2. Academic Validation
  3. Discovery of a genetic module essential for assigning left-right asymmetry in humans and ancestral vertebrates

Discovery of a genetic module essential for assigning left-right asymmetry in humans and ancestral vertebrates

  • Nat Genet. 2022 Jan;54(1):62-72. doi: 10.1038/s41588-021-00970-4.
Emmanuelle Szenker-Ravi # 1,  Tim Ott # 2,  Muznah Khatoo 3,  Anne Moreau de Bellaing 4,  Wei Xuan Goh 3,  Yan Ling Chong 5 6,  Anja Beckers 7 8,  Darshini Kannesan 3,  Guillaume Louvel 9 10,  Priyanka Anujan 5 11,  Vydianathan Ravi 5,  Carine Bonnard 12,  Sébastien Moutton 13,  Patric Schoen 14,  Mélanie Fradin 15,  Estelle Colin 16,  André Megarbane 17 18,  Linda Daou 19,  Ghassan Chehab 19 20,  Sylvie Di Filippo 21,  Caroline Rooryck 22,  Jean-François Deleuze 23,  Anne Boland 23,  Nicolas Arribard 24,  Rukiye Eker 25,  Sumanty Tohari 5,  Alvin Yu-Jin Ng 26,  Marlène Rio 27 28,  Chun Teck Lim 29 30,  Birgit Eisenhaber 29 31,  Frank Eisenhaber 29 31 32,  Byrappa Venkatesh 5 33,  Jeanne Amiel 27 34,  Hugues Roest Crollius 9,  Christopher T Gordon 34,  Achim Gossler 7 8,  Sudipto Roy 5 33 35,  Tania Attie-Bitach 27 36,  Martin Blum 37,  Patrice Bouvagnet 38,  Bruno Reversade 39 40 41 42
Affiliations

