De Novo Mutations in FOXJ1 Result in a Motile Ciliopathy with Hydrocephalus and Randomization of Left/Right Body Asymmetry.
FOXJ1
cilia
ciliogenesis
ependyma
hydrocephalus
lung disease
Journal
American journal of human genetics
ISSN: 1537-6605
Titre abrégé: Am J Hum Genet
Pays: United States
ID NLM: 0370475
Informations de publication
Date de publication:
07 11 2019
07 11 2019
Historique:
received:
05
04
2019
accepted:
18
09
2019
pubmed:
22
10
2019
medline:
1
4
2020
entrez:
22
10
2019
Statut:
ppublish
Résumé
Hydrocephalus is one of the most prevalent form of developmental central nervous system (CNS) malformations. Cerebrospinal fluid (CSF) flow depends on both heartbeat and body movement. Furthermore, it has been shown that CSF flow within and across brain ventricles depends on cilia motility of the ependymal cells lining the brain ventricles, which play a crucial role to maintain patency of the narrow sites of CSF passage during brain formation in mice. Using whole-exome and whole-genome sequencing, we identified an autosomal-dominant cause of a distinct motile ciliopathy related to defective ciliogenesis of the ependymal cilia in six individuals. Heterozygous de novo mutations in FOXJ1, which encodes a well-known member of the forkhead transcription factors important for ciliogenesis of motile cilia, cause a motile ciliopathy that is characterized by hydrocephalus internus, chronic destructive airway disease, and randomization of left/right body asymmetry. Mutant respiratory epithelial cells are unable to generate a fluid flow and exhibit a reduced number of cilia per cell, as documented by high-speed video microscopy (HVMA), transmission electron microscopy (TEM), and immunofluorescence analysis (IF). TEM and IF demonstrate mislocalized basal bodies. In line with this finding, the focal adhesion protein PTK2 displays aberrant localization in the cytoplasm of the mutant respiratory epithelial cells.
Identifiants
pubmed: 31630787
pii: S0002-9297(19)30362-3
doi: 10.1016/j.ajhg.2019.09.022
pmc: PMC6849114
pii:
doi:
Substances chimiques
FOXJ1 protein, human
0
Forkhead Transcription Factors
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
1030-1039Subventions
Organisme : Department of Health
ID : NIHR-HCS-P13-04-004
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R01 HL128370
Pays : United States
Organisme : NHLBI NIH HHS
ID : U54 HL096458
Pays : United States
Organisme : NHGRI NIH HHS
ID : UM1 HG006504
Pays : United States
Informations de copyright
Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
Références
Nat Rev Mol Cell Biol. 2007 Nov;8(11):880-93
pubmed: 17955020
Nat Genet. 2002 Feb;30(2):143-4
pubmed: 11788826
Nat Commun. 2014 Jul 22;5:4418
pubmed: 25048963
Biochem Biophys Res Commun. 2004 Nov 26;324(4):1413-20
pubmed: 15504371
Development. 2014 Apr;141(7):1427-41
pubmed: 24644260
Ann Am Thorac Soc. 2013 Dec;10(6):574-81
pubmed: 24024753
Nat Genet. 2008 Dec;40(12):1445-53
pubmed: 19011630
Eur Respir J. 2016 Apr;47(4):1103-12
pubmed: 26917608
Hum Mutat. 2016 Apr;37(4):396-405
pubmed: 26777464
Pediatr Pulmonol. 2015 Dec;50(12):1374-82
pubmed: 25731630
Proc Natl Acad Sci U S A. 2007 Oct 2;104(40):15765-70
pubmed: 17884984
Lancet. 2016 Feb 20;387(10020):788-99
pubmed: 26256071
Am J Hum Genet. 2008 Jul;83(1):89-93
pubmed: 18571142
Am J Respir Cell Mol Biol. 1999 Aug;21(2):168-76
pubmed: 10423398
Front Genet. 2019 Mar 01;10:23
pubmed: 30881373
Nature. 2016 Aug 17;536(7616):285-91
pubmed: 27535533
Nat Genet. 2011 Jan;43(1):79-84
pubmed: 21131974
Nat Commun. 2018 Apr 25;9(1):1655
pubmed: 29695808
Nat Genet. 2014 Jun;46(6):646-51
pubmed: 24747639
J Cell Sci. 2004 Mar 15;117(Pt 8):1329-37
pubmed: 14996907
Am J Respir Cell Mol Biol. 2015 Oct;53(4):563-73
pubmed: 25789548
Hum Mol Genet. 2004 Sep 15;13(18):2133-41
pubmed: 15269178
Proc Natl Acad Sci U S A. 1995 May 9;92(10):4249-53
pubmed: 7753791
Am J Respir Cell Mol Biol. 2000 Jul;23(1):45-51
pubmed: 10873152
Biol Chem. 2016 Aug 1;397(8):791-801
pubmed: 27021259
Eur Respir J. 2017 Jan 4;49(1):
pubmed: 27836958
Hum Reprod. 2015 Dec;30(12):2871-80
pubmed: 26373788
Am J Hum Genet. 2008 Nov;83(5):547-58
pubmed: 18950741
Circulation. 2007 Jun 5;115(22):2814-21
pubmed: 17515466
Paediatr Respir Rev. 2016 Mar;18:25-32
pubmed: 26545972
Brain. 2012 Aug;135(Pt 8):2409-15
pubmed: 22763745
Eur Respir J. 2017 Nov 9;50(5):
pubmed: 29122913
J Clin Invest. 1998 Sep 15;102(6):1077-82
pubmed: 9739041
Nat Genet. 2008 Dec;40(12):1454-60
pubmed: 19011629
Hum Mol Genet. 2000 Apr 12;9(7):1021-32
pubmed: 10767326
Hum Mutat. 2013 Mar;34(3):462-72
pubmed: 23255504
Front Genet. 2019 Mar 11;10:127
pubmed: 30915099
Development. 2009 Dec;136(23):4021-31
pubmed: 19906869
Dev Cell. 2014 Jan 13;28(1):70-80
pubmed: 24434137
Nat Genet. 2011 Jan;43(1):72-8
pubmed: 21131972
Pediatr Pulmonol. 2016 Feb;51(2):115-32
pubmed: 26418604
Curr Biol. 2019 Jan 21;29(2):229-241.e6
pubmed: 30612902