Pathogenic effect of a TGFBR1 mutation in a family with Loeys–Dietz syndrome
Abstract 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, includin...
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doaj-927adda4807d40978d49bc3bb1b09e322020-11-25T02:00:09ZengWileyMolecular Genetics & Genomic Medicine2324-92692019-10-01710n/an/a10.1002/mgg3.943Pathogenic effect of a TGFBR1 mutation in a family with Loeys–Dietz syndromeLuc Cozijnsen0Astrid S. Plomp1Jan G. Post2Gerard Pals3Natalija Bogunovic4Kak K. Yeung5Hans W. M. Niessen6Marie‐José T. H. Goumans7Daniela Q. C. M. Barge‐Schaapveld8Dimitra Micha9Department of Cardiology Gelre Hospital Apeldoorn The NetherlandsDepartment of Clinical Genetics Amsterdam University Medical Centre, AMC Amsterdam The NetherlandsDepartment of Genetics University Medical Centre Utrecht The NetherlandsDepartment of Clinical Genetics Amsterdam University Medical Centre, VUMC, Amsterdam Cardiovascular Sciences Amsterdam The NetherlandsDepartment of Physiology Amsterdam University Medical Centre, VUMC, Amsterdam Cardiovascular Sciences Amsterdam The NetherlandsDepartment of Physiology Amsterdam University Medical Centre, VUMC, Amsterdam Cardiovascular Sciences Amsterdam The NetherlandsDepartment of Pathology and Cardiac Surgery Amsterdam University Medical Centre, VUMC, Amsterdam Cardiovascular Sciences Amsterdam The NetherlandsDepartment of Cell and Chemical Biology Leiden University Medical Centre Leiden The NetherlandsDepartment of Clinical Genetics Leiden University Medical Centre Leiden The NetherlandsDepartment of Clinical Genetics Amsterdam University Medical Centre, VUMC, Amsterdam Cardiovascular Sciences Amsterdam The NetherlandsAbstract 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.https://doi.org/10.1002/mgg3.943Loeys–Dietz syndromeMyogenic transdifferentiation of fibroblastsSmooth muscle‐like cellsTGFBR1 mutationThoracic aortic aneurysm and aortic dissection |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Luc Cozijnsen Astrid S. Plomp Jan G. Post Gerard Pals Natalija Bogunovic Kak K. Yeung Hans W. M. Niessen Marie‐José T. H. Goumans Daniela Q. C. M. Barge‐Schaapveld Dimitra Micha |
spellingShingle |
Luc Cozijnsen Astrid S. Plomp Jan G. Post Gerard Pals Natalija Bogunovic Kak K. Yeung Hans W. M. Niessen Marie‐José T. H. Goumans Daniela Q. C. M. Barge‐Schaapveld Dimitra Micha Pathogenic effect of a TGFBR1 mutation in a family with Loeys–Dietz syndrome Molecular Genetics & Genomic Medicine Loeys–Dietz syndrome Myogenic transdifferentiation of fibroblasts Smooth muscle‐like cells TGFBR1 mutation Thoracic aortic aneurysm and aortic dissection |
author_facet |
Luc Cozijnsen Astrid S. Plomp Jan G. Post Gerard Pals Natalija Bogunovic Kak K. Yeung Hans W. M. Niessen Marie‐José T. H. Goumans Daniela Q. C. M. Barge‐Schaapveld Dimitra Micha |
author_sort |
Luc Cozijnsen |
title |
Pathogenic effect of a TGFBR1 mutation in a family with Loeys–Dietz syndrome |
title_short |
Pathogenic effect of a TGFBR1 mutation in a family with Loeys–Dietz syndrome |
title_full |
Pathogenic effect of a TGFBR1 mutation in a family with Loeys–Dietz syndrome |
title_fullStr |
Pathogenic effect of a TGFBR1 mutation in a family with Loeys–Dietz syndrome |
title_full_unstemmed |
Pathogenic effect of a TGFBR1 mutation in a family with Loeys–Dietz syndrome |
title_sort |
pathogenic effect of a tgfbr1 mutation in a family with loeys–dietz syndrome |
publisher |
Wiley |
series |
Molecular Genetics & Genomic Medicine |
issn |
2324-9269 |
publishDate |
2019-10-01 |
description |
Abstract 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. |
topic |
Loeys–Dietz syndrome Myogenic transdifferentiation of fibroblasts Smooth muscle‐like cells TGFBR1 mutation Thoracic aortic aneurysm and aortic dissection |
url |
https://doi.org/10.1002/mgg3.943 |
work_keys_str_mv |
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