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