Variants identified in PTK7 associated with neural tube defects.
PTK7
neural tube defects
planar cell polarity
Journal
Molecular genetics & genomic medicine
ISSN: 2324-9269
Titre abrégé: Mol Genet Genomic Med
Pays: United States
ID NLM: 101603758
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
13
09
2018
revised:
21
11
2018
accepted:
31
12
2018
pubmed:
29
1
2019
medline:
22
5
2019
entrez:
29
1
2019
Statut:
ppublish
Résumé
Variants in planar cell polarity (PCP) pathway genes have been repeatedly implicated in the pathogenesis of NTDs in both mouse models and in human cohorts. Mouse models indicate that the homogenous disruption of the Ptk7 gene, a PCP regulator, results in craniorachischisis; while embryos that are doubly heterozygous for Ptk7 In this study, we initially sequenced exons of the human PTK7 gene in 192 spina bifida patients and 190 controls from a California population. A phase II validation study was performed in 343 Chinese NTD cohort. Functional assays including immunoblotting and immunoprecipitation were used to study identified variants effect on PTK7 function. We identified three rare (MAF <0.001) missense heterozygous PTK7 variants (NM_001270398.1:c.581C>T, p.Arg630Ser and p.Tyr725Phe) in the spina bifida patients. In our functional analyses, p.Arg630Ser affected PTK7 mutant protein stability and increased interaction with Dvl2, while the p.Thr186Met variant decreased PTK7 interactions with Dvl2. No novel predicted-to-be-damaging variant or function-disrupted PTK7 variant was identified among the control subjects. We subsequently re-sequenced the PTK7 CDS region in 343 NTDs from China to validate the association between PTK7 and NTDs. The frequency of PTK7 rare missense variants in the Chinese NTD samples is significantly higher than in gnomAD controls. Our study suggests that rare missense variants in PTK7 contribute to the genetic risk of NTDs.
Sections du résumé
BACKGROUND
Variants in planar cell polarity (PCP) pathway genes have been repeatedly implicated in the pathogenesis of NTDs in both mouse models and in human cohorts. Mouse models indicate that the homogenous disruption of the Ptk7 gene, a PCP regulator, results in craniorachischisis; while embryos that are doubly heterozygous for Ptk7
METHODS
In this study, we initially sequenced exons of the human PTK7 gene in 192 spina bifida patients and 190 controls from a California population. A phase II validation study was performed in 343 Chinese NTD cohort. Functional assays including immunoblotting and immunoprecipitation were used to study identified variants effect on PTK7 function.
RESULTS
We identified three rare (MAF <0.001) missense heterozygous PTK7 variants (NM_001270398.1:c.581C>T, p.Arg630Ser and p.Tyr725Phe) in the spina bifida patients. In our functional analyses, p.Arg630Ser affected PTK7 mutant protein stability and increased interaction with Dvl2, while the p.Thr186Met variant decreased PTK7 interactions with Dvl2. No novel predicted-to-be-damaging variant or function-disrupted PTK7 variant was identified among the control subjects. We subsequently re-sequenced the PTK7 CDS region in 343 NTDs from China to validate the association between PTK7 and NTDs. The frequency of PTK7 rare missense variants in the Chinese NTD samples is significantly higher than in gnomAD controls.
CONCLUSION
Our study suggests that rare missense variants in PTK7 contribute to the genetic risk of NTDs.
