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

Swan, Anna L.; Schuett, Christine; Rozman, Jan; Moreno, Maria del Mar Muniz; Brandmaier, Stefan; Simon, Michelle; Leuchtenberger, Stefanie; Griffiths, Mark; Brommage, Robert; Keskivali-Bond, Piia; Grallert, Harald; Werner, Thomas; Teperino, Raffaele; Becker, Lore; Miller, Gregor; Moshiri, Ala; Seavitt, John R.; Cissell, Derek D.; Meehan, Terrence F.; Acar, Elif F.; Lelliott, Christopher J.; Flenniken, Ann M.; Champy, Marie-France; Sorg, Tania; Ayadi, Abdel; Braun, Robert E.; Cater, Heather; Dickinson, Mary E.; Flicek, Paul; Gallegos, Juan; Ghirardello, Elena J.; Heaney, Jason D.; Jacquot, Sylvie; Lally, Connor; Logan, John G.; Teboul, Lydia; Mason, Jeremy; Spielmann, Nadine; McKerlie, Colin; Murray, Stephen A.; Nutter, Lauryl M. J.; Odfalk, Kristian F.; Parkinson, Helen; Prochazka, Jan; Reynolds, Corey L.; Selloum, Mohammed; Spoutil, Frantisek; Svenson, Karen L.; Vales, Taylor S.; Wells, Sara E.; White, Jacqueline K.; Sedlacek, Radislav; Wurst, Wolfgang; Lloyd, Kent K. C.; Croucher, Peter; Fuchs, Helmut; Williams, Graham R.; Bassett, Duncan; Gailus-Durner, Valerie; Herault, Yann; Mallon, Ann-Marie; Brown, Steve D. M.; Mayer-Kuckuk, Philipp und de Angelis, Martin Hrabe (2020): Mouse mutant phenotyping at scale reveals novel genes controlling bone mineral density.
In: PLOS Genetics 16(12), e1009190

Abstract

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. Author summary Patients affected by osteoporosis frequently present with decreased BMD and increased fracture risk. Genes are known to control the onset and progression of bone diseases such as osteoporosis. Therefore, we aimed to identify osteoporosis-related genes using BMD measures obtained from a large pool of mutant mice genetically modified for deletion of individual genes (knockout mice). In a collaborative endeavor involving several research sites world-wide, we generated and phenotyped 3,823 knockout mice and identified 200 genes which regulated BMD. Of the 200 BMD genes, 141 genes were previously not known to affect BMD. The discovery and study of novel BMD genes will help to better understand the causes and therapeutic options for patients with low BMD. In the long run, this will improve the clinical management of osteoporosis.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin ; Medizin > Munich Cluster for Systems Neurology (SyNergy)
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 1553-7404
• Sprache: Englisch
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 390857198