Mutational Analysis Mapping on The Molecular Structure of The ACVRL1 Protein and Implications For Rendu-Osler-Weber (ROW)

George N. Goulielmos, Elias Eliopoulos, Alexandros Karatzanis, Maria I. Zervou, Emmanuel Fountakis, Stylianos G. Velegrakis, Trias Thireou, Emmanuel P. Prokopakis

About 80% of Rendu-Osler–Weber (ROW) patients carry mutations in endoglin (ENG) or activin receptor-like kinase1 (ACVRL1; ALK1) genes. In order to investigate the molecular mechanisms that govern the pathogenic effect of the mutations in ACVRL1, we have collected and analyzed the mutational effect of over 80 different predominant mutations, as well as their location, on the 3D molecular structures of N- and C-terminal domains of ACVRL1. We have used macromolecular modeling on the protein structural components of ACVLR1 and structural component interface analysis to locate position and interaction of point mutations. Specific mutations were identified using genomic DNA sequencing from blood leucocytes. Out of the 151 point mutations reported for the ALK1 gene, the majority are located on the surface of the ARD and PK structural domains, with some on the interaction interface. New observed mutation Cys90Phe found in two Cretan ROW patients, located on loop F4 of ARD, introduces conformational steric hindrance and disruption of stability. We have mapped point mutations on the structural domains of ACVLR1, correlating location and severity of ROW. In addition, we report the identification and location of a novel missense mutation, Cys90Phe, which has not yet been described. It is identified in a Cretan ROW patient, and associated with severe clinical appearance according to the Curacao criteria.