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Article Dans Une Revue Nature Genetics Année : 2022

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

1 GIS - Genome Institute of Singapore
2 University of Hohenheim
3 GHE - Groupement Hospitalier Lyon-Est
4 IMCB / A*STAR - Institute of Molecular and Cell Biology [Singapore, Singapore]
5 NUH - National University Hospital [Singapore]
6 CHU-Liège - Centre Hospitalier Universitaire de Liège
7 MHH - Medizinische Hochschule Hannover = Hannover Medical School
8 REBIRTH Cluster of Excellence [Hannover]
9 IBENS - Institut de biologie de l'ENS Paris
10 ESE - Ecologie Systématique et Evolution
11 Hammersmith Hospital NHS Imperial College Healthcare
12 SRIS / A*STAR - Skin Research Institute of Singapore [Singapore, Singapore]
13 MSPB - Maison de Santé Protestante de Bordeaux-Bagatelle
14 2PS - Praxis Dr Patric SCHÖN [Oberschleissheim, Germany]
15 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
16 CHU Angers - Centre Hospitalier Universitaire d'Angers
17 Gilbert and Rose-Marie Chagoury School of Medicine [Lebanese American University]
18 Institut Jérôme Lejeune
19 USJ - Université Saint-Joseph de Beyrouth
20 LU / ULB - الجامعة اللبنانية [بيروت] = Lebanese University [Beirut] = Université libanaise [Beyrouth]
21 CarMeN - Cardiovasculaire, métabolisme, diabétologie et nutrition
22 U1211 INSERM/MRGM - Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux)
23 CNRGH - Centre National de Recherche en Génomique Humaine
24 HUDERF - Hôpital Universitaire des Enfants Reine Fabiola [Bruxelles, Belgique]
25 Istanbul University
26 AP-HP Espace éthique - Assistance publique-Hôpitaux de Paris - Espace éthique
27 Hôpital Necker - Enfants Malades [AP-HP]
28 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
29 SIFBI - Singapore Institute of Food and Biotechnology Innovation
30 Bioinformatics Institute [Singapore]
31 Nanyang Technological University [Singapour]
32 NUS - National University of Singapore
33 Service de Génétique Médicale [CHU Necker]
34 MFME [Fort de France] - Maison de la Femme de la Mère et de l'Enfant [CHU de la Martinique]
35 KUSOM - Koc University School of Medicine [Istanbul, Turkey]
T. Ott
  • Fonction : Auteur
R. Eker
  • Fonction : Auteur
M. Blum
  • Fonction : Auteur correspondant

Résumé

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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Dates et versions

inserm-03752860 , version 1 (17-08-2022)

Identifiants

Citer

E. Szenker-Ravi, T. Ott, M. Khatoo, A. M. De Bellaing, W. X. Goh, et al.. Discovery of a genetic module essential for assigning left-right asymmetry in humans and ancestral vertebrates. Nature Genetics, 2022, 54 (1), pp.62-72. ⟨10.1038/s41588-021-00970-4⟩. ⟨inserm-03752860⟩
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