Identification of TGFBR2 Mutations in Chinese patients with Marfan Syndrome (MFS) using DHPLC (Denaturing High Performance Liquid Chromatography)

Dr Chung, Brian Hon Yin   (Principal Investigator (PI))

Dr Lun Kin Shing   (Co-Investigator)

Professor Lau Yu Lung   (Co-Investigator)

12

2007-01-01

70000

Identification of TGFBR2 Mutations in Chinese patients with Marfan Syndrome (MFS) using DHPLC (Denaturing High Performance Liquid Chromatography)

DHPLC, Marfan syndrome, TGFBR2

Paediatrics

200607176072

Small Project Funding

2006

Completed

Marfan syndrome (MFS) is an autosomal dominant mulit-systemic connective tissue disease with involvement of cardiovascular, musculo-skeletal, ocular and many other systems. It has an estimated incidence of up to 1: 5,000 (1). Among all the clinical features, progressive aortic root dilatation and aortic dissection is the most serious one and it represents the predominant cause of death in over 90% of patients. The first genetic defect identified for MFS is the fibrillin-1(FBN1) gene located in the long arm of chromosome 15. Up to date, there are at least 562 published FBN1 mutations (2) which scattered over the 200 kb FBN1 gene. In our previous study (3), 24 mutations in FBN1 gene could be identified in 66 probands with MPS (n=17 fulfil Ghent criteria, 14/17 FBN1 mutation positive) and marfan-like phenotypes (1). In 1991, a second disease-locus for MFS was mapped to 3p24.2-p25 in a large French family and later found to encode the transforming growth factor-beta-receptor type II (TGFBR2) gene in 2004 (4). This has provided the first genetic evidence of a link between abnormal TGF-beta signalling and human connective tissue disorders. Several functional studies have been performed following this discovery and have increased our understanding of the pathogenesis of MFS and its related disroders e.g. Loeys-Dietz syndrome (5). FBN1 mutations are shown to be positive in up to 90% probands who fulfil Ghent diagnostic criteria (2). And the study by Matyas et al, have shown that TGFBR2 mutations could be identified in ~10% of non-FBN1-patients with MFS-related disorders (6). Probands with TGFBR2 mutations have comparable clinical features with those with FBN1 mutations but often with milder ocular abnormalities and infrequent dural ectasia (2,4,7). From our local Chinese cohort, FBN1 mutations were detected only in 36% probands (76% in those fulfilling Ghent criteria) (3). Analysis of their phenotypic characteristics reveals that our patients have relatively infrequent ocular abnormalities (9%) and dural ectasia (6%) . We hypothesize that TGBFR2 mutations could be a major underlyinig genetic abnormality in Chinese MFS patients and our objective is to examine the mutation spectrum of TGFBR2 in non-FBN1 Chinese patients with MFS and its related phenotypes. References: 1. Pyeritz RE. The Marfan syndrome. Annu Rev Med 2000; 51: 481-510. 2. Boileau C, Jondeau G, Mizuguchi T, Matsumoto N. Molecular genetics of Marfan syndrome. Curr Opin Cardiol 2005; 20:194-200. 3. Chung B.H.Y., Lam S.T.S., Tong T.M.F., Li S., Lun K.S., Chan H.C., Or S.F., and Lau Y.L. Identification of 21 novel and 3 known FBN1 mutations in 66 unrelated Chinese probands with Marfan syndrome or Marfan-like phenotypes. Joint 6th Human Genome Organization (HUGO) Pacific Meeting and the 7th Asia-Pacific Human Genetics Conference, Taipei, Taiwan, 6-10 March 2006 (poster presentation). 4. Mizuguchi T, Collod-Beroud G, Akiyama T, Abifadel M, Harada N, Morisaki T, Allard D, Varret M, Claustres M, Morisaki H, Ihara M, Kinoshita A, Yoshiura K, Junien C, Kajii T, Jondeau G, Ohta T, Kishikno T, Furukawa Y, Nakamura Y, Niikawa N, Boileau C, Matsumoto N. Heterozygous TGFBR2 mutations in Marfan syndrome. Nat Gen 2004; 36(8):855-860. 5. Singh KK, Rommel K, Mishra A, Karck M, Haverich A, Schmidtke J, Arslan-Kirchner M. TGFBR1 and TGFBR2 mutations in patients with features of marfan syndrome and Loeys-Dietz syndrome. Hum Mutat 2006; 27(8):770-777. 6. Matyas G, Arnold E, Carrel T, Baumgartner D, Boileau C, Berger W, Steinmann B. Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations in marfan syndrome-related disorders. Hum Mutat 2006; 27(8):760-769. 7. Disabella E, Grasso M, Marziliano N, Ansaldi S, Lucchelli C, Porcu E, Tagliani M, Pilotto A, Diegoli M, Lanzarini L, Malattia C, Pelliccia A, Ficcadenti A, Gabrielli O, Arbustini E. Two novel and one known mutation of the TGFBR2 gene in marfan syndrome not associated with FBN1 gene defects. Eur J Hum Gen 2006;14:34-38.