11, Issue 513, eaan6831
DOI: 10.1126/scisignal.aan6831

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Processing microRNAs for blood vessels

Individuals with hereditary hemorrhagic telangiectasia (HHT) form direct and fragile connections between arteries and veins that are prone to rupture. Most HHT patients have mutations in components of the transforming growth factor–β and bone morphogenetic protein signaling pathways, which regulate blood vessel formation. Noting that the microRNA processing enzyme Drosha interacts with effector proteins in these pathways, Jiang et al. showed that Drosha-deficient zebrafish and mice with an endothelial cell–specific ablation of Drosha had vascular defects reminiscent of those found in HHT patients. Rare mutations in DROSHA were overrepresented in HHT patients who lacked the typical disease-associated mutations. Two of these mutants showed reduced activity and could not rescue the vascular phenotypes of Drosha-deficient zebrafish. Because the mutations in humans and zebrafish were global and not specific to endothelial cells, the predominantly vascular phenotypes suggest that endothelial cells are particularly sensitive to changes in microRNA abundance.