Abstract
Marfan syndrome is an autosomal dominant disease caused by mutations in the gene encoding for fibrillin-1 (FBN1). More than 1,000 FBN1 mutations have been identified, which may lead to multiple organ involvement, particularly of the ocular, skeletal, and cardiovascular systems. Mutations in exons 59–65 have been reported in the past to cause mild Marfan-like fibrillinopathies. We report a family with a mutation in exon 63 that manifests with significant cardiovascular system involvement such as aortic root dilatations, dissection of the aorta, and sudden death at a young age. Genetic analysis revealed that four related individuals are positive for a novel heterozygous Cys2633Arg mutation in exon 63. Their genotype–phenotype profile (based on the revised Ghent nosology) is described. We postulate that the Cys2633Arg mutation may manifest with significant and progressive enlargement of the aortic root, risk of aortic dissections, and minor skeletal abnormalities, without involving the ocular system (i.e., ectopia lentis).
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Attanasio M, Lapini I, Evangelisti L, Lucarini L, Giusti B, Porciani MC, Fattori R, Anichini C, Abbate R, Gensini GF, Pepe G (2008) FBN1 mutation screening of patients with Marfan syndrome and related disorders: detection of 46 novel FBN1 mutations. Clin Genet 74:39–46
Byers PH (2004) Determination of the molecular basis of Marfan syndrome: a growth industry. J Clin Invest 114:161–163
Dietz HC, Pyeritz RE (1995) Mutations in the human gene for fibrillin-1 (FBN1) in the Marfan syndrome and related disorders. Hum Mol Genet 4:1799–1809
Dietz HC, Cutting GR, Pyeritz RE, Maslen CL, Sakai LY, Corson GM, Puffenberger EG, Hamosh A, Nanthakumar EJ, Curristin SM, Stetten G, Meyers DA, Francomano CA (1991) Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352:337–339
Faivre L, Collod-Beroud G, Loeys BL, Child A, Binquet C, Gautier E, Callewaert B, Arbustini E, Mayer K, Arslan-Kirchner M, Kiotsekoglou A, Comeglio M, Marziliano N, Dietz HC, Halliday D, Beroud C, Bonithon-Kopp C, Claustres M, Muti C, Plauchu H, Robinson PN, Adès L, Biggin A, Benetts B, Brett M, Holman KJ, De Backer J, Coucke P, Francke U, De Paepe A, Jondeau G, Boileau C (2007) Effect of mutation type and location on clinical outcome in 1013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study. Am J Med Genet 81:454–466
Handford PA (2000) Fibrillin-1, a calcium binding protein of extracellular matrix. Biochim Biophys Acta 1498:84–90
Judge DP, Dietz HC (2005) Marfan syndrome. Lancet 366:1965–1976
Keane MG, Pyeritz RE (2008) Medical management of Marfan syndrome. Circulation 117:2802–2813
Loeys BL, Dietz HC, Braverman AC, Callewaert BL, De Backer J, Devereux RB, Hilhorst-Hofstee Y, Jondeau G, Faivre L, Milewicz DM, Pyeritz RE, Sponseller PD, Wordsworth P, De Paepe AM (2010) The revised Ghent nosology for the Marfan syndrome. J Med Genet 47:476–485
Milewicz DM, Dietz HC, Miller DC (2005) Treatment of aortic disease in patients with Marfan syndrome. Circulation 111:e150–e157
Palz M, Tiecke F, Booms P, Goldner B, Rosenberg T, Fuchs J, Skovby F, Schumacher H, Kaufmann UC, von Kodolitsch Y, Nienaber CA, Leitner C, Katzke S, Vetter B, Hagemeier C, Robinson PN (2000) Clustering of mutations associated with mild Marfan-like phenotypes in the 3′ region of FBN1 suggests a potential genotype–phenotype correlation. Med Genet 91:212–221
Rand-Hendriksen S, Theldhorn L, Lundby R, Semb SO, Offstad J, Anderson K, Geiran O, Paus B (2007) Search for correlations between FBN1 genotype and complete Ghent phenotype in 44 unrelated Norwegian patients with Marfan patients. Am J Med Genet 143:1968–1977
Robinson PN, Godfrey M (2000) The molecular genetics of Marfan syndrome and related microfibrillopathies. J Med Genet 37:9–25
Robinson PN, Booms P, Katzke S, Ladewig M, Neumann L, Palz M, Pregla R, Tiecke F, Rosenberg T (2002) Mutations of the FBN1 and genotype–phenotype correlations in Marfan syndrome and related fibrillinopathies. Hum Mutat 20:153–161
Schrijver I, Liu W, Brenn T, Furthmayr H, Francke U (1999) Cysteine substitutions in epidermal growth factor-like domains of fibrillin-1: distinct effects on biochemical and clinical phenotypes. Am J Hum Genet 65:1007–1020
UniProt Consortium (2013) Update on activities at the Universal Protein Resource (UniProt). Nucleic Acids Res 41:D43–D47
van Kein PK, Baux D, Pallares-Ruiz N, Baudoin C, Plancke A, Chassaing N, Collignon P, Drouin-Garraud V, Hovnanian A, Martin-Coignard D, Collod-Beroud G, Beroud C, Roux A-F, Claustres M (2010) Missense mutations of conserved glycine residues in fibrillin-1 highlight a potential subtype of cb-EGF-like domains. Hum Mutat 31:E1021–E1042
Acknowledgments
We are extremely grateful to Kim Nagel for her help with the application for REB approval. We thank Leslie Berry for critically reviewing this manuscript. Dr. Anthony K. C. Chan holds a McMaster Children’s Hospital/Hamilton Health Sciences Foundation Chair in Pediatric Thrombosis and Hemostasis.
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Stevic, I., Kozenko, M., LoStracco, R. et al. Phenotype Presentation for a Novel Mutation Affecting a Conserved Cysteine Residue in Exon 63 of Fibrillin-1 (Cys2633Arg). Biochem Genet 52, 225–232 (2014). https://doi.org/10.1007/s10528-014-9642-0
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DOI: https://doi.org/10.1007/s10528-014-9642-0