title: Holt-Oram syndrome with intermediate atrioventricular canal defect, and aortic coarctation: functional characterization of a de novo TBX5 mutation.
abstract: Holt-Oram syndrome (HOS) is a rare autosomal dominant disorder characterized by upper limb defects and congenital heart defects (CHD), which are often simple septal and conduction defects, less frequently complex CHDs. We report on a 9 year-old boy with clinical and radiologic features of HOS consisting of bilateral asymmetric hypoplastic thumbs, generalized brachydactyly, limited supination due to radioulnar synostosis, and sloping shoulders, and intermediate atrioventricular canal defect (AVCD) with aortic coarctation. A de novo, previously described mutation, (Arg279ter) was identified in the TBX5 gene. Molecular characterization of this mutation was carried out due to the atypical CHD. In order to investigate whether the mutated transcript of TBX5 was able to escape the post-transcriptional surveillance mechanism and to produce a truncated TBX5 protein, we analyzed the TBX5 transcript, and protein pattern in HOS, and WT cardiac tissues. Our results demonstrate that the mutant TBX5 transcript is cleared by the cellular mechanism of surveillance. This data provides some support for the hypothesis that a dominant negative mutation, which strongly impairs the WT allele, might be too hazardous to be maintained. The literature suggests that HOS is relatively common among syndromes associated with AVCD.
authors.affiliation: Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.
authors.forename: Anwar
authors.initials: A
authors.lastname: Baban
authors.forename: Letizia
authors.initials: L
authors.lastname: Pitto
authors.forename: Silvia
authors.initials: S
authors.lastname: Pulignani
authors.forename: Monica
authors.initials: M
authors.lastname: Cresci
authors.forename: Laura
authors.initials: L
authors.lastname: Mariani
authors.forename: Carolina
authors.initials: C
authors.lastname: Gambacciani
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Digilio
authors.forename: Giacomo
authors.initials: G
authors.lastname: Pongiglione
authors.forename: Sonia
authors.initials: S
authors.lastname: Albanese
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D001017:Aortic Coarctation / Q000235:genetics*; D001483:Base Sequence; D059327:Brachydactyly / Q000235:genetics; D002648:Child; D004694:Endocardial Cushion Defects / Q000235:genetics*; D006330:Heart Defects, Congenital / Q000235:genetics*; D006343:Heart Septal Defects; D006344:Heart Septal Defects, Atrial / Q000235:genetics*; D006801:Humans; D038061:Lower Extremity Deformities, Congenital / Q000235:genetics*; D008297:Male; D009154:Mutation; D011884:Radius / Q000002:abnormalities; D017422:Sequence Analysis, DNA; D013580:Synostosis / Q000235:genetics; D020825:T-Box Domain Proteins / Q000235:genetics*; D014457:Ulna / Q000002:abnormalities; D038062:Upper Extremity Deformities, Congenital / Q000235:genetics*
chemical_list: D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5
keywords: Holt-Oram syndrome (HOS); TBX5; aortic coarctation (COA); atrioventricular canal defect (AVCD)