Identifiants
pubmed: 30689296
doi: 10.1002/mgg3.584
pmc: PMC6465732
doi:
Substances chimiques
Cell Adhesion Molecules
0
PTK7 protein, human
EC 2.7.10.1
Receptor Protein-Tyrosine Kinases
EC 2.7.10.1
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
e00584Subventions
Organisme : NICHD NIH HHS
ID : R01 HD081216
Pays : United States
Organisme : NCBDD CDC HHS
ID : U01 DD001226
Pays : United States
Organisme : NCBDD CDC HHS
ID : U01 DD001033
Pays : United States
Informations de copyright
© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
Références
N Engl J Med. 2010 Jun 10;362(23):2232-5
pubmed: 20558380
Birth Defects Res A Clin Mol Teratol. 2010 Aug;88(8):653-69
pubmed: 20740593
Hum Mutat. 2015 Mar;36(3):342-9
pubmed: 25546815
J Biol Chem. 2010 Nov 12;285(46):35740-9
pubmed: 20837484
Hum Mol Genet. 2011 Nov 15;20(22):4324-33
pubmed: 21840926
Hum Mutat. 2012 Feb;33(2):440-7
pubmed: 22095531
PLoS One. 2014 Mar 14;9(3):e92207
pubmed: 24632739
Cell Res. 2018 Oct;28(10):1039-1041
pubmed: 29976953
Clin Sci (Lond). 2016 Dec 1;130(24):2329-2340
pubmed: 27756857
Hum Mutat. 2012 Oct;33(10):1450-5
pubmed: 22610794
Hum Mutat. 2011 Dec;32(12):1371-5
pubmed: 21901791
Development. 2011 Apr;138(7):1321-7
pubmed: 21350015
N Engl J Med. 1999 Nov 11;341(20):1509-19
pubmed: 10559453
Hum Mutat. 2009 Jul;30(7):E706-15
pubmed: 19319979
Front Cell Dev Biol. 2017 Apr 05;5:31
pubmed: 28424771
Mol Genet Metab. 2018 May;124(1):94-100
pubmed: 29573971
Semin Cell Dev Biol. 2009 Oct;20(8):986-97
pubmed: 19761865
N Engl J Med. 1992 Dec 24;327(26):1832-5
pubmed: 1307234
PLoS One. 2016 Aug 04;11(8):e0160519
pubmed: 27490490
Hum Mutat. 2012 Feb;33(2):384-90
pubmed: 22045688
J Cell Sci. 2017 Jun 1;130(11):1890-1903
pubmed: 28420671
Development. 2009 Jun;136(12):2039-48
pubmed: 19439496
PLoS One. 2013 Jul 26;8(7):e69262
pubmed: 23922697
BMC Med Genomics. 2018 Apr 4;11(1):38
pubmed: 29618362
Clin Genet. 2007 Apr;71(4):295-310
pubmed: 17470131
Annu Rev Genet. 2014;48:583-611
pubmed: 25292356
N Engl J Med. 1999 Nov 11;341(20):1485-90
pubmed: 10559448
Birth Defects Res A Clin Mol Teratol. 2012 Mar;94(3):176-81
pubmed: 22371354
Clin Genet. 2011 Jul;80(1):76-82
pubmed: 20738329
Hum Mol Genet. 2014 Apr 1;23(7):1687-99
pubmed: 24203697
Nature. 2004 Jul 1;430(6995):93-8
pubmed: 15229603
Mol Genet Genomic Med. 2019 Apr;7(4):e00584
pubmed: 30689296
PLoS One. 2016 Apr 11;11(4):e0151586
pubmed: 27064786
Arch Biochem Biophys. 2012 Aug 1;524(1):71-6
pubmed: 22230326
EMBO J. 2011 Jul 19;30(18):3729-40
pubmed: 21772251
Lancet. 1991 Jul 20;338(8760):131-7
pubmed: 1677062
J Neuroradiol. 2004 Jan;31(1):3-24
pubmed: 15026728
Development. 2008 Dec;135(24):4015-24
pubmed: 19004858
N Engl J Med. 2007 Apr 5;356(14):1432-7
pubmed: 17409324
Birth Defects Res A Clin Mol Teratol. 2015 Dec;103(12):1021-7
pubmed: 26368655
Paediatr Perinat Epidemiol. 1991 Oct;5(4):423-7
pubmed: 1754501
Hum Genet. 2018 Mar;137(3):195-202
pubmed: 29423651