Pathogenic effect of a TGFBR1 mutation in a family with Loeys-Dietz syndrome.
Loeys-Dietz syndrome
Myogenic transdifferentiation of fibroblasts
Smooth muscle-like cells
TGFBR1 mutation
Thoracic aortic aneurysm and aortic dissection
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:
10 2019
10 2019
Historique:
received:
07
08
2018
accepted:
30
07
2019
pubmed:
3
9
2019
medline:
23
6
2020
entrez:
3
9
2019
Statut:
ppublish
Résumé
Thoracic aortic aneurysms and dissections (TAAD) may have a heritable cause in up to 20% of cases. We aimed to investigate the pathogenic effect of a TGFBR1 mutation in relation to TAAD. Co-segregation analysis was performed followed by functional investigations, including myogenic transdifferentiation. The c.1043G>A TGFBR1 mutation was found in the index patient, in a deceased brother, and in five presymptomatic family members. Evidence for pathogenicity was found by the predicted damaging effect of this mutation and the co-segregation in the family. Functional analysis with myogenic transdifferentiation of dermal fibroblasts to smooth muscle-like cells, revealed increased myogenic differentiation in patient cells with the TGFBR1 mutation, shown by a higher expression of myogenic markers ACTA2, MYH11 and CNN1 compared to cells from healthy controls. Our findings confirm the pathogenic effect of the TGFBR1 mutation in causing TAAD in Loeys-Dietz syndrome and show increased myogenic differentiation of patient fibroblasts.
Sections du résumé
BACKGROUND
Thoracic aortic aneurysms and dissections (TAAD) may have a heritable cause in up to 20% of cases. We aimed to investigate the pathogenic effect of a TGFBR1 mutation in relation to TAAD.
METHODS
Co-segregation analysis was performed followed by functional investigations, including myogenic transdifferentiation.
RESULTS
The c.1043G>A TGFBR1 mutation was found in the index patient, in a deceased brother, and in five presymptomatic family members. Evidence for pathogenicity was found by the predicted damaging effect of this mutation and the co-segregation in the family. Functional analysis with myogenic transdifferentiation of dermal fibroblasts to smooth muscle-like cells, revealed increased myogenic differentiation in patient cells with the TGFBR1 mutation, shown by a higher expression of myogenic markers ACTA2, MYH11 and CNN1 compared to cells from healthy controls.
CONCLUSION
Our findings confirm the pathogenic effect of the TGFBR1 mutation in causing TAAD in Loeys-Dietz syndrome and show increased myogenic differentiation of patient fibroblasts.
Identifiants
pubmed: 31475485
doi: 10.1002/mgg3.943
pmc: PMC6785444
doi:
Substances chimiques
ACTA2 protein, human
0
Actins
0
MYH11 protein, human
0
Receptor, Transforming Growth Factor-beta Type I
EC 2.7.11.30
TGFBR1 protein, human
EC 2.7.11.30
Myosin Heavy Chains
EC 3.6.4.1
Types de publication
Case Reports
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e00943Informations de copyright
© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
Références
N Engl J Med. 2006 Aug 24;355(8):788-98
pubmed: 16928994
Nat Genet. 2011 Feb 27;43(4):365-9
pubmed: 21358634
Inflamm Bowel Dis. 2016 Sep;22(9):2058-2062
pubmed: 27508510
World J Biol Chem. 2012 Mar 26;3(3):41-52
pubmed: 22451850
J Cell Sci. 2004 Feb 15;117(Pt 5):667-75
pubmed: 14754903
J Med Genet. 2010 Jul;47(7):476-85
pubmed: 20591885
Clin Immunol. 2014 Jan;150(1):43-50
pubmed: 24333532
Circulation. 2011 Mar 1;123(8):924-8
pubmed: 21357847
Hum Mutat. 2017 Apr;38(4):439-450
pubmed: 28074631
Mol Genet Genomic Med. 2019 Oct;7(10):e00943
pubmed: 31475485
Circ Cardiovasc Genet. 2016 Dec;9(6):548-558
pubmed: 27879313
Nat Genet. 2012 Jul 27;44(8):838-9
pubmed: 22836090
Am J Med Genet. 1996 Apr 24;62(4):417-26
pubmed: 8723076
Cancer Res. 2009 Jul 15;69(14):5918-26
pubmed: 19584284
Arterioscler Thromb Vasc Biol. 2017 Jan;37(1):26-34
pubmed: 27879251
Can J Cardiol. 2016 Jan;32(1):26-34
pubmed: 26724508
Cardiovasc Res. 2010 Dec 1;88(3):520-9
pubmed: 20628007
Arch Surg. 1999 Apr;134(4):361-7
pubmed: 10199307
PLoS One. 2017 Oct 17;12(10):e0186603
pubmed: 29040313
Arterioscler Thromb Vasc Biol. 2015 Apr;35(4):960-72
pubmed: 25593132
J Med Genet. 2009 Sep;46(9):607-13
pubmed: 19542084
Science. 2014 May 2;344(6183):477-9
pubmed: 24786066
Nat Genet. 2005 Mar;37(3):275-81
pubmed: 15731757
Clin Genet. 2015;87(1):11-20
pubmed: 24867163
J Pathol. 2009 May;218(1):131-42
pubmed: 19224541
Eur Heart J. 2014 Nov 1;35(41):2873-926
pubmed: 25173340
Hum Mutat. 2018 May;39(5):621-634
pubmed: 29392890
Circ Res. 2015 Apr 10;116(8):1448-61
pubmed: 25858068
Genet Med. 2014 Aug;16(8):576-87
pubmed: 24577266
Ann Thorac Surg. 2006 Oct;82(4):1400-5
pubmed: 16996941