Novel TBX5 mutations and molecular mechanism for Holt-Oram syndrome

Fan, Chun; Duhagon, Marı́a Ana; Oberti, Carlos; Chen, S.; Hiroi, Yukio; Komuro, Issei; Duhagon, P. I.; Canessa, R.; Wang, Qing Kenneth

doi:10.1136/jmg.40.3.e29

Cited by 43 publications

(25 citation statements)

References 32 publications

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“…A novel nonsense mutation in the exon 3 of TBX5 associated with single HOS patient, 192G>A (p. W64X) results in the truncation of TBX5 polypeptide by 88%. Here, the substitution happens at the 2 nd position of codon 64 where tryptophan residue changes into stop codon and is located at the T-box domain [29]. A study demonstrated that expressivity of malformation in patients with HOS cannot be predicted by either by the location of the mutation in the T-box domain or the TBX5 mutation [30].…”

Section: Discussionmentioning

confidence: 99%

A Tbx5 Nonsense Mutation in Siblings With Divergent Phenotypes Associated With Isolated Septal Defects

Borkar

Nayak

Shetty

et al. 2017

Asian J Pharm Clin Res

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Objective: Heart septal defects (HSD) account for 50% of the congenital heart malformations and are characterized by the hole in the wall of tissue which separates the heart chambers. The known causes of the SD are multifactorial and complex inheritance.Methods: Isolated 15 subjects with ostium secundum atrial SD (OS-ASD) and one subject with perimembranous ventricular SD (VSD) among 125 clinically diagnosed SD were included in the study. Sanger sequencing was performed for all the exons of TBX5 genes using genomic DNA of these patients.Results: Sequence variation c.444 G>A substitution, leads to the alteration of tryptophan residue into premature stop codon at codon 148. We observed a divergent phenotype within a family of four, where one sibling and the mother had OS-ASD, another sibling had phenotype of perimembranous VSD, and the father had normal genotype. Conclusion:We believe that this novel sequence variant in TBX5 gene is one of the factors in the SD and may hold a key determining the role of TBX5 gene in the heart development.

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Section: Discussionmentioning

confidence: 99%

A Tbx5 Nonsense Mutation in Siblings With Divergent Phenotypes Associated With Isolated Septal Defects

Borkar

Nayak

Shetty

et al. 2017

Asian J Pharm Clin Res

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“…The normal cellular localisation of the TBX5 protein is in the nucleus in cardiomyocytes. 28 Fan et al 29,30 analysed various missense mutations and in frame deletions and described their possible pathogenetic mechanisms as either: (a) abnormal cellular localisation of mutant TBX5 protein or (b) altered interactions with cardiac or limb specific co-factors (eg, NKX2.5, GATA4, Cx40 and SALL4). They showed increased concentrations within the cytoplasm of TBX5 mutant proteins from various missense mutations and one in-frame deletion, providing evidence of altered nuclear localisation.…”

Section: Discussionmentioning

confidence: 99%

TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype

Patel

Silcock²,

McMullan³

et al. 2012

Eur J Hum Genet

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Holt-Oram syndrome (HOS) is a rare autosomal dominant heart-hand syndrome due to mutations in the TBX5 transcription factor. Affected individuals can have structural cardiac defects and/or conduction abnormalities, and exclusively upper limb defects (typically bilateral, asymmetrical radial ray defects). TBX5 mutations reported include nonsense, missense, splicing mutations and exon deletions. Most result in a null allele and haploinsufficiency, but some impair nuclear localisation of TBX5 protein or disrupt its interaction with co-factors and downstream targets. We present a five generation family of nine affected individuals with an atypical HOS phenotype, consisting of ulnar ray defects (ulnar hypoplasia, short fifth fingers with clinodactyly) and very mild radial ray defects (short thumbs, bowing of the radius and dislocation of the radial head). The cardiac defects seen are those more rarely reported in HOS (atrioventricular septal defect, hypoplastic left heart syndrome, mitral valve disease and pulmonary stenosis). Conduction abnormalities include atrial fibrillation, atrial flutter and sick sinus syndrome. TBX5 mutation screening (exons 3-10) identified no mutations. Array comparative genomic hybridisation (CGH) revealed a 48 kb duplication at 12q24.21, encompassing exons 2-9 of the TBX5 gene, with breakpoints within introns 1-2 and 9-10. The duplication segregates with the phenotype in the family, and is likely to be pathogenic. This is the first known report of an intragenic duplication of TBX5 and its clinical effects; an atypical HOS phenotype. Further functional studies are needed to establish the effects of the duplication and pathogenic mechanism. All typical/atypical HOS cases should be screened for TBX5 exon duplications.

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“…Mutations included 6 nonsense, 1 deletion/frameshift, 5 splice site, and 3 missense mutations. Of these mutations, 11 had not been previously reported; 3 mutations (Y136ter, S196ter, and T223M) (12,14,21) had been previously documented in patients with HOS. Six of the identified TBX5 mutations disrupt the T-box DNA binding domain, whereas the remainder occur downstream of the T-box and modify exons 7 and 8.…”

Section: Mutational Analysesmentioning

confidence: 99%

TBX5 Genetic Testing Validates Strict Clinical Criteria for Holt-Oram Syndrome

et al. 2005

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Holt-Oram syndrome (HOS) is an autosomal dominant hearthand syndrome characterized by congenital heart disease (CHD) and upper limb deformity, and caused by mutations in the TBX5 gene. To date, the sensitivity of TBX5 genetic testing for HOS has been unclear. We now report mutational analyses of a nongenetically selected population of 54 unrelated individuals who were consecutively referred to our center with a clinical diagnosis of HOS. TBX5 mutational analyses were performed in all individuals, and clinical histories and findings were reviewed for each patient without reference to the genotypes. Twenty-six percent of the complete cohort was shown to have mutations of the TBX5 gene. However, among those subjects for whom clinical review demonstrated that their presentations met strict diagnostic criteria for HOS, TBX5 mutations were identified in 74%. No mutations were identified in those subjects who did not meet these criteria. Thus, these studies validate our clinical diagnostic criteria for HOS including an absolute requirement for preaxial radial ray upper limb malformation. Accordingly, TBX5 genotyping has high sensitivity and specificity for HOS if stringent diagnostic criteria are used in assigning the clinical diagnosis. HOS is the most common of the heart-hand syndromes. It segregates in an autosomal dominant fashion and is estimated to occur in at least 1/100,000 live births (1). HOS is characterized by upper limb anomalies involving the preaxial radial ray and CHD (2,3). Upper limb deformity may be bilateral but asymmetric or even unilateral. The most common forms of CHD associated with HOS are ASD, usually of the ostium secundum variety, and VSD, usually occurring in the muscular trabeculated septum. Cardiac conduction disease may also occur, regardless of the presence or absence of structural cardiac disease (3

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Novel TBX5 mutations and molecular mechanism for Holt-Oram syndrome

Cited by 43 publications

References 32 publications

A Tbx5 Nonsense Mutation in Siblings With Divergent Phenotypes Associated With Isolated Septal Defects

A Tbx5 Nonsense Mutation in Siblings With Divergent Phenotypes Associated With Isolated Septal Defects

TBX5 intragenic duplication: a family with an atypical Holt–Oram syndrome phenotype

TBX5 Genetic Testing Validates Strict Clinical Criteria for Holt-Oram Syndrome

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