Affiliations

  • 1 Laboratory of Human Genetics and Therapeutics, Genome Institute of Singapore (GIS), A*STAR, Singapore, Singapore. [email protected].
  • 2 Institute of Biology, University of Hohenheim, Stuttgart, Germany.
  • 3 Laboratory of Human Genetics and Therapeutics, Genome Institute of Singapore (GIS), A*STAR, Singapore, Singapore.
  • 4 Laboratoire de Cardiogénétique, Groupe Hospitalier Est, Hospices Civils de Lyon, Lyon, France.
  • 5 Institute of Molecular and Cell Biology (IMCB), A*STAR, Singapore, Singapore.
  • 6 Department of Pathology, National University Hospital, Singapore, Singapore.
  • 7 Institute for Molecular Biology, Hannover Medical School, Hannover, Germany.
  • 8 REBIRTH Cluster of Excellence, Hannover, Germany.
  • 9 Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, CNRS, INSERM, PSL Research University, Paris, France.
  • 10 Écologie, Systématique et Évolution, UMR 8079 CNRS - Université Paris-Saclay - AgroParisTech, Orsay, France.
  • 11 Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Imperial College, London, UK.
  • 12 Skin Research Institute of Singapore (SRIS), A*STAR, Singapore, Singapore.
  • 13 CPDPN, Pôle mère enfant, Maison de Santé Protestante Bordeaux Bagatelle, Talence, France.
  • 14 Praxis Dr Patric SCHÖN, Oberschleissheim, Germany.
  • 15 Service de Génétique Médicale, Hôpital Sud, CHU de Rennes, Rennes, France.
  • 16 Service de Génétique Médicale, CHU d'Angers, Angers, France.
  • 17 Department of Human Genetics, Gilbert and Rose-Marie Chagoury School of Medicine, Lebanese American University, Beirut, Lebanon.
  • 18 Institut Jérôme LEJEUNE, Paris, France.
  • 19 Department of Pediatric Cardiology, Hôtel Dieu de France University Medical Center, Saint Joseph University, Alfred Naccache Boulevard, Achrafieh, Beirut, Lebanon.
  • 20 Department of Pediatrics, Lebanese University, Faculty of Medical Sciences, Hadath, Greater Beirut, Lebanon.
  • 21 Service de Cardiologie Pédiatrique, Groupe Hospitalier Est, Hospices Civils de Lyon, Bron, France.
  • 22 Service de Génétique, University of Bordeaux, MRGM, INSERM U1211, CHU de Bordeaux, Bordeaux, France.
  • 23 Université Paris-Saclay, CEA, Centre National de Recherche en Génomique Humaine (CNRGH), Evry, France.
  • 24 Service de Cardiologie Pédiatrique, Hôpital Universitaire des Enfants Reine Fabiola (HUDERF), Brussels, Belgium.
  • 25 Pediatrics Department, Pediatric Cardiology Division, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
  • 26 Molecular Diagnosis Centre (MDC), National University Hospital (NUH), Singapore, Singapore.
  • 27 Fédération de Génétique, Hôpital Necker-Enfants Malades, Assistance Publique Hôpitaux de Paris, Paris, France.
  • 28 Developmental Brain Disorders Laboratory, Université de Paris, Imagine Institute, INSERM UMR 1163, Paris, France.
  • 29 Bioinformatics Institute (BII), A*STAR, Singapore, Singapore.
  • 30 Singapore Institute of Food and Biotechnology Innovation (SIFBI), A*STAR, Singapore, Singapore.
  • 31 Genome Institute of Singapore (GIS), A*STAR, Singapore, Singapore.
  • 32 School of Biological Sciences (SBS), Nanyang Technological University (NTU), Singapore, Singapore.
  • 33 Department of Pediatrics, National University of Singapore (NUS), Singapore, Singapore.
  • 34 Laboratory of Embryology and Genetics of Malformations, Université de Paris, Imagine Institute, INSERM UMR 1163, Paris, France.
  • 35 Department of Biological Sciences, National University of Singapore (NUS), Singapore, Singapore.
  • 36 Laboratory of Genetics and Development of the Cerebral Cortex, Université de Paris, Imagine Institute, INSERM UMR 1163, Paris, France.
  • 37 Institute of Biology, University of Hohenheim, Stuttgart, Germany. [email protected].
  • 38 CPDPN, Hôpital MFME, CHU de Martinique, Fort de France, France. [email protected].
  • 39 Laboratory of Human Genetics and Therapeutics, Genome Institute of Singapore (GIS), A*STAR, Singapore, Singapore. [email protected].
  • 40 Institute of Molecular and Cell Biology (IMCB), A*STAR, Singapore, Singapore. [email protected].
  • 41 Department of Pediatrics, National University of Singapore (NUS), Singapore, Singapore. [email protected].
  • 42 Medical Genetics Department, Koç University School of Medicine (KUSOM), Istanbul, Turkey. [email protected].
  • # Contributed equally.
PMID: 34903892 DOI: 10.1038/s41588-021-00970-4
Abstract

The vertebrate left-right axis is specified during embryogenesis by a transient organ: the left-right organizer (LRO). Species including fish, amphibians, rodents and humans deploy motile cilia in the LRO to break bilateral symmetry, while reptiles, birds, even-toed mammals and cetaceans are believed to have LROs without motile cilia. We searched for genes whose loss during vertebrate evolution follows this pattern and identified five genes encoding extracellular proteins, including a putative protease with hitherto unknown functions that we named ciliated left-right organizer metallopeptide (CIROP). Here, we show that CIROP is specifically expressed in ciliated LROs. In zebrafish and Xenopus, CIROP is required solely on the left side, downstream of the leftward flow, but upstream of DAND5, the first asymmetrically expressed gene. We further ascertained 21 human patients with loss-of-function CIROP mutations presenting with recessive situs anomalies. Our findings posit the existence of an ancestral genetic module that has twice disappeared during vertebrate evolution but remains essential for distinguishing left from right in humans.

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