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

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

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.


The transforming growth factor–β (TGF-β) and bone morphogenetic protein (BMP) family of cytokines critically regulates vascular morphogenesis and homeostasis. Impairment of TGF-β or BMP signaling leads to heritable vascular disorders, including hereditary hemorrhagic telangiectasia (HHT). Drosha, a key enzyme for microRNA (miRNA) biogenesis, also regulates the TGF-β and BMP pathway through interaction with Smads and their joint control of gene expression through miRNAs. We report that mice lacking Drosha in the vascular endothelium developed a vascular phenotype resembling HHT that included dilated and disorganized vasculature, arteriovenous fistulae, and hemorrhages. Exome sequencing of HHT patients who lacked known pathogenic mutations revealed an overrepresentation of rare nonsynonymous variants of DROSHA. Two of these DROSHA variants (P100L and R279L) did not interact with Smads and were partially catalytically active. In zebrafish, expression of these mutants or morpholino-directed knockdown of Drosha resulted in angiogenesis defects and abnormal vascular permeability. Together, our studies point to an essential role of Drosha in vascular development and the maintenance of vascular integrity, and reveal a previously unappreciated link between Drosha dysfunction and HHT.

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