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

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          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.

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          Author and article information

          Journal
          Am. J. Hum. Genet.
          American journal of human genetics
          Elsevier BV
          1537-6605
          0002-9297
          Aug 04 2016
          : 99
          : 2
          Affiliations
          [1 ] Department of Medical Genetics, Gene Mapping Laboratory, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey.
          [2 ] Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648, Singapore.
          [3 ] Department of Plastic and Reconstructive Surgery, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey.
          [4 ] Department of Pathology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey.
          [5 ] Department of Plastic and Reconstructive Surgery, Faculty of Medicine, Acıbadem University, Istanbul 34457, Turkey.
          [6 ] Advanced Genomics and Bioinformatics Research Center (IGBAM), BILGEM, TUBITAK, Kocaeli 41400, Turkey.
          [7 ] Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT 84108, USA.
          [8 ] Department of Pediatrics, Maternity Children Hospital, Makkah 24341, Saudi Arabia.
          [9 ] Department of Medical Genetics, Gene Mapping Laboratory, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey; Department of Molecular Biology and Genetics, Faculty of Arts and Sciences, Uludag University, Bursa 16059, Turkey.
          [10 ] Genetic Engineering and Biotechnology Institute, TUBITAK Marmara Research Center, Kocaeli 41400, Turkey.
          [11 ] Department of Pathology, Faculty of Medicine, Koç University, Istanbul 34450, Turkey.
          [12 ] Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
          [13 ] Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648, Singapore; Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore. Electronic address: bruno@reversade.com.
          [14 ] Department of Medical Genetics, Gene Mapping Laboratory, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey; Center for Biobanking and Genomics, Hacettepe University, Ankara 06100, Turkey. Electronic address: nakarsu@hacettepe.edu.tr.
          Article
          S0002-9297(16)30210-5
          10.1016/j.ajhg.2016.06.008
          4974086
          27476657

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