title: 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.
authors.affiliation: Department of Medical Genetics, Gene Mapping Laboratory, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey.
authors.forename: Arda
authors.initials: A
authors.lastname: Cetinkaya
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648, Singapore.
authors.forename: Jingwei Rachel
authors.initials: JR
authors.lastname: Xiong
authors.affiliation: Department of Plastic and Reconstructive Surgery, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey.
authors.forename: İbrahim
authors.initials: İ
authors.lastname: Vargel
authors.affiliation: Department of Pathology, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey.
authors.forename: Kemal
authors.initials: K
authors.lastname: Kösemehmetoğlu
authors.affiliation: Department of Plastic and Reconstructive Surgery, Faculty of Medicine, Acıbadem University, Istanbul 34457, Turkey.
authors.forename: Halil İbrahim
authors.initials: Hİ
authors.lastname: Canter
authors.affiliation: Advanced Genomics and Bioinformatics Research Center (IGBAM), BILGEM, TUBITAK, Kocaeli 41400, Turkey.
authors.forename: Ömer Faruk
authors.initials: ÖF
authors.lastname: Gerdan
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT 84108, USA.
authors.forename: Nicola
authors.initials: N
authors.lastname: Longo
authors.affiliation: Department of Pediatrics, Maternity Children Hospital, Makkah 24341, Saudi Arabia.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Alzahrani
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648, Singapore.
authors.forename: Mireia Perez
authors.initials: MP
authors.lastname: Camps
authors.affiliation: Department of Medical Genetics, Gene Mapping Laboratory, Faculty of Medicine, Hacettepe University, Ankara 06100, Turkey.
authors.forename: Ekim Zihni
authors.initials: EZ
authors.lastname: Taskiran
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648, Singapore.
authors.forename: Simone
authors.initials: S
authors.lastname: Laupheimer
authors.affiliation: Division of Medical Genetics, Department of Pediatrics, University of Utah, Salt Lake City, UT 84108, USA.
authors.forename: Lorenzo D
authors.initials: LD
authors.lastname: Botto
authors.affiliation: Institute of Medical Biology, Human Genetics and Embryology Laboratory, A(∗)STAR, Singapore 138648, Singapore.
authors.forename: Eeswari
authors.initials: E
authors.lastname: Paramalingam
authors.affiliation: Advanced Genomics and Bioinformatics Research Center (IGBAM), BILGEM, TUBITAK, Kocaeli 41400, Turkey.
authors.forename: Zeliha
authors.initials: Z
authors.lastname: Gormez
authors.affiliation: 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.
authors.forename: Elif
authors.initials: E
authors.lastname: Uz
authors.affiliation: Genetic Engineering and Biotechnology Institute, TUBITAK Marmara Research Center, Kocaeli 41400, Turkey.
authors.forename: Bayram
authors.initials: B
authors.lastname: Yuksel
authors.affiliation: Department of Pathology, Faculty of Medicine, Koç University, Istanbul 34450, Turkey.
authors.forename: Şevket
authors.initials: Ş
authors.lastname: Ruacan
authors.affiliation: Advanced Genomics and Bioinformatics Research Center (IGBAM), BILGEM, TUBITAK, Kocaeli 41400, Turkey.
authors.forename: Mahmut Şamil
authors.initials: MŞ
authors.lastname: Sağıroğlu
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Tokiharu
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: 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.
authors.forename: Bruno
authors.initials: B
authors.lastname: Reversade
authors.affiliation: 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.
authors.forename: Nurten Ayse
authors.initials: NA
authors.lastname: Akarsu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000483:Alleles; D000818:Animals; D001842:Bone and Bones / Q000098:blood supply*; D002465:Cell Movement; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D019143:Evolution, Molecular; D005260:Female; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D010802:Phylogeny; D015398:Signal Transduction / Q000235:genetics*; D013045:Species Specificity; D054079:Vascular Malformations / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015027:Zebrafish / Q000235:genetics / Q000502:physiology; D020744:rac GTP-Binding Proteins / Q000235:genetics; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D003598:Cytoskeletal Proteins; C099818:DOCK1 protein, human; C486678:ELMO2 protein, human; C107953:RAC1 protein, human; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein