title: De novo mutations in PLXND1 and REV3L cause Möbius syndrome.
abstract: Möbius syndrome (MBS) is a neurological disorder that is characterized by paralysis of the facial nerves and variable other congenital anomalies. The aetiology of this syndrome has been enigmatic since the initial descriptions by von Graefe in 1880 and by Möbius in 1888, and it has been debated for decades whether MBS has a genetic or a non-genetic aetiology. Here, we report de novo mutations affecting two genes, PLXND1 and REV3L in MBS patients. PLXND1 and REV3L represent totally unrelated pathways involved in hindbrain development: neural migration and DNA translesion synthesis, essential for the replication of endogenously damaged DNA, respectively. Interestingly, analysis of Plxnd1 and Rev3l mutant mice shows that disruption of these separate pathways converge at the facial branchiomotor nucleus, affecting either motoneuron migration or proliferation. The finding that PLXND1 and REV3L mutations are responsible for a proportion of MBS patients suggests that de novo mutations in other genes might account for other MBS patients.
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, PO Box 9101, Nijmegen 6500 HB, The Netherlands.|Department of Human Anatomy and Psychobiology, School of Medicine, University of Murcia, 30100 Espinardo (Murcia), Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Tomas-Roca
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Tsaalbi-Shtylik
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Jacob G
authors.initials: JG
authors.lastname: Jansen
authors.affiliation: Department of Cell and Developmental Biology, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, 9-105 SCTR, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.|Signature Research Program in Cardiovascular and Metabolic Disorders, Duke-NUS Graduate Medical School Singapore, National Heart Center Singapore, 8 College Road, Singapore 169857, Singapore.
authors.forename: Manvendra K
authors.initials: MK
authors.lastname: Singh
authors.affiliation: Department of Cell and Developmental Biology, Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, 9-105 SCTR, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
authors.affiliation: Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Millet Caddesi, Capa, Fatih 34093, Turkey.
authors.forename: Umut
authors.initials: U
authors.lastname: Altunoglu
authors.affiliation: Department of Neurology, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, PO Box 9101, Nijmegen 6500 HB, The Netherlands.
authors.forename: Harriette
authors.initials: H
authors.lastname: Verzijl
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, PO Box 9101, Nijmegen 6500 HB, The Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: Soria
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, PO Box 9101, Nijmegen 6500 HB, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: van Beusekom
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, PO Box 9101, Nijmegen 6500 HB, The Netherlands.|The Kinghorn Centre for Clinical Genomics, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
authors.forename: Tony
authors.initials: T
authors.lastname: Roscioli
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, PO Box 9101, Nijmegen 6500 HB, The Netherlands.
authors.forename: Zafar
authors.initials: Z
authors.lastname: Iqbal
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, PO Box 9101, Nijmegen 6500 HB, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Radboud Institute for Molecular Life Sciences (RIMLS), PO Box 9101, Nijmegen 6500 HB, The Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, PO Box 9101, Nijmegen 6500 HB, The Netherlands.
authors.forename: Arjan P M
authors.initials: APM
authors.lastname: de Brouwer
authors.affiliation: Department of Neurology, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, PO Box 9101, Nijmegen 6500 HB, The Netherlands.
authors.forename: Corrie
authors.initials: C
authors.lastname: Erasmus
authors.affiliation: Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, PO Box 9101, Nijmegen 6500 HB, The Netherlands.
authors.forename: Dirk
authors.initials: D
authors.lastname: Schubert
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, PO Box 9101, Nijmegen 6500 HB, The Netherlands.|Department of Clinical Genetics, Maastricht University Medical Center, PO Box 5800, Maastricht 6200AZ, The Netherlands.
authors.forename: Han
authors.initials: H
authors.lastname: Brunner
authors.affiliation: Dysmorphology and Reproductive Genetics Unit, Moebius Syndrome Foundation of Spain, University Hospital LA FE, Valencia 46540, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Pérez Aytés
authors.affiliation: Department of Human Anatomy and Psychobiology, School of Medicine, University of Murcia, 30100 Espinardo (Murcia), Spain.
authors.forename: Faustino
authors.initials: F
authors.lastname: Marin
authors.affiliation: Department of Human Anatomy and Psychobiology, School of Medicine, University of Murcia, 30100 Espinardo (Murcia), Spain.
authors.forename: Pilar
authors.initials: P
authors.lastname: Aroca
authors.affiliation: Medical Genetics Department, Istanbul Medical Faculty, Istanbul University, Millet Caddesi, Capa, Fatih 34093, Turkey.
authors.forename: Hülya
authors.initials: H
authors.lastname: Kayserili
authors.affiliation: Ophthalmology Unit, Department of Biomedical, Biotechnological and Translational Sciences (S.Bi.Bi.T.), University of Parma, via Gramsci 14, 43126, Parma, Italy.
authors.forename: Arturo
authors.initials: A
authors.lastname: Carta
authors.affiliation: Department of Human Genetics, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands.
authors.forename: Niels
authors.initials: N
authors.lastname: de Wind
authors.affiliation: Department of Neurology, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, PO Box 9101, Nijmegen 6500 HB, The Netherlands.
authors.forename: George W
authors.initials: GW
authors.lastname: Padberg
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, PO Box 9101, Nijmegen 6500 HB, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
mesh_terms: D000818:Animals; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000235:genetics*; D004259:DNA-Directed DNA Polymerase / Q000235:genetics*; D059472:Exome; D006579:Heterozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D051379:Mice; D008817:Mice, Mutant Strains; D020331:Mobius Syndrome / Q000235:genetics*; D009154:Mutation
chemical_list: D015816:Cell Adhesion Molecules, Neuronal; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C493082:PLXND1 protein, human; D004259:DNA-Directed DNA Polymerase; C118285:REV3L protein, human