Germline Saturation Mutagenesis Induces Skeletal Phenotypes in Mice

Jonathan J. Rios, Kristin Denton, Jamie Russell, Julia Kozlitina, Carlos R. Ferreira, Amy F. Lewanda, Joshua E. Mayfield, Eva Moresco, Sara Ludwig, Miao Tang, Xiaohong Li, Stephen Lyon, Anas Khanshour, Nandina Paria, Aysha Khalid, Yang Li, Xudong Xie, Jian Q. Feng, Qian Xu, Yongbo LuRobert E. Hammer, Carol A. Wise, Bruce Beutler

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


Proper embryonic and postnatal skeletal development require coordination of myriad complex molecular mechanisms. Disruption of these processes, through genetic mutation, contributes to variation in skeletal development. We developed a high-throughput N-ethyl-N-nitrosourea (ENU)-induced saturation mutagenesis skeletal screening approach in mice to identify genes required for proper skeletal development. Here, we report initial results from live-animal X-ray and dual-energy X-ray absorptiometry (DXA) imaging of 27,607 G3 mice from 806 pedigrees, testing the effects of 32,198 coding/splicing mutations in 13,020 genes. A total of 39.7% of all autosomal genes were severely damaged or destroyed by mutations tested twice or more in the homozygous state. Results from our study demonstrate the feasibility of in vivo mutagenesis to identify mouse models of skeletal disease. Furthermore, our study demonstrates how ENU mutagenesis provides opportunities to create and characterize putative hypomorphic mutations in developmentally essential genes. Finally, we present a viable mouse model and case report of recessive skeletal disease caused by mutations in FAM20B. Results from this study, including engineered mouse models, are made publicly available via the online Mutagenetix database.

Original languageEnglish (US)
Pages (from-to)1548-1565
Number of pages18
JournalJournal of Bone and Mineral Research
Issue number8
StatePublished - Aug 2021


  • DXA

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine


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