Loss-of-Function Mutations in ELMO2 Cause Intraosseous Vascular Malformation by Impeding RAC1 Signaling

Abstract

Vascular malformations are non-neoplastic expansions of blood vessels that arise due to errors during angiogenesis. They are a heterogeneous group of sporadic or inherited vascular disorders characterized by localized lesions of arteriovenous, capillary, or lymphatic origin. Vascular malformations that occur inside bone tissue are rare. Herein, we report loss-of-function mutations in ELMO2 (which translates extracellular signals into cellular movements) that are 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 downregulation of binding partner DOCK1, resulting in deficient RAC1-dependent cell migration. Unexpectedly, elmo2-knockout zebrafish appeared phenotypically normal, suggesting that there might be human-specific ELMO2 requirements in bone vasculature homeostasis or genetic compensation by related genes. Comparative phylogenetic analysis indicated that elmo2 originated upon the appearance of intramembranous bones and the jaw in ancestral vertebrates, implying that elmo2 might have been involved in the evolution of these novel traits. The present findings highlight the necessity of ELMO2 for maintaining vascular integrity, specifically in intramembranous bones.

Structure of BAI1/ELMO2 complex reveals an action mechanism of adhesion GPCRs via ELMO family scaffolds

“…ELMO2 was associated with intraosseous vascular malformation (VMOS), a disease characterized with non-neoplastic expansions of blood vessels due to errors during angiogenesis 32 . A deletion mutant of ELMO2, p.Ala311_Thr355del, was found in VMOS patients and caused a significant decreased level of DOCK1, thus resulting in deficient Rac1-depedent cell migration 32 . Based on our structures, the deletion mutant is expected to impair the RAE supramodular assembly of ELMO2, thus affecting the binding(s) of ELMO2-RAE with its target(s)(such as BAIs).…”

A Low-Cost Time-Correlated Single Photon Counting Portable DNA Analyzer

“…In this work, a low-cost TCSPC portable DNA analyzer by utilizing lifetime analysis technique and optimizing system composition is presented. As similar lifetime analysis techniques have demonstrated successful detection of mutation and mismatch of DNA and RNA [30,31,32,33,34], the feasibility of the proposed system for the detection of above bio-samples is worthy of further investigation.…”

Homozygous mutation in ELMO2 may cause Ramon syndrome

“…However, in the VMOS, there is no intellectual disability, no seizures, no short stature, no hypertrichosis, and no heart malformations. Furthermore, the vascular venous malformation that is characteristic of VMOS differs from the fibrous dysplasia observed in Ramon in which abundant cellular fibrous tissue between bone trabeculae is diagnostic (Table ).…”

“…Recently, loss of function mutations consisting of small insertions and deletions in ELMO2 gene were reported in 5 families with a rare entity, the primary intraosseous vascular malformation or intraosseous hemangioma: VMOS (OMIM 606893) . The latter appears in early childhood, and is characterized by severe blood vessel expansions leading to painless swelling of the mandible, enlargement of facial bones, clavicles, ribs, and vertebrae with increased intracranial pressure, exophthalmos, spinal cord compression, all secondary to compression of organ compartments by the expanding vascular lesions.…”