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