Affiliations: Department of Pediatrics, National Defense Medical College, Tokorozawa-city, Saitama, Japan | Department of Pediatric Cardiology, Tokyo Women’s Medical University, Shinjuku-ku, Tokyo, Japan | Department of Radiology, National Center for Child Health and Development, Setagaya-ku Tokyo, Japan | Department of Radiology, Toho University Ohashi Medical Center, Tokyo, Japan
Note: [] Corresponding author: Dr. Toshio Nakanishi, Department of Pediatric Cardiology, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. Tel.: +81 3 3353 8112 ext. 24067; Fax: +81 3 3352 3088; E-mail: pnakanis@hij.twmu.ac.jp.
Abstract: Although mutations in the RASA1 gene in vein of Galen aneurysmal malformation (VGAM) and an endoglin gene mutation in a VGAM patient with a family history of hereditary hemorrhagic telangiectasia (HHT) have been identified, most VGAM cases have no mutation in these genes. We sought to detect mutations in other genes related to HHT. We screened for mutations in RASA1 and three genes (endoglin, activin receptor-like kinase 1 (ACVRL1), encoding ALK1, and SMAD4) related to HHT in four VGAM patients. One variant (c.652 C>T p.R218W) in ACVRL1 was identified. Immunoblotting revealed that the ALK1-R218W protein could not promote SMAD1/5/8 phosphorylation by BMP9 stimulation. On the other hand, wild-type ALK1 could enhance the phosphorylation as expected. Furthermore, the transcriptional activation of ALK1-R218W was less efficient than that of wild-type ALK1. We identified 1 variant in ACVRL1 in a VGAM patient. These findings suggest that the ACVRL1 variant-R218W may be associated with the pathogenesis of VGAM.
Keywords: ACVRL1, gene variant, vein of Galen aneurysmal malformation
