Genetic association and characterization of FSTL5 in isolated clubfoot.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
21 01 2021
21 01 2021
Historique:
received:
10
08
2020
revised:
28
09
2020
accepted:
14
10
2020
pubmed:
27
10
2020
medline:
10
9
2021
entrez:
26
10
2020
Statut:
ppublish
Résumé
Talipes equinovarus (clubfoot, TEV) is a congenital rotational foot deformity occurring in 1 per 1000 births with increased prevalence in males compared with females. The genetic etiology of isolated clubfoot (iTEV) remains unclear. Using a genome-wide association study, we identified a locus within FSTL5, encoding follistatin-like 5, significantly associated with iTEV. FSTL5 is an uncharacterized gene whose potential role in embryonic and postnatal development was previously unstudied. Utilizing multiple model systems, we found that Fstl5 was expressed during later stages of embryonic hindlimb development, and, in mice, expression was restricted to the condensing cartilage anlage destined to form the limb skeleton. In the postnatal growth plate, Fstl5 was specifically expressed in prehypertrophic chondrocytes. As Fstl5 knockout rats displayed no gross malformations, we engineered a conditional transgenic mouse line (Fstl5LSL) to overexpress Fstl5 in skeletal osteochondroprogenitors. We observed that hindlimbs were slightly shorter and that bone mineral density was reduced in adult male, but not female, Prrx1-cre;Fstl5LSL mice compared with control. No overt clubfoot-like deformity was observed in Prrx1-cre;Fstl5LSL mice, suggesting FSTL5 may function in other cell types to contribute to iTEV pathogenesis. Interrogating published mouse embryonic single-cell expression data showed that Fstl5 was expressed in cell lineage subclusters whose transcriptomes were associated with neural system development. Moreover, our results suggest that lineage-specific expression of the Fstl genes correlates with their divergent roles as modulators of transforming growth factor beta and bone morphogenetic protein signaling. Results from this study associate FSTL5 with iTEV and suggest a potential sexually dimorphic role for Fstl5 in vivo.
Identifiants
pubmed: 33105483
pii: 5940462
doi: 10.1093/hmg/ddaa236
pmc: PMC7823076
doi:
Substances chimiques
FSTL5 protein, human
0
Follistatin-Related Proteins
0
Homeodomain Proteins
0
Prrx1 protein, mouse
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3717-3728Subventions
Organisme : NHLBI NIH HHS
ID : HHSN268201100012C
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201100009I
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201100010C
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201100008C
Pays : United States
Organisme : NIH HHS
ID : R24 OD011108
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201100007C
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201100011I
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201100011C
Pays : United States
Organisme : NHGRI NIH HHS
ID : U01 HG004402
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201100006C
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201100005I
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201100005G
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201100008I
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201100009C
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201100005C
Pays : United States
Organisme : NHLBI NIH HHS
ID : HHSN268201100007I
Pays : United States
Organisme : NIAMS NIH HHS
ID : R01 AR067715
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD036022
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD053889
Pays : United States
Organisme : NICHD NIH HHS
ID : R01 HD043342
Pays : United States
Organisme : Biotechnology and Biological Sciences Research Council
Pays : United Kingdom
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Références
Am J Hum Genet. 1998 Oct;63(4):1153-9
pubmed: 9758599
Exp Biol Med (Maywood). 2002 Oct;227(9):724-52
pubmed: 12324653
Nature. 2003 May 15;423(6937):332-6
pubmed: 12748651
Am J Med Genet. 1998 Sep 1;79(2):90-6
pubmed: 9741465
Development. 2018 Feb 8;145(3):
pubmed: 29439133
Bioinformatics. 2010 Sep 15;26(18):2336-7
pubmed: 20634204
Am J Med Genet A. 2013 Jul;161A(7):1569-78
pubmed: 23686911
Am J Med Genet A. 2012 Jul;158A(7):1620-7
pubmed: 22678995
Am J Hum Genet. 2010 Jul 9;87(1):154-60
pubmed: 20598276
Am J Epidemiol. 1989 Apr;129(4):687-702
pubmed: 2646917
Nature. 1995 Mar 23;374(6520):360-3
pubmed: 7885475
Clin Orthop Relat Res. 1972 May;84:9-13
pubmed: 5032855
Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):7058-63
pubmed: 21482757
Birth Defects Res C Embryo Today. 2013 Mar;99(1):61-9
pubmed: 23723173
Development. 2000 Aug;127(15):3313-24
pubmed: 10887087
BMC Evol Biol. 2004 Nov 04;4:43
pubmed: 15527507
J Med Genet. 2014 May;51(5):334-9
pubmed: 24667120
PLoS One. 2008 Feb 06;3(2):e1533
pubmed: 18253481
N Z Med J. 1978 Aug 23;88(618):144-6
pubmed: 280791
J Anat. 2013 Jul;223(1):1-13
pubmed: 23678942
Gene Expr Patterns. 2007 Feb;7(4):491-500
pubmed: 17129766
Am J Hum Genet. 2012 Oct 5;91(4):629-35
pubmed: 23022097
J Pediatr Orthop. 2020 Nov/Dec;40(10):597-603
pubmed: 32558742
PLoS One. 2011;6(8):e22616
pubmed: 21826198
Nat Genet. 2012 Jul 22;44(8):955-9
pubmed: 22820512
Nat Protoc. 2011 Sep 08;6(10):1521-35
pubmed: 21959235
Gene Expr Patterns. 2015 Sep-Nov;19(1-2):45-51
pubmed: 26220830
Gigascience. 2015 Feb 25;4:7
pubmed: 25722852
Development. 2015 Mar 1;142(5):817-31
pubmed: 25715393
Genet Epidemiol. 2010 Dec;34(8):816-34
pubmed: 21058334
Nat Methods. 2010 Jun;7(6):443-5
pubmed: 20473302
PLoS One. 2009;4(4):e5173
pubmed: 19352514
J Pediatr Orthop B. 2012 Jan;21(1):7-9
pubmed: 21817922
Ann Rheum Dis. 2015 Jul;74(7):1467-73
pubmed: 24641944
Proc Natl Acad Sci U S A. 2007 Jan 23;104(4):1348-53
pubmed: 17229845
Nat Genet. 2016 May;48(5):528-36
pubmed: 27019111
Proc Natl Acad Sci U S A. 2002 Nov 12;99(23):14931-6
pubmed: 12391306
Nature. 2003 May 15;423(6937):316-8
pubmed: 12748648
J Clin Endocrinol Metab. 2010 Feb;95(2):800-9
pubmed: 19965915
Nat Methods. 2009 Jun;6(6):415-22
pubmed: 19478801
Science. 2020 Feb 14;367(6479):
pubmed: 31974159
Genes Dev. 2000 Mar 15;14(6):627-44
pubmed: 10733523
Biol Reprod. 2009 Jul;81(1):77-86
pubmed: 19299316
Neurobiol Learn Mem. 2018 Jul;152:61-70
pubmed: 29783061
Nature. 2019 Feb;566(7745):496-502
pubmed: 30787437
Am J Cardiol. 2004 Jun 15;93(12):1473-80
pubmed: 15194016
Clin Orthop Relat Res. 2009 May;467(5):1278-82
pubmed: 19242767
Mol Endocrinol. 2004 Jan;18(1):228-40
pubmed: 14563935
Am J Hum Genet. 2008 Nov;83(5):616-22
pubmed: 18950742
Eur J Hum Genet. 2013 Apr;21(4):373-80
pubmed: 22892537
Hum Mol Genet. 2011 Oct 15;20(20):3943-52
pubmed: 21775501