Altered TGFbeta signaling and cardiovascular manifestations in patients with autosomal recessive cutis laxa type I caused by fibulin-4 deficiency.
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 TGFbeta signaling in the pathogenesis of FBLN4 mutations in humans.
Renard
Marjolijn
M
Center for Medical Genetics, University Hospital Ghent, De Pintelaan 185, Ghent, Belgium.
Holm
Tammy
T
Veith
Regan
R
Callewaert
Bert L
BL
Adès
Lesley C
LC
Baspinar
Osman
O
Pickart
Angela
A
Dasouki
Majed
M
Hoyer
Juliane
J
Rauch
Anita
A
Trapane
Pamela
P
Earing
Michael G
MG
Coucke
Paul J
PJ
Sakai
Lynn Y
LY
Dietz
Harry C
HC
De Paepe
Anne M
AM
Loeys
Bart L
BL
D001014:Aortic Aneurysm / Q000235:genetics / Q000378:metabolism; D001018:Aortic Diseases / Q000235:genetics / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002648:Child; D003251:Constriction, Pathologic; D003483:Cutis Laxa / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D004547:Elastic Tissue / Q000378:metabolism / Q000473:pathology; D016326:Extracellular Matrix Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020125:Mutation, Missense; D015398:Signal Transduction; D012867:Skin / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D055815:Young Adult
C403672:EFEMP2 protein, human; D016326:Extracellular Matrix Proteins; D016212:Transforming Growth Factor beta
J Invest Dermatol. 2006 Jul;126(7):1506-9
16691202
Nat Genet. 2009 Sep;41(9):1016-21
19648921
Am J Hum Genet. 2009 Jul;85(1):120-9
19576563
Matrix Biol. 1999 Oct;18(5):469-80
10601734
Biochem J. 2005 May 15;388(Pt 1):1-5
15790312
J Med Genet. 2006 Mar;43(3):255-8
16085695
Am J Med Genet. 1996 Dec 18;66(3):289-99
8985490
Circ Res. 2007 Mar 16;100(5):738-46
17293478
Nat Genet. 2008 Jan;40(1):32-4
18157129
Am J Hum Genet. 2003 Apr;72(4):998-1004
12618961
N Engl J Med. 2006 Aug 24;355(8):788-98
16928994
Arch Dermatol. 2004 Sep;140(9):1135-9
15381555
J Biol Chem. 2009 Jun 19;284(25):16872-16881
19349279
Hum Mutat. 2008 Jan;29(1):150-8
17935213
Eur J Hum Genet. 2009 Sep;17(9):1099-110
19401719
Nature. 2002 Jan 10;415(6868):168-71
11805834
Can J Cardiol. 2005 Mar;21(3):299-301
15776121
Am J Hum Genet. 2006 Jun;78(6):1075-80
16685658
J Biol Chem. 1999 Jan 8;274(2):981-6
9873040
J Biol Chem. 2007 Apr 20;282(16):11805-16
17324935
Nat Genet. 2003 Mar;33(3):407-11
12598898
Cell. 1995 Jul 14;82(1):131-41
7606779
J Clin Invest. 2004 Dec;114(11):1586-92
15546004
Nat Genet. 2006 Apr;38(4):452-7
16550171
Nature. 2002 Jan 10;415(6868):171-5
11805835
J Invest Dermatol. 2006 Feb;126(2):283-90
16374472
Nat Genet. 2005 Mar;37(3):275-81
15731757
Clin Dysmorphol. 2008 Apr;17(2):99-107
18388779
Mol Cell Biol. 2006 Mar;26(5):1700-9
16478991
J Invest Dermatol. 2008 Jun;128(6):1442-50
18185537
FEBS Lett. 1999 Oct 29;460(2):280-4
10544250
Hum Mol Genet. 1998 Jun;7(6):1021-8
9580666
Clin Genet. 2009 Sep;76(3):276-81
19664000
Science. 2006 Apr 7;312(5770):117-21
16601194
Am J Med Genet A. 2007 Nov 15;143A(22):2635-41
17937443
Hum Mol Genet. 2002 Sep 1;11(18):2113-8
12189163
Circ Res. 2010 Feb 19;106(3):583-92
20019329
EMBO Rep. 2003 Dec;4(12):1127-31
14647206