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Altered TGFβ signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency

Marjolijn Renard UGent, Tammy Holm, Regan Veith, Bert Callewaert UGent, Lesley C Adès, Osman Baspinar, Angela Pickart, Majed Dasouki, Juliane Hoyer and Anita Rauch, et al. (2010) EUROPEAN JOURNAL OF HUMAN GENETICS. 18(8). p.895-901
abstract
Fibulin-4 is a member of the fibulin family, a group of extracellular matrix proteins prominently expressed in medial layers of large veins and arteries. Involvement of the FBLN4 gene in cardiovascular pathology was shown in a murine model and in three patients affected with cutis laxa in association with systemic involvement. To elucidate the contribution of FBLN4 in human disease, we investigated two cohorts of patients. Direct sequencing of 17 patients with cutis laxa revealed no FBLN4 mutations. In a second group of 22 patients presenting with arterial tortuosity, stenosis and aneurysms, FBLN4 mutations were identified in three patients, two homozygous missense mutations (p.Glu126Lys and p.Ala397Thr) and compound heterozygosity for missense mutation p.Glu126Val and frameshift mutation c.577delC. Immunoblotting analysis showed a decreased amount of fibulin-4 protein in the fibroblast culture media of two patients, a finding sustained by diminished fibulin-4 in the extracellular matrix of the aortic wall on immunohistochemistry. pSmad2 and CTGF immunostaining of aortic and lung tissue revealed an increase in transforming growth factor (TGF)beta signaling. This was confirmed by pSmad2 immunoblotting of fibroblast cultures. In conclusion, patients with recessive FBLN4 mutations are predominantly characterized by aortic aneurysms, arterial tortuosity and stenosis. This confirms the important role of fibulin-4 in vascular elastic fiber assembly. Furthermore, we provide the first evidence for the involvement of altered TGF beta signaling in the pathogenesis of FBLN4 mutations in humans.
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author
organization
alternative title
Altered TGFbeta signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency
year
type
journalArticle (original)
publication status
published
subject
keyword
BINDING, ELASTOGENESIS, MOUSE MODEL, AORTIC-ANEURYSM, MISSENSE MUTATION, TISSUE LOCALIZATION, MARFAN-SYNDROME, ELASTIN GENE, ARTERIAL-TORTUOSITY-SYNDROME, EXTRACELLULAR-MATRIX PROTEINS, arterial tortuosity, aortic aneurysm, cutis laxa, TGF beta, fibulin-4
journal title
EUROPEAN JOURNAL OF HUMAN GENETICS
Eur. J. Hum. Genet.
volume
18
issue
8
pages
895 - 901
Web of Science type
Article
Web of Science id
000280145100007
JCR category
GENETICS & HEREDITY
JCR impact factor
4.38 (2010)
JCR rank
30/154 (2010)
JCR quartile
1 (2010)
ISSN
1018-4813
DOI
10.1038/ejhg.2010.45
language
English
UGent publication?
yes
classification
A1
copyright statement
I have transferred the copyright for this publication to the publisher
id
1016447
handle
http://hdl.handle.net/1854/LU-1016447
date created
2010-08-02 10:31:31
date last changed
2011-07-12 14:07:56
@article{1016447,
  abstract     = {Fibulin-4 is a member of the fibulin family, a group of extracellular matrix proteins prominently expressed in medial layers of large veins and arteries. Involvement of the FBLN4 gene in cardiovascular pathology was shown in a murine model and in three patients affected with cutis laxa in association with systemic involvement. To elucidate the contribution of FBLN4 in human disease, we investigated two cohorts of patients. Direct sequencing of 17 patients with cutis laxa revealed no FBLN4 mutations. In a second group of 22 patients presenting with arterial tortuosity, stenosis and aneurysms, FBLN4 mutations were identified in three patients, two homozygous missense mutations (p.Glu126Lys and p.Ala397Thr) and compound heterozygosity for missense mutation p.Glu126Val and frameshift mutation c.577delC. Immunoblotting analysis showed a decreased amount of fibulin-4 protein in the fibroblast culture media of two patients, a finding sustained by diminished fibulin-4 in the extracellular matrix of the aortic wall on immunohistochemistry. pSmad2 and CTGF immunostaining of aortic and lung tissue revealed an increase in transforming growth factor (TGF)beta signaling. This was confirmed by pSmad2 immunoblotting of fibroblast cultures. In conclusion, patients with recessive FBLN4 mutations are predominantly characterized by aortic aneurysms, arterial tortuosity and stenosis. This confirms the important role of fibulin-4 in vascular elastic fiber assembly. Furthermore, we provide the first evidence for the involvement of altered TGF beta signaling in the pathogenesis of FBLN4 mutations in humans.},
  author       = {Renard, Marjolijn and Holm, Tammy and Veith, Regan and Callewaert, Bert and Ad{\`e}s, Lesley C and Baspinar, Osman and Pickart, Angela and Dasouki, Majed and Hoyer, Juliane and Rauch, Anita and Trapane, Pamela and Earing, Michael and Coucke, Paul and Sakai, Lynn Y and Dietz, Harry C and De Paepe, Anne and Loeys, Bart},
  issn         = {1018-4813},
  journal      = {EUROPEAN JOURNAL OF HUMAN GENETICS},
  keyword      = {BINDING,ELASTOGENESIS,MOUSE MODEL,AORTIC-ANEURYSM,MISSENSE MUTATION,TISSUE LOCALIZATION,MARFAN-SYNDROME,ELASTIN GENE,ARTERIAL-TORTUOSITY-SYNDROME,EXTRACELLULAR-MATRIX PROTEINS,arterial tortuosity,aortic aneurysm,cutis laxa,TGF beta,fibulin-4},
  language     = {eng},
  number       = {8},
  pages        = {895--901},
  title        = {Altered TGF\ensuremath{\beta} signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency},
  url          = {http://dx.doi.org/10.1038/ejhg.2010.45},
  volume       = {18},
  year         = {2010},
}

Chicago
Renard, Marjolijn, Tammy Holm, Regan Veith, Bert Callewaert, Lesley C Adès, Osman Baspinar, Angela Pickart, et al. 2010. “Altered TGFβ Signaling and Cardiovascular Manifestations in Patients with Autosomal Recessive Cutis Laxa Type I Caused by Fibulin-4 Deficiency.” European Journal of Human Genetics 18 (8): 895–901.
APA
Renard, M., Holm, T., Veith, R., Callewaert, B., Adès, L. C., Baspinar, O., Pickart, A., et al. (2010). Altered TGFβ signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency. EUROPEAN JOURNAL OF HUMAN GENETICS, 18(8), 895–901.
Vancouver
1.
Renard M, Holm T, Veith R, Callewaert B, Adès LC, Baspinar O, et al. Altered TGFβ signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency. EUROPEAN JOURNAL OF HUMAN GENETICS. 2010;18(8):895–901.
MLA
Renard, Marjolijn, Tammy Holm, Regan Veith, et al. “Altered TGFβ Signaling and Cardiovascular Manifestations in Patients with Autosomal Recessive Cutis Laxa Type I Caused by Fibulin-4 Deficiency.” EUROPEAN JOURNAL OF HUMAN GENETICS 18.8 (2010): 895–901. Print.