Germline Saturation Mutagenesis Induces Skeletal Phenotypes in Mice

ABSTRACT 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 satu...

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Bibliographic Details
Published in:Journal of bone and mineral research 2021-08, Vol.36 (8), p.1548-1565
Main Authors: Rios, Jonathan J, Denton, Kristin, Russell, Jamie, Kozlitina, Julia, Ferreira, Carlos R, Lewanda, Amy F, Mayfield, Joshua E, Moresco, Eva, Ludwig, Sara, Tang, Miao, Li, Xiaohong, Lyon, Stephen, Khanshour, Anas, Paria, Nandina, Khalid, Aysha, Li, Yang, Xie, Xudong, Feng, Jian Q, Xu, Qian, Lu, Yongbo, Hammer, Robert E, Wise, Carol A, Beutler, Bruce
Format: Article
Language:English
Subjects:
Animal models
Animals
Bone Diseases - genetics
Dual energy X-ray absorptiometry
DXA
Embryogenesis
Ethyl nitrosourea
Ethylnitrosourea
Feasibility studies
GENETIC ANIMAL MODELS
Genetic diversity
Germ Cells
Humans
Mice
Molecular modelling
MOLECULAR PATHWAYS—DEVELOPMENT
Mutagenesis
Mutation
OSTEOBLASTS
Phenotype
Phenotypes
Phosphotransferases (Alcohol Group Acceptor) - genetics
Saturation mutagenesis
WNT/B‐CATENIN/LRPs
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Summary:ABSTRACT 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. © 2021 American Society for Bone and Mineral Research (ASBMR).
ISSN:0884-0431
1523-4681
DOI:10.1002/jbmr.4323