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TBX5 mutations and congenital heart disease: Holt-Oram syndrome revealed.
Curr Opin Cardiol 2004; 19(3):211-5CO

Abstract

PURPOSE OF REVIEW

Mutations in the T-box transcription factor TBX5 cause Holt-Oram syndrome (HOS), an autosomal-dominant condition characterized by a familial history of congenital heart defects and preaxial radial ray upper limb defects. This review summarizes recent developments in the study of TBX5 as it relates to congenital heart disease and the pathology of HOS.

RECENT FINDINGS

Currently, 37 mutations in TBX5 have been found in patients with HOS. Most of these mutations cause premature truncation of the primary TBX5 transcript, thereby presumably causing haploinsufficiency. Conversely, missense mutations diminish the interaction of TBX5 with other transcription factors and reduce nuclear localization of mutant protein. Although mutations are found throughout the TBX5 gene, no evidence exists to suggest that genotype affects the location of heart and limb defects or the severity of HOS manifestation. However, genetic background, and to a lesser extent, environmental and stochastic modifiers are believed to influence greatly the severity of HOS manifestation and may account for the large variation seen in the severity of defects, even among members of the same kindred. Careful clinical examination of patients who seek treatment with heart and limb malformations is necessary to avoid misdiagnosis of similar congenital conditions. With the proper examination, TBX5 mutations can be identified in more than 70% of patients with a clinical diagnosis of HOS.

SUMMARY

Genetic analysis of patient populations and the biochemical characterization of the mutated proteins have provided considerable insight into the function of TBX5 in cardiac development and disease pathology. Novel discoveries await as these two paradigms merge.

Authors+Show Affiliations

Program in Cardiovascular Research, Hospital for Sick Children, University of Toronto, Toronto, Canada.No affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

15096952

Citation

Mori, Alessandro D., and Benoit G. Bruneau. "TBX5 Mutations and Congenital Heart Disease: Holt-Oram Syndrome Revealed." Current Opinion in Cardiology, vol. 19, no. 3, 2004, pp. 211-5.
Mori AD, Bruneau BG. TBX5 mutations and congenital heart disease: Holt-Oram syndrome revealed. Curr Opin Cardiol. 2004;19(3):211-5.
Mori, A. D., & Bruneau, B. G. (2004). TBX5 mutations and congenital heart disease: Holt-Oram syndrome revealed. Current Opinion in Cardiology, 19(3), pp. 211-5.
Mori AD, Bruneau BG. TBX5 Mutations and Congenital Heart Disease: Holt-Oram Syndrome Revealed. Curr Opin Cardiol. 2004;19(3):211-5. PubMed PMID: 15096952.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TBX5 mutations and congenital heart disease: Holt-Oram syndrome revealed. AU - Mori,Alessandro D, AU - Bruneau,Benoit G, PY - 2004/4/21/pubmed PY - 2004/9/10/medline PY - 2004/4/21/entrez SP - 211 EP - 5 JF - Current opinion in cardiology JO - Curr. Opin. Cardiol. VL - 19 IS - 3 N2 - PURPOSE OF REVIEW: Mutations in the T-box transcription factor TBX5 cause Holt-Oram syndrome (HOS), an autosomal-dominant condition characterized by a familial history of congenital heart defects and preaxial radial ray upper limb defects. This review summarizes recent developments in the study of TBX5 as it relates to congenital heart disease and the pathology of HOS. RECENT FINDINGS: Currently, 37 mutations in TBX5 have been found in patients with HOS. Most of these mutations cause premature truncation of the primary TBX5 transcript, thereby presumably causing haploinsufficiency. Conversely, missense mutations diminish the interaction of TBX5 with other transcription factors and reduce nuclear localization of mutant protein. Although mutations are found throughout the TBX5 gene, no evidence exists to suggest that genotype affects the location of heart and limb defects or the severity of HOS manifestation. However, genetic background, and to a lesser extent, environmental and stochastic modifiers are believed to influence greatly the severity of HOS manifestation and may account for the large variation seen in the severity of defects, even among members of the same kindred. Careful clinical examination of patients who seek treatment with heart and limb malformations is necessary to avoid misdiagnosis of similar congenital conditions. With the proper examination, TBX5 mutations can be identified in more than 70% of patients with a clinical diagnosis of HOS. SUMMARY: Genetic analysis of patient populations and the biochemical characterization of the mutated proteins have provided considerable insight into the function of TBX5 in cardiac development and disease pathology. Novel discoveries await as these two paradigms merge. SN - 0268-4705 UR - https://www.unboundmedicine.com/medline/citation/15096952/TBX5_mutations_and_congenital_heart_disease:_Holt_Oram_syndrome_revealed_ L2 - http://dx.doi.org/10.1097/00001573-200405000-00004 DB - PRIME DP - Unbound Medicine ER -