Identification and in silico analyses of novelTGFBR1 andTGFBR2 mutations in Marfan syndrome-related disorders

Abstract

Very recently, heterozygous mutations in the genes encoding transforming growth factor beta receptors I (TGFBR1) and II (TGFBR2) have been reported in Loeys-Dietz aortic aneurysm syndrome (LDS). In addition, dominant TGFBR2 mutations have been identified in Marfan syndrome type 2 (MFS2) and familial thoracic aortic aneurysms and dissections (TAAD). In the past, mutations of these genes were associated with atherosclerosis and several human cancers. Here, we report a total of nine novel and one known heterozygous sequence variants in the TGFBR1 and TGFBR2 genes in nine of 70 unrelated individuals with MFS-like phenotypes who previously tested negative for mutations in the gene encoding the extracellular matrix protein fibrillin-1 (FBN1). To assess the pathogenic impact of these sequence variants, in silico analyses were performed by the PolyPhen, SIFT, and Fold-X algorithms and by means of a 3D homology model of the TGFBR2 kinase domain. Our results showed that in all but one of the patients the pathogenic effect of at least one sequence variant is highly probable (c.722C > T, c.799A > C, and c.1460G > A in TGFBR1 and c.773T > G, c.1106G > T, c.1159G > A, c.1181G > A, and c.1561T > C in TGFBR2). These deleterious alleles occurred de novo or segregated with the disease in the families, indicating a causative association between the sequence variants and clinical phenotypes. Since TGFBR2 mutations found in patients with MFS-related disorders cannot be distinguished from heterozygous TGFBR2 mutations reported in tumor samples, we emphasize the importance of segregation analysis in affected families. In order to be able to find the mutation that is indeed responsible for a MFS-related phenotype, we also propose that genetic testing for sequence alterations in TGFBR1 and TGFBR2 should be complemented by mutation screening of the FBN1 gene.

Editor's Choice – Management of Descending Thoracic Aorta Diseases

“…271 These mutations are in the gene encoding transforming growth factor beta receptor 2 (TGFb R2), which has already been reported in LDS. 272 A diagnosis of MFS can be established by clinical evaluation alone in the majority of cases. In 1998, the Ghent criteria specified the characteristics of the phenotype and genotype that can be assessed through history, physical examination, imaging, and molecular genetic testing.…”

Increased Vertebral Artery Tortuosity Index Is Associated With Adverse Outcomes in Children and Young Adults With Connective Tissue Disorders

“…[1][2][3][4][5] Although published reports suggest that tortuosity is present in 84% to 100% of patients with LDS, there is no accepted definition or measure of proximal head and neck arterial tortuosity. In contrast, arterial tortuosity has been described rarely in Marfan syndrome (MS).…”

Genetics and Genomics for the Prevention and Treatment of Cardiovascular Disease: Update

“…Variants in ACTA2, the vascular smooth muscle cell-specific isoform of α-actin, smooth muscle myosin gene (MYH11), [61][62][63] and multiple transforming growth factor-β signaling genes, including TGFBR1, [64][65][66][67] TGFBR2, [68][69][70] TGFB2, 71,72 and SMAD3, 73,74 have been shown to cause familial aortic aneurysms and dissection and to have cerebrovascular manifestations. [64][65][66][67][68][69][70]75 More recently and similar to the pleiotropic effects of the 9p21 locus, some of the same variants associated with premature CAD are also associated with premature ischemic stroke, including moyamoya disease, which is also associated with other variants such as RNF213. 76,77 Laboratory studies demonstrate that these mutations are associated with increased proliferation of smooth muscle cells.…”

“…Familial forms of aortic diseases are attributable to a number of known rare variant mutations in extracellular matrix proteins such as collagen 3A1 (COL3A1) in vascular-type Ehlers-Danlos syndrome (type IV) 328 and fibrillin (FBN) in Marfan syndrome, as well as genes involved in smooth muscle cell structure and function such as ACTA2 mutations in an autosomal-dominant inherited thoracic aortic aneurysm, 75,78,328 variants in the smooth muscle myosin gene (MYH11), and variants in multiple transforming growth factor-β signaling genes, including TGFBR1, TGFBR2, TGFB2, and SMAD3 (Table 8). [61][62][63][64][65][66]68,[71][72][73][74]308 Genetic forms of thoracic aortic aneurysms are also known in conditions such as bicuspid aortic valve, although the causal December 24/31, 2013 gene is not known for most cases. 329 In the context of bicuspid aortic valve, screening of first-degree family members is recommended by echocardiography to define the structure of the aortic valve and aortic root measurement in case a bicuspid aortic valve is detected.…”