TY - JOUR
T1 - Pathogenic effect of a TGFBR1 mutation in a family with Loeys–Dietz syndrome
AU - Cozijnsen, Luc
AU - Plomp, Astrid S.
AU - Post, Jan G.
AU - Pals, Gerard
AU - Bogunovic, Natalija
AU - Yeung, Kak K.
AU - Niessen, Hans W. M.
AU - Goumans, Marie-José T. H.
AU - Barge-Schaapveld, Daniela Q. C. M.
AU - Micha, Dimitra
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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.
AB - 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.
KW - Loeys–Dietz syndrome
KW - Myogenic transdifferentiation of fibroblasts
KW - Smooth muscle-like cells
KW - TGFBR1 mutation
KW - Thoracic aortic aneurysm and aortic dissection
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85071450839&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/31475485
U2 - https://doi.org/10.1002/mgg3.943
DO - https://doi.org/10.1002/mgg3.943
M3 - Article
C2 - 31475485
SN - 2324-9269
VL - 7
JO - Molecular genetics and genomic medicine
JF - Molecular genetics and genomic medicine
IS - 10
M1 - e943
ER -