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Case Reports
. 2019 Oct;7(10):e00943.
doi: 10.1002/mgg3.943. Epub 2019 Sep 1.

Pathogenic effect of a TGFBR1 mutation in a family with Loeys-Dietz syndrome

Luc Cozijnsen  1 , Astrid S Plomp  2 , Jan G Post  3 , Gerard Pals  4 , Natalija Bogunovic  5   6 , Kak K Yeung  5   6 , Hans W M Niessen  7 , Marie-José T H Goumans  8 , Daniela Q C M Barge-Schaapveld  9 , Dimitra Micha  4
Affiliations
Case Reports

Pathogenic effect of a TGFBR1 mutation in a family with Loeys-Dietz syndrome

Luc Cozijnsen et al. Mol Genet Genomic Med. 2019 Oct.

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.

Keywords: Loeys-Dietz syndrome; Myogenic transdifferentiation of fibroblasts; Smooth muscle-like cells; TGFBR1 mutation; Thoracic aortic aneurysm and aortic dissection.

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Conflict of interest statement

None of the authors have any conflicts of interest to report.

Figures

Figure 1
Figure 1
Pedigree of the family. Three generation pedigree of the family. Arrow indicates the index patient II.5. Family members with ± are tested: “+” are carriers (including one deceased, obligate carrier, II.2), “−” are noncarriers. Symbols with slashes indicate deceased family members. Black filled‐in symbols indicate affected mutation carriers. Right: photographs of the mouth of the index patient II.5 and one of her sons III.7 revealing split uvulas
Figure 2
Figure 2
Analysis of myogenic transdifferentiation. (a) Increased myogenic transdifferentiation of fibroblasts of patients with the TGFBR1 c.1043G>A mutation. Dermal fibroblasts (FIB) from patients (n = 4) and healthy controls (n = 4) were subjected to myogenic transdifferentiation (MYO) for 14 days. Expression of ACTA2, SM22, CNN1 and MYH11 mRNA was measured by qPCR. Relative expression was normalized based on expression of TBP. Each square indicates the average of gene expression per group per condition and error bars ± standard deviation. p values lower than .05 (p < .05) were considered to be significant based on Mann–Whitney test. (b) Protein expression of myogenic markers after myogenic transdifferentiation of fibroblasts with the TGFBR1 c.1043G>A mutation. Dermal fibroblasts (FIB) of the indicated patients and healthy controls (c) were subjected to myogenic transdifferentiation (MYO) for 14 days. Expression of αSMA, calponin, MYH11 and SM22 in whole cell lysates was measured by western blotting. Actin was used as loading control. The expression was quantified and normalized based on the expression of the housekeeping gene. Each square indicates the average of patients or controls, before (FIB) or after myogenic transdifferentiation (MYO); errors bars show the standard deviation per group. Differences were significant (*) when p < .05 measured by Mann–Whitney test
See this image and copyright information in PMC

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