title: Identification and in silico analyses of novel TGFBR1 and TGFBR2 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.
authors.affiliation: University of Zurich, Institute of Medical Genetics, Division of Medical Molecular Genetics and Gene Diagnostics, Zurich, Switzerland. matyas@medgen.unizh.ch
authors.forename: Gábor
authors.initials: G
authors.lastname: Mátyás
authors.forename: Eliane
authors.initials: E
authors.lastname: Arnold
authors.forename: Thierry
authors.initials: T
authors.lastname: Carrel
authors.forename: Daniela
authors.initials: D
authors.lastname: Baumgartner
authors.forename: Catherine
authors.initials: C
authors.lastname: Boileau
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Berger
authors.forename: Beat
authors.initials: B
authors.lastname: Steinmann
mesh_terms: D030201:Activin Receptors, Type I / Q000737:chemistry / Q000235:genetics*; D000483:Alleles; D000595:Amino Acid Sequence; D000784:Aortic Dissection / Q000175:diagnosis / Q000235:genetics; D017545:Aortic Aneurysm, Thoracic / Q000175:diagnosis / Q000235:genetics; D015331:Cohort Studies; D019295:Computational Biology; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000175:diagnosis / Q000235:genetics*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000737:chemistry / Q000235:genetics*; D016415:Sequence Alignment; D040681:Structural Homology, Protein; D013577:Syndrome
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D030201:Activin Receptors, Type I; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; C000625841:TGFBR1 protein, human