Autologous correction in patient induced pluripotent stem cell-endothelialcells to identify a novel pathogenic mutation of hereditary hemorrhagictelangiectasia

摘要

Hereditary hemorrhagic telangiectasia is a rare disease with autosomal dominantinheritance. More than 80% hereditary hemorrhagic telangiectasia patients carryheterozygous mutations of Endoglin or Activin receptor-likekinase-1 genes. Endoglin plays important roles in vasculogenesis and humanvascular disease. In this report, we found a novel missense mutation (c.88T > C) ofEndoglin gene in a hereditary hemorrhagic telangiectasia 1 patient.Induced pluripotent stem cells of the patient were generated and differentiated intoendothelial cells. The hereditary hemorrhagic telangiectasia-induced pluripotent stemcells have reduced differentiation potential toward vascular endothelial cells anddefective angiogenesis with impaired tube formation. Endoplasmic reticulum retention ofthe mutant Endoglin (Cys30Arg, C30R) causes less functional protein trafficking to cellsurface, which contributes to the pathogenesis of hereditary hemorrhagic telangiectasia.Clustered Regularly Interspaced Short Palindromic Repeats/Cas9 genetic correction of thec.88T > C mutation in induced pluripotent stem cells revealed that C30R mutation ofEndoglin affects bone morphogenetic protein 9 downstream signaling. By establishing ahuman induced pluripotent stem cell from hereditary hemorrhagic telangiectasia patientperipheral blood mononuclear cells and autologous correction on mutant hereditaryhemorrhagic telangiectasia-induced pluripotent stem cells, we were able to identify a newdisease-causing mutation, which facilitates us to understand the roles of Endoglin invascular development and pathogenesis of related vascular diseases.