Germline Saturation Mutagenesis Induces Skeletal Phenotypes in Mice.
DXA
GENETIC ANIMAL MODELS
MOLECULAR PATHWAYS-DEVELOPMENT
OSTEOBLASTS
WNT/B-CATENIN/LRPs
Journal
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
ISSN: 1523-4681
Titre abrégé: J Bone Miner Res
Pays: United States
ID NLM: 8610640
Informations de publication
Date de publication:
08 2021
08 2021
Historique:
revised:
07
04
2021
received:
06
10
2020
accepted:
21
04
2021
pubmed:
28
4
2021
medline:
10
8
2021
entrez:
27
4
2021
Statut:
ppublish
Résumé
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).
Identifiants
pubmed: 33905568
doi: 10.1002/jbmr.4323
pmc: PMC8862308
mid: NIHMS1777663
doi:
Substances chimiques
FAM20B protein, mouse
0
FAM20B protein, human
EC 2.7.1.-
Phosphotransferases (Alcohol Group Acceptor)
EC 2.7.1.-
Ethylnitrosourea
P8M1T4190R
Types de publication
Case Reports
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1548-1565Subventions
Organisme : NIAID NIH HHS
ID : R01 AI125581
Pays : United States
Organisme : NIAID NIH HHS
ID : U19 AI100627
Pays : United States
Informations de copyright
© 2021 American Society for Bone and Mineral Research (ASBMR).
Références
Am J Hum Genet. 2010 Feb 12;86(2):126-37
pubmed: 20137779
PLoS One. 2018 Jul 26;13(7):e0200785
pubmed: 30048462
Hum Mol Genet. 2015 Dec 15;24(24):7075-86
pubmed: 26427607
Proc Natl Acad Sci U S A. 1997 Mar 4;94(5):1852-6
pubmed: 9050868
Nature. 2015 Oct 1;526(7571):112-7
pubmed: 26367794
Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8214-9
pubmed: 8710849
J Bone Miner Res. 2014 Mar;29(3):761-9
pubmed: 23929766
Mamm Genome. 1999 Dec;10(12):1119-25
pubmed: 10594233
Mol Endocrinol. 2007 Jul;21(7):1593-602
pubmed: 17440044
Nat Genet. 2012 Apr 15;44(5):491-501
pubmed: 22504420
Horm Metab Res. 2016 Nov;48(11):745-754
pubmed: 27871115
Biomed Res Int. 2014;2014:495764
pubmed: 25126564
Nat Commun. 2018 Jan 30;9(1):441
pubmed: 29382827
Nucleic Acids Res. 2018 Jul 2;46(W1):W350-W355
pubmed: 29718330
J Embryol Exp Morphol. 1978 Feb;43:71-84
pubmed: 632744
Genes Dev. 1995 Nov 15;9(22):2821-30
pubmed: 7590256
Nat Genet. 2006 Nov;38(11):1310-5
pubmed: 17033621
J Hered. 1986 May-Jun;77(3):205-6
pubmed: 3734407
Am J Hum Genet. 2009 Jan;84(1):72-9
pubmed: 19110214
Protein Sci. 2021 Jan;30(1):20-30
pubmed: 32734663
Nat Genet. 1994 Jun;7(2):154-7
pubmed: 7920633
Development. 1996 Dec;123:37-46
pubmed: 9007227
J Cell Physiol. 2016 Jul;231(7):1468-75
pubmed: 26595451
PLoS One. 2011;6(12):e29422
pubmed: 22206015
Am J Med Genet A. 2016 Oct;170(10):2711-8
pubmed: 27320698
Am J Med Genet A. 2011 May;155A(5):943-68
pubmed: 21438135
Nat Commun. 2016 Aug 18;7:12444
pubmed: 27534441
Best Pract Res Clin Endocrinol Metab. 2017 Mar;31(2):225-240
pubmed: 28648510
Bone. 2018 Oct;115:50-58
pubmed: 28844835
J Biol Chem. 2014 Aug 1;289(31):21533-43
pubmed: 24917674
Endocr Rev. 2002 Jun;23(3):303-26
pubmed: 12050122
Nat Med. 2011 Jun;17(6):684-91
pubmed: 21602802
Clin Genet. 2019 Jun;95(6):713-717
pubmed: 30847897
Rheumatology (Oxford). 2011 Dec;50 Suppl 5:v19-25
pubmed: 22210666
Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12956-61
