The Marfan syndrome genetics

  • Galina Pungerčič
Keywords: Marfan syndrome, fibrillin-1, connective tissue, mutations, heritable disorder


Background: The Marfan syndrome is an autosomal dominant heritable disorder of connective tissue. It is caused by mutations in the fibrillin-1 gene encoding glycoprotein fibrillin-1, a component of microfibrils of extracellular matrix. Patients with Marfan syndrome show wide spectra of clinical signs, primarily on skeletal, cardiovascular and ocular organ systems. Cardiovascular complications (especially aortic aneurysm and aortic dissection) are the most common cause of mortality of Marfan syndrome patients. Discovering genotype-phenotype correlations is complicated because of the large number of mutations reported as well as clinical heterogeneity among individuals with the same mutation. Despite the progress in the knowledge of the molecular nature of Marfan syndrome the diagnosis is still based mainly on the clinical features in the different body systems.

Conclusions: Early identification of patient with Marfan syndrome is of considerable importance because of appropriate treatment that can greatly improve life expectancy. Unfortunately, despite the improvement of diagnostic methods, medical and surgical therapy, the mortality due to undiagnosed Marfan syndrome is still high. The present article reviews the molecular genetic studies of Marfan syndrome since the discovery of the mutations in the fibrillin-1 gene.


Download data is not yet available.


Uyeda T, Takahashi T, Eto S, Sato T, Xu G, Kanezaki R, et al. Three novel mutations of the fibrillin-1 gene and ten single nucleotide polymorphisms of the fibrillin-3 gene in Marfan syndrome patients. J Hum Genet 2004; 49: 404–7.

Pyeritz RE. The Marfan syndrome. Annu Rev Med 2000; 51: 481–510.

Pyeritz ER, Gasner C. The Marfan syndrome. Fifth edition . New York: National Marfan foundation; 1999.

Sakai LY, Keene DR, Engvall E. Fibrillin, a new 350-kD glycoprotein, is a component of extracellular microfibrils. J Cell Biol 1986; 103: 2499–509.

Biery NJ, Eldadah ZA, Moore CS, Stetten G, Spencer F, Dietz HC. Revised genomic organization of FBN1 and significance for regulated gene expression. Genomics 1999; 56: 70–7.

Kielty CM, Baldock C, Lee D, Rock MJ, Ashworth JL, Shuttleworth CA. Fibrillin: from microfibril assembly to biomechanical function. Philos Trans R Soc Lond B Biol Sci 2002; 357: 207–17.

Handford PA, Mayhew M, Brownlee GG. Calcium binding to fibrillin? Nature 1991; 353: 395.

Hollister DW, Godfrey M, Sakai LY, Pyeritz RE. Immunohistologic abnormalities of the microfibrillar-fiber system in the Marfan syndrome. N Engl J Med 1990; 323: 152–9.

Kainulainen K, Pulkkinen L, Savolainen A, Kaitila I, Peltonen L. Location on chromosome 15 of the gene defect causing Marfan syndrome. N Engl J Med 1990; 323: 935–9.

Dietz HC, Pyeritz RE, Hall BD, Cadle RG, Hamosh A, Schwartz J, et al. The Marfan syndrome locus: confirmation of assignment to chromosome 15 and identification of tightly linked markers at 15q15-q21.3. Genomics 1991; 9: 355–61.

Magenis RE, Maslen CL, Smith L, Allen L, Sakai LY. Localization of the fibrillin (FBN) gene to chromosome 15, band q21.1. Genomics 1991; 11: 346–51.

Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, et al. Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 1991; 352: 337–9.

Collod-Beroud G, Le Bourdelles S, Ades L, Ala-Kokko L, Booms P, Boxer M, et al. Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat 2003; 22: 199–208.

Kainulainen K, Karttunen L, Puhakka L, Sakai L, Peltonen L. Mutations in the fibrillin gene responsible for dominant ectopia lentis and neonatal Marfan syndrome. Nat Genet 1994; 6: 64–9.

Putnam EA, Cho M, Zinn AB, Towbin JA, Byers PH, Milewicz DM. Delineation of the Marfan phenotype associated with mutations in exons 23-32 of the FBN1 gene. Am J Med Genet 1996; 62: 233–42.

Tiecke F, Katzke S, Booms P, Robinson PN, Neumann L, Godfrey M, et al. Classic, atypically severe and neonatal Marfan syndrome: twelve mutations and genotype-phenotype correlations in FBN1 exons 24-40. Eur J Hum Genet 2001; 9: 13–21.

Palz M, Tiecke F, Booms P, Goldner B, Rosenberg T, Fuchs J, et al. Clustering of mutations associated with mild Marfan-like phenotypes in the 3' region of FBN1 suggests a potential genotype-phenotype correlation. Am J Med Genet 2000; 91: 212–21.

