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5 W+ J' , , 0 , , 0 Encyclopedia of MEDICAL Genomics and Proteomics, Vol 1
edited Jrgen Fuchs and Maurizio Podda
Marfan Syndrome and Related Fibrillinopathies (pp761-765)
Gwenalle Collod-Broud1, 2 and Catherine Boileau1,3
1: INSERM U383, Universit Paris V, Hpital Necker-Enfants Malades, 149-161 rue de svres, 75743 Paris Cedex 15, France.
2: Laboratoire de Gntique Molculaire, Institut Universitaire de Recherche Clinique, 641 avenue du Doyen Gaston Giraud, 34093 Montpellier Cedex 5.
3: Laboratoire de Biochimie, dHormonologie et de Gntique Molculaire, Hpital Ambroise Par AP-HP, 9 av Charles de Gaulle, 92104 Boulogne Cedex, France.
Correspondence should be addressed to:
Pr. Catherine BOILEAU, HYPERLINK "mailto:boileau@necker.fr" boileau@necker.fr; +33 1 44 49 44 83 (phone) +33 1 47 83 32 06 (fax)
Dr. Gwenalle COLLOD-BEROUD, HYPERLINK "mailto:gwenaelle.beroud@igh.cnrs.fr" gwenaelle.beroud@igh.cnrs.fr, +33 4 67 41 53 60 (phone), +33 4 67 41 53 65 (fax).
KEYWORDS:
Marfan syndrome, Fibrillin, fibrillinopathies, microfibrils, extracellular matrix
Introduction:
Marfan syndrome (MFS, OMIM#154700) is the founding member of connective tissue disorders. It is autosomal dominant and has an estimated incidence of 1/5 000 with probably over 25 % of sporadic cases. The syndrome involves many systems (skeletal, ocular, cardiovascular, pulmonary, skin and integument, and dura) but its more prominent manifestations are skeletal, ocular and cardiovascular. It is characterized by extreme variability in phenotype severity between different affected members of a given family. At least two genes are implicated in MFS: in the majority of cases, mutations in FBN1, the gene encoding fibrillin-1 the major component of microfibrils, are implicated. Linkage analyses have localized a second gene in 3p24.2-p25. Since no specific clinical anomaly is associated with mutations in each gene, both must be tested for molecular diagnosis.
Clinical definition
In 1986, an international group of experts agreed upon diagnostic criteria to distinguish classic MFS from many related disorders. These criteria constitute what is currently referred to as the "Berlin nosology" ADDIN EN.CITE Beighton19883600Beighton, P.De Paepe, A.Danks, D.Finidori, G.Gedde-Dahl, T.Goodman, R.Hall, J.G.Hollister, D.W.Horton, W.McKusick, V.A.Opitz, J.M.Pope, F.M.Pyeritz, R.E.Rimoin, D.L.Sillence, D.Spranger, J.W.Thompson, E.Tsipouras, P.Viljoen, D.Winship, I.Young, I.1988International nosology of heritable disorders of connective tissue, Berlin, 1986American journal of medical genetics29581-594(1). Patients are diagnosed based on involvement of the skeletal system and two other systems with at least one major manifestation (ectopia lentis, aortic dilation/dissection, or dural ectasia). Patients with an affected first degree relative are required to have involvement of at least two other systems with one major manifestation preferred but not required. This nosology has been revised in 1996 and referred to as the "Ghent nosology" ADDIN EN.CITE De Paepe199611350De Paepe, A.Devereux, R.B.Dietz, HC.Hennekam, C.M.Pyeritz, R.E.1996Revised diagnostic criteria for the Marfan syndromeAmerican Journal of Medical Genetics62417-426(2). This new formulation requires involvement of three systems with two major diagnostic manifestations. It provides for major skeletal manifestations and considers affected first-degree relatives or molecular data as major diagnostic criteria.
