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The Molecular Genetics of Marfan Syndrome and Related Disorders

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The Molecular Genetics of Marfan Syndrome and Related Disorders The molecular genetics of Marfan syndrome and related disorders. Peter Robinson, Emilio Arteaga-Solis, Clair Baldock, Gwenaëlle Collod-Béroud, Patrick Booms, Anne de Paepe, Harry Dietz, Gao Guo, Penny Handford, Daniel Judge, et al. To cite this version: Peter Robinson, Emilio Arteaga-Solis, Clair Baldock, Gwenaëlle Collod-Béroud, Patrick Booms, et al.. The molecular genetics of Marfan syndrome and related disorders.. Journal of Medical Genetics, BMJ Publishing Group, 2006, 43 (10), pp.769-87. 10.1136/jmg.2005.039669. inserm-00143572 HAL Id: inserm-00143572 https://www.hal.inserm.fr/inserm-00143572 Submitted on 20 Dec 2017 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Rev 7.51n/W (Jan 20 2003) Journal of Medical Genetics mg39669 Module 2 17/4/06 12:55:12 Topics: 11; 259 1 REVIEW The molecular genetics of Marfan syndrome and related disorders P Robinson, E Arteaga-Solis, C Baldock, G Collod-Be´roud, P Booms, A De Paepe, H C Dietz, G Guo, P A Handford, D P Judge, C M Kielty, B Loeys, D M Milewicz, A Ney, F Ramirez, D P Reinhardt, K Tiedemann, P Whiteman, M Godfrey . J Med Genet 2006;000:1–23. doi: 10.1136/jmg.2005.039669 Marfan syndrome (MFS), a relatively common autosomal of fibrillin-rich microfibrils as purely architec- tural elements in the extracellular matrix. Recent dominant hereditary disorder of connective tissue with findings greatly enhanced our understanding of prominent manifestations in the skeletal, ocular, and the pathogenesis of MFS by demonstrating cardiovascular systems, is caused by mutations in the gene changes in growth factor signalling and other changes in matrix-cell interactions, which has for fibrillin-1 (FBN1). The leading cause of premature set the stage for attempts to develop novel forms death in untreated individuals with MFS is acute aortic of treatment. dissection, which often follows a period of progressive The current review will focus on the fibrillin- LTBP gene family and tissue organisation of dilatation of the ascending aorta. Recent research on the microfibrils, mutations in genes associated with molecular physiology of fibrillin and the pathophysiology MFS and related phenotypes, the structure of of MFS and related disorders has changed our fibrillin-1 domains, FBN1 mutations and proteo- lysis, and the genetics of MFS in mouse models. understanding of this disorder by demonstrating changes The current review will highlight advances in growth factor signalling and in matrix-cell interactions. published after the first review; interested read- The purpose of this review is to provide a comprehensive ers are referred to the previous article for more 3 overview of recent advances in the molecular biology of information on other topics. fibrillin and fibrillin-rich microfibrils. Mutations in FBN1 THE FIBRILLIN-LTBP GENE FAMILY and other genes found in MFS and related disorders will be The fibrillins and the latent-TGFb-binding pro- discussed, and novel concepts concerning the complex and teins (LTBPs) form two closely related protein multiple mechanisms of the pathogenesis of MFS will be families with structural and non-structural func- tions in the extracellular matrix. Both families explained. are characterised by a modular domain structure . with repeated cysteine-rich modules. Members of the fibrillin-LTBP family have both structural and non-structural functions. ; arfan syndrome (MFS; MIM 154700) is a Three closely related fibrillins have been relatively common autosomal dominant described. Fibrillin-24 and the recently discovered hereditary disorder of connective tissue M fibrillin-35 have a domain organisation identical with prominent manifestations in the skeletal, to that of fibrillin-1 and an overall level of amino ocular, and cardiovascular systems. MFS is acid identity of between 61% and 69%. Several caused by mutations in the gene for fibrillin-1 lines of evidence suggest that the fibrillins have (FBN1). Many affected individuals have a char- both overlapping and unique functions.5 6 All acteristic habitus with tall stature, long slender three fibrillins are structural components of limbs (dolichostenomelia), arachnodactyly, sco- liosis, and pectus excavatum or carinatum. Ectopia lentis affects up to 80% of individuals Abbreviations: BMP, bone morphogenetic protein; with MFS and is almost always bilateral. The cbEGF, calcium binding epidermal growth factor; CCA, See end of article for congenital contractural arachnodactyly; CMN, cystic