title: Two novel and one known mutation of the TGFBR2 gene in Marfan syndrome not associated with FBN1 gene defects.
abstract: TGF-beta-receptor 2 (TGFBR2) gene defects have been recently associated with Marfan syndrome (MFS) with prominent cardio-skeletal phenotype in patients with negative fibrillin-1 (FBN1) gene screening. Four mutations have been identified to date in five unrelated families. We screened TGFBR2 gene by direct automated sequencing in two adult patients diagnosed with MFS according to Ghent criteria, and in one girl clinically suspected as affected on the basis of a major cardiovascular criterion and skeletal involvement, all proven not to carry mutations in the exon-intron boundaries of FBN1 gene. We identified two novel and one known TGFBR2 gene mutations in the three unrelated probands. The D446N was identified in a 4-year-old girl with de novo disease characterized by severe cardiovascular disease and skeletal involvement. The M425V and R460H mutations were identified in two familial, autosomal dominant MFSs, both characterized by major cardio-skeletal signs and absence of major ocular signs. The mutation R460H has been recently reported in a family with thoracic aortic aneurysms and dissection. The three mutations are absent in 192 controls and affect evolutionarily conserved residues of the serine/threonine kinase domain (exon 5). Our data support the recently reported association between TGFBR2 gene and MFS without major ocular signs (MFS2). The number of genotyped cases however is too low to confirm that major ocular signs are characteristically absent in MFS2. Accordingly, all patients proven or suspected to be affected by MFS with negative FBN1 gene screening could benefit from rapid investigation of the TGFBR2 gene.
authors.affiliation: Molecular Diagnostics, Cardiovascular and Transplant Pathology Laboratory, Transplant Research Area, Pavia, Italy.
authors.forename: Eliana
authors.initials: E
authors.lastname: Disabella
authors.forename: Maurizia
authors.initials: M
authors.lastname: Grasso
authors.forename: Nicola
authors.initials: N
authors.lastname: Marziliano
authors.forename: Silvia
authors.initials: S
authors.lastname: Ansaldi
authors.forename: Claudia
authors.initials: C
authors.lastname: Lucchelli
authors.forename: Emanuele
authors.initials: E
authors.lastname: Porcu
authors.forename: Marilena
authors.initials: M
authors.lastname: Tagliani
authors.forename: Andrea
authors.initials: A
authors.lastname: Pilotto
authors.forename: Marta
authors.initials: M
authors.lastname: Diegoli
authors.forename: Luca
authors.initials: L
authors.lastname: Lanzarini
authors.forename: Clara
authors.initials: C
authors.lastname: Malattia
authors.forename: Antonio
authors.initials: A
authors.lastname: Pelliccia
authors.forename: Anna
authors.initials: A
authors.lastname: Ficcadenti
authors.forename: Orazio
authors.initials: O
authors.lastname: Gabrielli
authors.forename: Eloisa
authors.initials: E
authors.lastname: Arbustini
mesh_terms: D000328:Adult; D001011:Aorta / Q000002:abnormalities; D016022:Case-Control Studies; D002675:Child, Preschool; D005260:Female; D000071838:Fibrillin-1; D000071837:Fibrillins; D006801:Humans; D008297:Male; D008382:Marfan Syndrome / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D008840:Microfilament Proteins / Q000235:genetics*; D009154:Mutation; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D054392:Adipokines
chemical_list: D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; C000605722:FBN1 protein, human; D054392:Adipokines