Abstract
Marfan syndrome (MFS, OMIM #154700) is an autosomal dominant connective tissue disorder, clinically presenting with cardinal features of skeletal, ocular, and cardiovascular systems. In a classical concept of MFS, changes in connective tissue integrity can be explained by defects in fibrillin-1, a major component of extracellular microfibrils. Recently TGFBR2 and TGFBR1 mutations were identified in a subset of patients with MFS (MFS2, OMIM #154705) and other MFS-related disorders including Loeys-Dietz syndrome (LDS, #OMIM 609192) and familial thoracic aortic aneurysms and dissections (TAAD2, #OMIM 608987) [1]. These data may indicate that genetic heterogeneity exists in MFS and its related conditions and regulation of TGF-β signaling plays a significant role in these disorders. It is noteworthy that losartan, an angiotensin II type 1 receptor (AT1) antagonist, has been highlighted as a potential drug for protection of aortic aneurysm in a mice MFS model through suppression of abnormal TGF-β upregula-tion. In this lecture, comprehensive genetic study of MFS and MFS-related disorder in Japan is presented. Furthermore future direction for genetic study of a more common disorder, aortic dissection will be discussed.
Keywords
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsPreview
Unable to display preview. Download preview PDF.
References
Mizuguchi T and Matsumoto N (2007) Recent progress in genetics of Marfan syndrome and Marfan-associated disorders. J Hum Genet 52:1–12
De Paepe A, Devereux RB, Dietz HC, et al (1996) Revised diagnostic criteria for the Marfan syndrome. Am J Med Genet 62:417–426
Dietz HC, Cutting GR, Pyeritz RE, et al (1991) Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin gene. Nature 352:337–339
Collod-Beroud G, Le Bourdelles S, Ades L, et al (2003) Update of the UMD-FBN1 mutation database and creation of an FBN1 polymorphism database. Hum Mutat. 22:199–208
Katzke S, Booms P, Tiecke F, et al (2002) TGGE screening of the entire FBN1 coding sequence in 126 individuals with marfan syndrome and related fibrillinopathies. Hum Mutat 20:197–208
Loeys B, De Backer J, Van Acker P, et al (2004) Comprehensive molecular screening of the FBN1 gene favors locus homogeneity of classical Marfan syndrome. Hum Mutat 24:140–146
Tynan K, Comeau K, Pearson M, et al (1993) Mutation screening of complete fibrillin-1 coding sequence: report of five new mutations, including two in 8-cysteine domains. Hum Mol Genet 2:1813–1821
Mizuguchi T, Collod-Beroud G, Akiyama T, et al (2004) Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Genet 36:855–860
Loeys BL, Chen J, Neptune ER, et al (2005) A syndrome of altered cardiovascular, craniofa-cial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2. Nat Genet 37:275–281
Pannu H, Fadulu V T, Chang J, et al (2005) Mutations in transforming growth factor-beta receptor type II cause familial thoracic aortic aneurysms and dissections. Circulation 112:513–520
Kosaki K, Takahashi D, Udaka T, et al (2006) Molecular pathology of Shprintzen-Goldberg syndrome. Am J Med Genet A 140:104–108; author reply 109–110
Sakai H, Visser R, Ikegawa S, et al (2006) Comprehensive genetic analysis of relevant four genes in 49 patients with Marfan syndrome or Marfan-related phenotypes. Am J Med Genet A 140:1719–1725
Nishimura A, Sakai H, Ikegawa S, et al (2007) FBN2, FBN1, TGFBR1, and TGFBR2 analyses in congenital contractural arachnodactyly. Am J Med Genet A 143:694–698
Putnam EA, Zhang H, Ramirez F, et al (1995) Fibrillin-2 (FBN2) mutations result in the Marfan-like disorder, congenital contractural arachnodactyly. Nat Genet 11:456–458
Disabella E, Grasso M, Marziliano N, et al (2006) Two novel and one known mutation of the TGFBR2 gene in Marfan syndrome not associated with FBN1 gene defects. Eur J Hum Genet 14:34–38
Matyas G, Arnold E, Carrel T, et al (2006) Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in Marfan syndrome-related disorders. Hum Mutat 27: 760–769
Singh KK, Rommel K, Mishra A, et al (2006) TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome. Hum Mutat 27:770–777
Ki CS, Jin DK, Chang SH, et al (2005) Identification of a novel TGFBR2 gene mutation in a Korean patient with Loeys-Dietz aortic aneurysm syndrome; no mutation in TGFBR2 gene in 30 patients with classic Marfan's syndrome. Clin Genet 68:561–563
Isogai Z, Ono RN, Ushiro S, et al (2003) Latent transforming growth factor beta-binding protein 1 interacts with fibrillin and is a microfibril-associated protein J Biol Chem 278:2750–2757
Judge DP, Biery NJ, Keene DR, et al (2004) Evidence for a critical contribution of haploinsuf-ficiency in the complex pathogenesis of Marfan syndrome. J Clin Invest 114:172–181
Pereira L, Andrikopoulos K, Tian J, et al (1997) Targetting of the gene encoding fibrillin-1 recapitulates the vascular aspect of Marfan syndrome. Nat Genet 17:218–222
Pereira L, Lee SY, Gayraud B, et al (1999) Pathogenetic sequence for aneurysm revealed in mice underexpressing fibrillin-1. Proc Natl Acad Sci USA 96: 3819–3823
Habashi JP, Judge DP, Holm TM, et al (2006) Losartan, an AT1 antagonist, prevents aortic aneurysm in a mouse model of Marfan syndrome. Science 312:117–121
Neptune ER, Frischmeyer PA, Arking DE, et al (2003) Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome. Nat Genet 33:407–411
Ng CM, Cheng A, Myers LA, et al (2004) TGF-beta-dependent pathogenesis of mitral valve prolapse in a mouse model of Marfan syndrome. J Clin Invest 114:1586–1592
Ueda Y, Osada H, Osugi H (2007) Thracic and cardiovascular surgery in Japan during 2005. Annual report by the Japanese Association for Thoracic Surgery. Gen Thorac Cardiovasc Surg 55:377–399
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2009 Springer
About this paper
Cite this paper
Matsumoto, N. (2009). Gene Analysis of Marfan Syndrome. In: Kazui, T., Takamoto, S. (eds) Advances in Understanding Aortic Diseases. Springer, Tokyo. https://doi.org/10.1007/978-4-431-99237-0_5
Download citation
DOI: https://doi.org/10.1007/978-4-431-99237-0_5
Publisher Name: Springer, Tokyo
Print ISBN: 978-4-431-99236-3
Online ISBN: 978-4-431-99237-0
eBook Packages: MedicineMedicine (R0)