authors’ affiliations leading cause of premature death in untreated medial necrosis; CSGE, conformation sensitive gel . individuals with MFS is acute aortic dissection, electrophoresis; DHPLC, denaturing high performance which follows a period of progressive dilatation liquid chromatography; EBP, elastin-binding protein; Correspondence to: Dr Peter N Robinson, of the ascending aorta. Recent comprehensive ECM, extracellular matrix; HNPCC, hereditary non- Institute of Medical treatments of the clinical aspects of MFS have polyposis colorectal cancer; LAP, latency-associated Genetics, Charite´ been published.1 2 peptide; LDS, Loeys-Dietz aortic aneurysm syndrome; LLC, University Hospital, large latent complexes; LTBPs, latent-TGFb-binding A review of the molecular genetics of MFS proteins; MAGP-1, microfibril-associated glycoprotein-1; Humboldt University, 3 Augustenburger Platz 1, appeared in these pages in the year 2000. In the MFS, Marfan syndrome; MFS2, type 2 Marfan syndrome; 13353 Berlin, Germany; half decade since then, remarkable progress has MMP, matrix metalloproteinase; MMR, mismatch repair; [email protected] been made in elucidating the molecular anatomy MSI, microsatellite instability; NMR, nuclear magnetic of both fibrillin and the fibrillin-rich microfibrils resonance; PTC, premature termination codon; SSCP, Revised version received as well as in understanding the molecular single stranded conformation polymorphism; TAAD, 7 March 2006 thoracic ascending aortic aneurysms and dissections; Accepted for publication pathogenesis of MFS. Initial ideas about the TbRII, type II TGFb receptor; TGFb, transforming growth 9 March 2006 pathogenesis of MFS concentrated on a static factor-b; UMD, Universal Mutation Database; WMS, . dominant negative model based on the concept Weill-Marchesani syndrome www.jmedgenet.com Rev 7.51n/W (Jan 20 2003) Journal of Medical Genetics mg39669 Module 2 17/4/06 12:55:15 Topics: 11; 259 2 Robinson, Arteaga-Solis, Baldock, et al microfibrils4 5 7; however, fibrillin-2 and fibrillin-3 are pre- The 8-cys module (also variously referred to in the ferentially expressed in embryonic developmental stages,4 5 8 literature as the 8-cysteine module, the TB module, or the whereas fibrillin-1 is expressed from the gastrula to LTBP module) occurs only in the fibrillins and LTBPs. An throughout adult life.9 In addition, distinct phenotypes are experiment using a recombinant construct of one of the observed in fbn1 and fbn2 gene targeting experiments in mice; seven 8-cys modules of fibrillin-1 showed that the structure is since microfibrils are assembled in both mice, some overlap stabilised by four intradomain disulfide bonds.17 Some 8-cys of architectural functions appears likely.5 10–12 domains can mediate binding to the LAP-TGFb complex.18 19 The LTBPs associate with transforming growth factor-b Not all domains have this function; a recent study showed (TGFb), thereby regulating its secretion and spatial and that LTBP1 and LTBP3 bound efficiently to TGFb, LTBP4 temporal activation; in humans, four members of the LTBP bound weakly, and LTBP2 and fibrillin-1 and fibrillin-2 did family are known, three of which undergo alternative not bind.20 An additional cysteine-rich module with simila- = 13 splicing. TGFb is synthesised as a homodimeric proprotein, rities to both the cbEGF module and the 8-cys module, whereby the dimeric propeptide is cleaved intracellularly termed the 8-cys hybrid module,21 can mediate intermole- from the growth factor; the propeptide is called the latency- cular disulfide bonding between fibrillin-1 monomers, which associated peptide (LAP) because TGFb cannot bind to its may be an important step in the assembly of microfibrils.22 surface receptors when it is bound to the LAP. The LAP in The fibrillins share a globular C-terminal domain of about turn is usually disulfide-bonded to an LTBP; this aggregate is 120 residues with the fibulins23; in fibrillin-1, this module referred to as the large latent complexes (LLC). The LTBPs may be involved in homotypic interactions.24 thus have a dual function: as structural components of the extracellular matrix and as modulators of TGFb availability (the reader is referred to Rifkin14 and Todorovic et al15 for TISSUE ORGANISATION OF MICROFIBRILS recent reviews on this topic). Fibrillin microfibrils are widely distributed extracellular The fibrillins and LTBPs display a remarkably similar matrix multimolecular assemblies comprised of fibrillin and domain structure made up of repeated cysteine-rich struc- other proteins. The microfibrils endow elastic and non-elastic
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