Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density

Anna Swan (1) , Christine Schütt (2) , Jan Rozman (2, 3, 4) , Maria del Mar Muñiz Moreno (5) , Stefan Brandmaier (3, 6) , Michelle Simon (1) , Stefanie Leuchtenberger (2) , Mark Griffiths (7) , Robert Brommage (3) , Piia Keskivali-Bond (1) , Harald Grallert (3, 2) , Thomas Werner (8) , Raffaele Teperino (3, 2) , Lore Becker (6) , Gregor Miller (6) , Ala Moshiri (9) , John Seavitt (10) , Derek Cissell (9) , Terrence Meehan (11) , Elif Acar (12, 13) , Christopher Lelliott (7) , Ann Flenniken (14) , Marie-France Champy (5, 15) , Tania Sorg (5, 15) , Abdel Ayadi (5, 15) , Robert Braun (16) , Heather Cater (1) , Mary Dickinson (10) , Paul Flicek (17) , Juan Gallegos (10) , Elena Ghirardello (18) , Jason Heaney (10) , Sylvie Jacquot (5, 15) , Connor Lally (1) , John Logan (18) , Lydia Teboul (1) , Jeremy Mason (17) , Nadine Spielmann (2) , Colin Mckerlie (12) , Stephen Murray (16) , Lauryl Nutter (14) , Kristian Odfalk (10) , Helen Parkinson (17) , Jan Prochazka (4) , Corey Reynolds (10) , Mohammed Selloum (5, 15) , Frantisek Spoutil (4) , Karen Svenson (16) , Taylor Vales (10) , Sara Wells (1) , Jacqueline White (16) , Radislav Sedlacek (4) , Wolfgang Wurst (6, 19, 20, 21) , K. Lloyd (9) , Peter Croucher (22, 23, 24) , Helmut Fuchs (6) , Graham Williams (18) , J. Bassett (18) , Valerie Gailus-Durner (6) , Yann Herault (5, 15) , Ann-Marie Mallon (1) , Steve Brown (1) , Philipp Mayer-Kuckuk (6) , Martin Hrabe de Angelis (6, 4, 2, 19)

1 MRC Harwell Institute [UK]
2 German Research Center for Environmental Health - Helmholtz Center München (GmbH)
3 DZD - German Center for Diabetes Research - Deutsches Zentrum für Diabetesforschung [Neuherberg]
4 IMG / CAS - Institute of Molecular Genetics of the Czech Academy of Sciences
5 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
6 Helmholtz Zentrum München = German Research Center for Environmental Health
7 The Wellcome Trust Sanger Institute [Cambridge]
8 University of Michigan [Ann Arbor]
9 UC Davis - University of California [Davis]
10 BCM - Baylor College of Medicine
11 European Molecular Biology Laboratory [Hinxton]
12 University of Toronto
13 University of Manitoba [Winnipeg]
14 Lunenfeld-Tanenbaum Research Institute [Toronto, Canada]
15 PHENOMIN - French National Infrastructure for Mouse Phenogenomics
16 JAX - The Jackson Laboratory [Bar Harbor]
17 EMBL-EBI - European Bioinformatics Institute [Hinxton]
18 Imperial College London
19 TUM - Technische Universität Munchen - Technical University Munich - Université Technique de Munich
20 DZNE - Deutsches Zentrum für Neurodegenerative Erkrankungen [Ulm]
21 SyNergy - Munich Cluster for systems neurology [Munich]
22 Garvan Institute of medical research
23 St. Vincent’s Clinical School [Sydney, Australia]
24 Université de Nouvelle-Galles du Sud - UNSW [Sydney, Australia]

The genetic landscape of diseases associated with changes in bone mineral density (BMD), such as osteoporosis, is only partially understood. Here, we explored data from 3,823 mutant mouse strains for BMD, a measure that is frequently altered in a range of bone pathologies, including osteoporosis. A total of 200 genes were found to significantly affect BMD. This pool of BMD genes comprised 141 genes with previously unknown functions in bone biology and was complementary to pools derived from recent human studies. Nineteen of the 141 genes also caused skeletal abnormalities. Examination of the BMD genes in osteoclasts and osteoblasts underscored BMD pathways, including vesicle transport, in these cells and together with in silico bone turnover studies resulted in the prioritization of candidate genes for further investigation. Overall, the results add novel pathophysiological and molecular insight into bone health and disease.

Domaines: Génétique

Anna Swan, Christine Schütt, Jan Rozman, Maria del Mar Muñiz Moreno, Stefan Brandmaier, et al.. Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density. PLoS Genetics, 2020, 16 (12), pp.e1009190. ⟨10.1371/journal.pgen.1009190⟩. ⟨hal-03433523⟩