TY - JOUR
T1 - Holt-Oram syndrome with intermediate atrioventricular canal defect, and aortic coarctation
T2 - Functional characterization of a de novo TBX5 mutation
AU - Baban, Anwar
AU - Pitto, Letizia
AU - Pulignani, Silvia
AU - Cresci, Monica
AU - Mariani, Laura
AU - Gambacciani, Carolina
AU - Digilio, Maria Cristina
AU - Pongiglione, Giacomo
AU - Albanese, Sonia
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Aortic coarctation (COA)
KW - Atrioventricular canal defect (AVCD)
KW - Holt-Oram syndrome (HOS)
KW - TBX5
UR - http://www.scopus.com/inward/record.url?scp=84899977586&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84899977586&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.36459
DO - 10.1002/ajmg.a.36459
M3 - Article
C2 - 24664498
AN - SCOPUS:84899977586
VL - 164
SP - 1419
EP - 1424
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
SN - 1552-4825
IS - 6
ER -