MFS AND FBN1
In 1986, Sakai and co-workers identified a new extracellular matrix protein that they named fibrillin ADDIN EN.CITE Sakai19865220Sakai, L.,Keene, D.R.,Engvall, E.,1986Fibrillin, a new 350-kd glycoprotein, is a component of extracellular microfibrilsJournal of Cell Biology10362499-2509(3) (OMIM#134797). This protein is the major component of microfibrils that are structures found in the extracellular matrix either as isolated aggregates or closely associated with elastin fibers. Ultrastructurally, microfibrils display a typical "beads-on-a-string" appearance consisting of a long series of globules connected by multiple filaments. In 1990, Hollister et al. using a monoclonal antibody against fibrillin, reported abnormalities of the microfibrillar system in the MFS ADDIN EN.CITE Hollister19904500Hollister, DWGodfrey, MSakai, LPyeritz, RE1990Immunohistologic abnormalities of the microfibrillar-fiber system in the Marfan syndromeThe New England Journal of Medicine3233152-159(4). Kainulainen et al. ADDIN EN.CITE Kainulainen19904550Kainulainen, K.,Pulkkinen, L.,Savolainen, A.,Kaitila, I.,Peltonen, L.,1990Location on chromosome 15 of the gene defect causing Marfan syndromeThe New England Journal of Medicine32314935-939(5) demonstrated through linkage analysis that the gene involved in classic complete forms of the MFS was located on human chromosome 15. The gene encoding fibrillin-1 (FBN1) was cloned and located in 15q15-q21.1 ADDIN EN.CITE Maslen19914740Maslen, C.L.,Corson, G.M.,Maddox, B.K.,Glanville, R.W.,Sakai, L.,1991Partial sequence of a candidate gene for the Marfan syndromeNature352334-337Lee19914670Lee, B.,Godfrey, M.,Vitale, E.,Hori, H.,Mattei, M-G.,Sarfarazi, M.,Tsipouras, P.,Ramirez, F.,Hollister, DW.,1991Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genesNature352330-334(6; 7) and the first mutations in the gene were identified in MFS patients ADDIN EN.CITE Dietz19917500Dietz, HCCutting, GRPyeritz, REMaslen, CLSakai, LYCorson, GMPuffenberger, EGHamosh, ANanthakumar, EJCurristin, SMet al.,1991Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene [see comments]Nature3526333337-9AdultAmino Acid SequenceBase SequenceHumanMarfan Syndrome/*geneticsMicrofilament Proteins/*geneticsMolecular Sequence Data*MutationPolymerase Chain ReactionSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.(8).
FBN1 GENE
The gene encoding type 1 fibrillin (FBN1) is very large (over 230 kb) and highly fragmented into 65 exons, transcribed in a 10 kb mRNA that encodes a 2871 amino acid protein ADDIN EN.CITE Pereira19935020Pereira, L.,D'Alessio, M.,Ramirez, F.,Lynch, J.R.,Sykes, B.,Pangilinan, T.,Bonadio, J.,1993Genomic organization of the sequence coding for fibrillin, the defective gene product in Marfan SyndromeHuman Molecular Genetics2961-968Maslen19914740Maslen, C.L.,Corson, G.M.,Maddox, B.K.,Glanville, R.W.,Sakai, L.,1991Partial sequence of a candidate gene for the Marfan syndromeNature352334-337(7; 9). Three additional alternatively-spliced exons, most likely untranslated and well conserved between human, mouse and porcine, were found upstream of exon 1. This region is GC-rich, contains a CpG island, and lacks conventional TATA or CCAAT boxes ADDIN EN.CITE Biery19996940Biery, NJEldadah, ZAMoore, CSStetten, GSpencer, FDietz, HC1999Revised genomic organization of FBN1 and significance for regulated gene expression.Genomics56170-77(10).
The deduced primary structure reveals a highly repetitive protein that contains essentially three repeated modules:
EGF-like module that is homologous to one found in the epidermal growth factor. These modules contain six cysteine residues that form three intra-domain disulfide bonds. There are 47 of these throughout the fibrillin-1 protein. Among these, 43 contain a conserved consensus sequence for calcium binding and are called cb EGF-like modules. The presence of calcium ions significantly protects full-length or recombinant fragments of fibrillin-1 from proteolysis by trypsin, elastase, endoproteinase Glu-C, plasmin and matrix metalloproteinases ADDIN EN.CITE Reinhardt200010970Reinhardt, DPOno, RNNotbohm, HMuller, PKBachinger, HPSakai, LY2000Mutations in calcium-binding epidermal growth factor modules render fibrillin-1 susceptible to proteolysis. A potential disease-causing mechanism in Marfan syndromeJ Biol Chem27512339-12345(11).