Tynan K, Comeau K, Pearson M, Wilgenbus P, Levitt D, Gasner C, et al. Mutation screening of complete fibrillin-1 coding sequence: report of five new mutations, including two in 8-cysteine domains. Hum Mol Genet 1993; 2: 1813–21.

El-Aleem AA, Karck M, Haverich A, Schmidtke J, Arslan-Kirchner M. Identification of 9 novel FBN1 mutations in German patients with Marfan syndrome. Hum Mutat 1999; 14: 181.

Francke U, Berg MA, Tynan K, Brenn T, Liu W, Aoyama T, et al. A Gly1127Ser mutation in an EGF-like domain of the fibrillin-1 gene is a risk factor for ascending aortic aneurysm and dissection. Am J Hum Genet 1995; 56: 1287– 96.

Collod-Beroud G, Lackmy-Port-Lys M, Jondeau G, Mathieu M, Maingourd Y, Coulon M, et al. Demonstration of the recurrence of Marfan-like skeletal and cardiovascular manifestations due to germline mosaicism for an FBN1 mutation. Am J Hum Genet 1999; 65: 917–21.

Hutchinson S, Furger A, Halliday D, Judge DP, Jefferson A, Dietz HC, et al. Allelic variation in normal human FBN1 expression in a family with Marfan syndrome: a potential modifier of phenotype? Hum Mol Genet 2003; 12: 2269–76.

Lee B, Godfrey M, Vitale E, Hori H, Mattei MG, Sarfarazi M, et al. Linkage of Marfan syndrome and a phenotypically related disorder to two different fibrillin genes. Nature 1991; 352: 330–4.

Maslen C. Genetic variation of fibrillin-2 as a risk factor for congenital heart disease. Connective Issues-Marfan Research Update 2003; 22: 11.

Dietz HC, McIntosh I, Sakai LY, Corson GM, Chalberg SC, Pyeritz RE, et al. Four novel FBN1 mutations: significance for mutant transcript level and EGF-like domain calcium binding in the pathogenesis of Marfan syndrome. Genomics 1993; 17: 468–75.

Pereira L, Andrikopoulos K, Tian J, Lee SY, Keene DR, Ono R, et al. Targetting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome. Nat Genet 1997; 17: 218–22.

Pereira L, Lee SY, Gayraud B, Andrikopoulos K, Shapiro SD, Bunton T, et al. Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proc Natl Acad Sci USA 1999; 96: 3819–23.

Ramirez F, Gayraud B, Pereira L. Marfan syndrome: new clues to genotypephenotype correlations. Ann Med 1999; 31: 202–7.

Reinhardt DP, Ono RN, Sakai LY. Calcium stabilizes fibrillin-1 against proteolytic degradation. J Biol Chem 1997; 272: 1231–6.

Booms P, Tiecke F, Rosenberg T, Hagemeier C, Robinson PN. Differential effect of FBN1 mutations on in vitro proteolysis of recombinant fibrillin-1 fragments. Hum Genet 2000; 107: 216–24.

McGettrick AJ, Knott V, Willis A, Handford PA. Molecular effects of calcium binding mutations in Marfan syndrome depend on domain context. Hum Mol Genet 2000; 9: 1987–94.

Reinhardt DP, Ono RN, Notbohm H, Muller PK, Bachinger HP, Sakai LY. Mutations in calcium-binding epidermal growth factor modules render fibrillin-1 susceptible to proteolysis. A potential disease-causing mechanism in Marfan syndrome. J Biol Chem 2000; 275: 12339–45.

Neptune ER, Frischmeyer PA, Arking DE, Myers L, Bunton TE, Gayraud B, et al. Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet 2003; 33: 407–11.

De Paepe A, Devereux RB, Dietz HC, Hennekam RC, Pyeritz RE. Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 1996; 62: 417– 26.

Sakai LY. Development of a blood test to assess fibrillin fragmentation in the Marfan syndrome. Connective Issues 2004; 23: 11.

Kaartinen V, Warburton D. Fibrillin controls TGF-beta activation. Nat Genet 2003; 33: 331–2.

Grima J. Hope on the horizon: Revelations provided by the Marfan mouse. Connective Issues-Marfan Research Update 2002; 21: 9.

Dietz H. A whole lot of optimism (tempered by a healthy dose of caution). Connective Issues 2004; 23: 5.

Dietz H. Current research provides hope, promise for life-threatening complications of the Marfan syndrome. Connective Issues 2002; 21: 1.

Demak R. Sports illustrated 1986; 64: 30–5.

How to Cite
Pungerčič G. The Marfan syndrome genetics. ZdravVestn [Internet]. 1 [cited 27Jan.2020];74(5). Available from:
Review article

Most read articles by the same author(s)