Genetics of Vascular Malformations

Vascular malformations are nonneoplastic 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 intra membranous 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 zebra fish appeared phenotypically normal, suggesting human-specific ELMO2requirements in bone vasculature homeostasis or genetic compensation by related genes. The genetic basis for vascular malformations is incredibly complex. The great deal of phenotypic variability within known gene mutations suggests that we do not fully comprehend the exact genetic contribution to syndromes. However, further investigation will allow us to identify at-risk patients in the hopes of preventing the more severe sequelae of the syndromes. Furthermore, in-depth knowledge of the molecular basis of these lesions will provide ample opportunity to develop tissue-targeted therapy.