MUTATION SCREENING ANALYSIS OF TGFBR1 GENE IN PATIENTS WITH MARFAN SYNDROME
Abstract number: P-T-413
Lucarini1 L., Evangelisti1 L., Attanasio1 M., Fatini1 C., Sticchi1 E., Romano1 E., Cellai1 A., Pepe1 G., Abbate1 R., Gensini2 G.
11Department of Medical and Surgical Critical Care, University of Florence 22Fondazione Don Gnocchi, Centro S.Maria agli Ulivi, Florence, Italy
How-to-cite Lucarini L, Evangelisti L, Attanasio M, Fatini C, Sticchi E, Romano E, Cellai A, Pepe G, Abbate R, Gensini G. MUTATION SCREENING ANALYSIS OF TGFBR1 GENE IN PATIENTS WITH MARFAN SYNDROME. J Thromb Haemost 2007; 5 Supplement 2: P-T-413
Introduction: Marfan syndrome (MFS) is a dominantly inherited connective tissue disorder with an incidence of 1 in 5,000-10,000. Thoracic and rarely abdominal aortic aneurysms represent the main cause of morbidity. Mutations in FBN1 gene are the predominant cause of Marfan syndrome and are detected in 90% of cases. Heterozygous mutations in TGFBR2 and TGFBR1, genes codifying for receptors of TGFbeta, were found associated to MFS type 2, TAA and Loeys-Dietz syndrome.
Methods: We performed a genetic study using heteroduplex analysis of gDNA by DHPLC and direct sequencing. We screened the entire TGFBR1 gene in 46 Marfan patients in whom mutations in FBN1 and TGFBR2 genes were excluded. Successively, the analysis was extended to additional 114 Marfan patients and 237 controls.
Results: The mutation analysis of 46 Marfan patients allows us to detect two potentially pathological mutations both in ex1: the TGFBR1-6A allele and an insertion of 20 nucleotides in the 5'UTR. The TGFBR1-6A allele consists in a deletion of 3 GCG triplets coding for 3 alanine within a polyalanine tract of TGFBR1. The 6A allele is a known polymorphism, and it is reported to cause TGFbeta signalling perturbation in cancer patients.
The analysis of both mutations to a total of 160 Marfan patients and 237 controls showed the following results: the 6A allele frequency was higher in the group of Marfan patients (0.13) than in the controls (0.08) (p=0.013; OR=1.69); the insertion of 20 nucleotides was confirmed to be a familial silent mutation.
Conclusions: The results show that a highly significant association between the TGFBR1-6A allele and Marfan patients is present, suggesting that modifier mutations in TGFBR1 gene can modify the Marfan phenotype.
Further studies are required to confirm the association between 6A allele and Marfan patients, to verify if this mutation has preferential association with one or more systems involved and to check if it also acts as modifier gene in Marfan related disorders.