TGF b1- b i n d i n g p r o t e i n - l i k e m o d u l e ( T G F b1 - B P - l i k e m o d u l e ) , f o u n d 7 t i m e s i n t e r s p a c e d w i t h c b E G F - l i k e i n t h e p r o t e i n , i s h o m o l o g o u s t o m o d u l e s f o u n d i n t h e T r a n s f o r m i n g G r o w t h F a c t o r - b1 b i n d i n g p r o t e i n . T h i s d o m a i n a p p e a r s t o b e l i m i t e d t o p r o t e i n s t h a t l o c a l i z e t o m a t r i x f i b r i l s ( f i b r i l l i n s a n d l a t e n t t r a n s f o r m i n g g r o w t h f a c t o r b- b i n d i n g p r o t e i n s ( L T B P s ) ) . T h e s e m o d u l e s c o n t a i n e i g h t c y s t e i n e r e s i d u e s . N o s p e c i f i c f u n c t i o n h a s y e t b e e n a s c r i b e d t o t h e s e m o d u l e s . H o w e v e r , s o m e e v i d e n c e s u g g e s t s t h a t t h e s e d o m a ins mediate specific protein-protein interactions ADDIN EN.CITE Handford20007370Handford, P. A.Downing, A. K.Reinhardt, D. P.Sakai, L. Y.2000Fibrillin: from domain structure to supramolecular assemblyMatrix Biol196457-70(12).
hybrid module since it combines features of the two former. It consists of approximately 65 amino acids, and is found twice in the protein. This module is also found in LTBPs, which have a single hybrid domain.
Finally the protein contains three unique regions: a proline-rich region that may act as a hinge-like region ADDIN EN.CITE Corson19933940Corson, G.M.,Chalberg, S.C.,Dietz, H.C.,Charbonneau, N.L.,Sakai, L.S.,1993Fibrillin binds calcium and is coded by cDNAs that reveal a multidomain structure and alternatively spliced exons at the 5' endGenomics17476-484(13) and the amino and carboxy terminal domains. The N- and C-terminal domains of fibrillin display two prominent features: the presence of an even number of cysteine residues, four in the N-terminal and two in the C-terminal domains and the presence of the basic consensus sequence for processing by furin-type enzymes BXBB (B=basic amino acid residue, K or R) in each domain. The 4-cysteine domain in the N-terminus of fibrillin is homologous to similar 4-cysteine domains in the N-terminal extended forms of the LTBPs. The C-terminal domain of fibrillin is homologous to the C-terminal domain of all four members of the fibulin family, and thus a new type of extracellular module of approximately 120 amino acid residues in length has been proposed ADDIN EN.CITE Giltay199911510Giltay, R,Timpl, R,Kostka, G,1999Sequence, recombinant expression and tissue localization of two novel extracellular matrix proteins, fibulin-3 and fibulin-4Matrix Biol18469-480(14). This type of homology is not shared by the LTBPs.
Other members of the fibrillin family were identified: FBN2 gene in 5q23-q31 (fibrillin-2 protein) carrying mutations in congenital contractural arachnodactyly (CCA) (OMIM#120150); and FBNL gene (or EFEMP1 gene) in 2p16 (fibrillin-like protein) carrying mutations in Doyne honeycomb retinal dystrophy (DHRD; OMIM#126600), or malattia Leventinese (MLVT).
FIBRILLIN PROTEINS
The fibrillins are extracellular matrix glycoproteins that show a wide distribution in both elastic and non-elastic tissues and are integral components of 10 nm diameter microfibrils. Fibrillin-1 is synthesized as profibrillin and proteolytically processed to fibrillin. Wild type profibrillin is not incorporated into extracellular matrix until it is converted to fibrillin. The N-terminal region of each protein directs the formation of homodimers within a few hours after secretion and disulphide bonds stabilize the interaction ADDIN EN.CITE Trask19997020Trask, TMRitty, TMBroekelmann, TTisdale, CMecham, RP1999N-terminal domains of fibrillin 1 and fibrillin 2 direct the formation of homodimers: a possible first step in microfibril assembly.Biochem J3403693-701(15). Dimer formation occurs intracellularly, suggesting that the process of fibrillin aggregation is initiated early after biosynthesis of the molecules. Fibrillin is post-translationally modified by b- h y d r o x y l a t i o n a n d N - a n d O - l i n k e d c a r b o h y d r a t e f o r m a t i o n A D D I N E N . C I T E <