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Holt-Oram syndrome with intermediate atrioventricular canal defect, and aortic coarctation: functional characterization of a de novo TBX5 mutation.
Am J Med Genet A 2014; 164A(6):1419-24AJ

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+Show Affiliations

Department of Pediatric Cardiology and Cardiac Surgery, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Case Reports
Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24664498

Citation

Baban, Anwar, et al. "Holt-Oram Syndrome With Intermediate Atrioventricular Canal Defect, and Aortic Coarctation: Functional Characterization of a De Novo TBX5 Mutation." American Journal of Medical Genetics. Part A, vol. 164A, no. 6, 2014, pp. 1419-24.
Baban A, Pitto L, Pulignani S, et al. Holt-Oram syndrome with intermediate atrioventricular canal defect, and aortic coarctation: functional characterization of a de novo TBX5 mutation. Am J Med Genet A. 2014;164A(6):1419-24.
Baban, A., Pitto, L., Pulignani, S., Cresci, M., Mariani, L., Gambacciani, C., ... Albanese, S. (2014). Holt-Oram syndrome with intermediate atrioventricular canal defect, and aortic coarctation: functional characterization of a de novo TBX5 mutation. American Journal of Medical Genetics. Part A, 164A(6), pp. 1419-24. doi:10.1002/ajmg.a.36459.
Baban A, et al. Holt-Oram Syndrome With Intermediate Atrioventricular Canal Defect, and Aortic Coarctation: Functional Characterization of a De Novo TBX5 Mutation. Am J Med Genet A. 2014;164A(6):1419-24. PubMed PMID: 24664498.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Holt-Oram syndrome with intermediate atrioventricular canal defect, and aortic coarctation: 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, Y1 - 2014/03/24/ PY - 2013/05/13/received PY - 2013/12/26/accepted PY - 2014/3/26/entrez PY - 2014/3/26/pubmed PY - 2015/1/15/medline KW - Holt-Oram syndrome (HOS) KW - TBX5 KW - aortic coarctation (COA) KW - atrioventricular canal defect (AVCD) SP - 1419 EP - 24 JF - American journal of medical genetics. Part A JO - Am. J. Med. Genet. A VL - 164A IS - 6 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. SN - 1552-4833 UR - https://www.unboundmedicine.com/medline/citation/24664498/Holt_Oram_syndrome_with_intermediate_atrioventricular_canal_defect_and_aortic_coarctation:_functional_characterization_of_a_de_novo_TBX5_mutation_ L2 - https://doi.org/10.1002/ajmg.a.36459 DB - PRIME DP - Unbound Medicine ER -