GENETIC AND FUNCTIONAL CHARACTERIZATION OF HEREDITARY INTRAOSSEOUS VASCULAR MALFORMATION

Abstract

Vascular malformations are non-neoplastic expansions of blood vessels that arise due to errors in angiogenesis. Here we report loss-of-function mutations in ELMO2, which translates extracellular signals into cellular movements, as causative for autosomal recessive intraosseous vascular malformation (VMOS) in five different families. Individuals with VMOS suffer from life-threatening progressive expansion of the jaw, craniofacial and other intramembranous bones caused by malformed blood vessels that lack a mature vascular smooth muscle layer. Analysis of primary fibroblasts from an affected individual showed that absence of ELMO2 correlated with a significant down regulation of binding partner DOCK1, resulting in deficient RAC1-dependent cell migration. Unexpectedly, elmo2-knockout zebrafish appeared phenotypically normal, suggesting human-specific ELMO2 requirements in bone vasculature homeostasis or genetic compensation by related genes. The present findings highlight the necessity of ELMO2 for maintaining vascular integrity, specifically in intramembranous bones.