PMC5149071_01
Clinical and Molecular Findings. A. Family pedigree with multiple cases of aneurysms and dissections suggesting
autosomal dominant inheritance. The variant was detected in the index case
(IV:10) and III:1, IV:3 and IV:5. B. CT images showing an intimal
flap (red arrows) extending from the aortic valve into the thoracic aorta.
C. Elastin staining of IV:10 aorta showing extensive elastic
fibre fragmentation at the site of dissection (scale bar=6mm). D.
Sequencing chromatogram showing a missense variant (c.958C>T) in exon 6
of TGFB2. The variant is in a region of TGFB2 that is highly conserved across
species. SP; signal peptide, LAP; latency-associated-peptide.
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F1
The family history revealed several family members with aortic aneurysms and dissections: his mother (III:6) died following an aortic dissection, a maternal uncle (III:1) had emergency repair of an aortic aneurysm and his maternal grandfather (II:3) had a dissection of an abdominal aortic aneurysm and separate iliac artery aneurysms (Figure 1A). A CT scan with contrast showed a Stanford type-A dissection with an intimal flap extending the full length of the aorta from the aortic valve into both iliac arteries (Figure 1B). Histologic examination showed fragmentation and disruption of the aortic elastic fibers and cystic medial necrosis (Figure 1C). This variant causes a p.(Arg320Cys) substitution in a highly conserved region of TGFB2 (Figure 1D). The variant was also detected in the uncle (III:1) and two currently asymptomatic teenage family members (IV:3) and (IV:5).
Aortic Expression of TGFB2. A. Western blots of aortic TGFB2 expression in IV:10 compared to two age-matched
controls, TS218 and TS199. Signal intensities of TGFB2 normalized against
beta Actin indicate a twofold higher expression of TGFB2 in the case.
B. Immunofluorescent staining of TGFB2 (green) shows increased
expression in the aortic wall of IV:10 compared to TS218 and TS199. Elastic
fibres appear as blue (autofluorescence) and nuclei are counterstained red
(scale bar=50uM and the right-hand images are zoomed).
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F2
TGFB1 and TGFB2 expression in the aorta of the index case compared to age and gender-matched controls (Figure 2 and 3). This was confirmed by immunoblotting for both proteins in the aorta of IV:10 versus controls where the upregulation of TGFB1 was particularly striking (Figure 2 and 3).
Aortic Expression of TGFB1. A. Western blots of aortic TGFB1 expression in IV:10 compared to two age-matched
controls, TS218 and TS199. Signal intensities of TGFB1 normalized against
beta Actin indicate a 15-fold higher expression of TGFB1 in the case.
B. Immunofluorescent staining of TGFB1 (green) shows increased
expression in the aortic wall of IV:10 compared to TS218 and TS199. Elastic
fibres appear as blue (autofluorescence) and nuclei are counterstained red
(scale bar=50uM and the right-hand images are zoomed).
emss-70015-f003.jpg
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F3
TGFB1 and TGFB2 expression in the aorta of the index case compared to age and gender-matched controls (Figure 2 and 3). This was confirmed by immunoblotting for both proteins in the aorta of IV:10 versus controls where the upregulation of TGFB1 was particularly striking (Figure 2 and 3).