pubmed: 16126903
Am J Med Genet A. 2010 May;152A(5):1157-60
pubmed: 20425819
Am J Hum Genet. 2002 Aug;71(2):389-94
pubmed: 12058348
Hum Genet. 2014 Jan;133(1):29-39
pubmed: 23982343
Nat Commun. 2018 Mar 23;9(1):1218
pubmed: 29572475
J Med Genet. 2018 Jul;55(7):489-496
pubmed: 29514872
Development. 2004 Apr;131(8):1663-77
pubmed: 15084453
Am J Med Genet. 1986 Oct;25(2):273-9
pubmed: 3096137
Development. 2004 Mar;131(5):1187-94
pubmed: 14973274
Am J Hum Genet. 2014 Mar 6;94(3):405-14
pubmed: 24581741
Mol Cell Biol. 2004 Jun;24(11):4677-84
pubmed: 15143163
Clin Genet. 2004 Sep;66(3):208-13
pubmed: 15324318
J Dent Res. 2014 Jan;93(1):42-8
pubmed: 24196488
Mol Genet Metab. 2014 Feb;111(2):116-22
pubmed: 24100243
J Biol Chem. 2003 May 9;278(19):17500-8
pubmed: 12615915
Am J Hum Genet. 2002 Jan;70(1):11-9
pubmed: 11741193
Nat Med. 2013 Feb;19(2):179-92
pubmed: 23389618
Nature. 2016 Sep 22;537(7621):508-514
pubmed: 27626380
Proc Natl Acad Sci U S A. 2015 Feb 3;112(5):E440-9
pubmed: 25605905
Proc Natl Acad Sci U S A. 1998 Aug 18;95(17):9909-13
pubmed: 9707574
Orphanet J Rare Dis. 2020 Apr 16;15(1):93
pubmed: 32299476
N Engl J Med. 2002 Jul 11;347(2):95-102
pubmed: 12110737
PLoS Comput Biol. 2014 Apr 24;10(4):e1003569
pubmed: 24762569
Biochem J. 2009 Jun 26;421(2):157-62
pubmed: 19473117
Cell. 2001 Nov 16;107(4):513-23
pubmed: 11719191
Methods Mol Biol. 2008;415:1-16
pubmed: 18370145
Bone. 2020 Feb;131:115151
pubmed: 31751752
Dev Cell. 2006 Mar;10(3):317-27
pubmed: 16516835
J Cell Biol. 2002 Apr 15;157(2):303-14
pubmed: 11956231
Biochem Biophys Res Commun. 2012 Aug 3;424(3):641-6
pubmed: 22813642
Nature. 2015 Mar 12;519(7542):223-8
pubmed: 25533962
J Bone Miner Res. 2003 Jun;18(6):960-74
pubmed: 12817748
Am J Hum Genet. 2015 Jun 4;96(6):971-8
pubmed: 26027496
Eur J Pediatr. 1994 Feb;153(2):56-65
pubmed: 8157027
Am J Med Genet A. 2004 Jan 1;124A(1):54-9
pubmed: 14679587
Dis Model Mech. 2013 Nov;6(6):1316-24
pubmed: 24046356
J Bone Miner Res. 2013 Jul;28(7):1509-18
pubmed: 23630111
J Bone Miner Res. 2013 Sep;28(9):1962-74
pubmed: 23526378
Endocr Dev. 2011;21:30-41
pubmed: 21865752
Free Radic Biol Med. 2010 Dec 15;49(12):2040-8
pubmed: 21146788
Nat Rev Endocrinol. 2019 Jun;15(6):323-338
pubmed: 30886364
J Med Genet. 2016 Aug;53(8):568-74
pubmed: 27055475
N Engl J Med. 2002 May 16;346(20):1513-21
pubmed: 12015390
Cell Res. 2002 Mar;12(1):19-32
pubmed: 11942407
Open Biol. 2012 May;2(5):120061
pubmed: 22724066
Dis Model Mech. 2018 Sep 27;11(9):
pubmed: 30279225
Hum Mol Genet. 2006 Apr 1;15(7):1225-36
pubmed: 16505002
J Clin Invest. 1991 Dec;88(6):1901-5
pubmed: 1752952
Ann Hum Genet. 2020 Jan;84(1):102-106
pubmed: 31571209
Dev Biol. 2021 Mar;471:18-33
pubmed: 33290818
Nat Genet. 2017 Oct;49(10):1468-1475
pubmed: 28869591
Mol Cell Biol. 2005 Jun;25(12):4946-55
pubmed: 15923613
Am J Hum Genet. 2011 Jul 15;89(1):15-27
pubmed: 21763480
Vet Pathol. 2012 Nov;49(6):998-1017
pubmed: 22732358
Am J Pathol. 2013 May;182(5):1462-73
pubmed: 23608223
J Exp Med. 2020 Apr 6;217(4):
pubmed: 31985756
FEBS J. 2019 Aug;286(15):3008-3032
pubmed: 31286677
Genes Dev. 1999 Oct 1;13(19):2549-61
pubmed: 10521399