Functional analysis of novel TBX5 T-box mutations associated with Holt-Oram syndrome

Boogerd, Cornelis J.; Dooijes, Dennis; Ilgun, Aho; Mathijssen, Inge B.; Hordijk, Roel; Laar, Ingrid M.B.H. van de; Rump, Patrick; Veenstra‐Knol, Hermine E.; Moorman, Antoon F.M.; Barnett, Phil; Postma, Alex V.

doi:10.1093/cvr/cvq178

Cited by 43 publications

(44 citation statements)

References 43 publications

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“…The fourth member had bilateral rudimentary postaxial polydactyly. A normal upper limb phenotype was also noted in another two TBX5 mutations: Thr 223Met (Brassington et al, 2003) and Arg237Pro (Boogerd et al, 2010). This should increase the awareness that the presence of upper limb anomalies is not mandatory for the clinical diagnosis of Holt-Oram syndrome.…”

Section: Tbx5 Mutations and Non-classic Upper Limb Phenotypesmentioning

confidence: 73%

“…The authors propose that phocomelia may be a severe form of longitudinal deficiency which is expected to occur in some patients of Holt-Oram syndrome in whom there is severe suppression of FGF8 in the AER. In support of this hypothesis is the phenotype of the patient with Ile106Val (Boogerd et al, 2010). On the right, the patient had "distal" phocomelia (hand attached directly to the humerus) with monodactyly.…”

Section: Tbx5 Mutations and Non-classic Upper Limb Phenotypesmentioning

confidence: 83%

“…Both the radial ray deficiency and the cardiac anomaly were classified into mild or severe according to the criteria shown in Table 1. Table 2 summarizes the clinical features of previously reported cases of missense mutations of the TBX5 gene (Basson et al, 1999;Boogerd et al, 2010;Brassington et al, 2003;Cross et al, 2000;Debeer et al, 2007;Dias et al, 2007;Faria et al, 2008;Furniss et al, 2009;McDermott et al, 2005;Porto et al, 2010;Postma et al, 2008;Yang et al, 2000).…”

Section: Literature Reviewmentioning

confidence: 99%

Section: Genotype-cardiac Phenotype Correlationsmentioning

confidence: 99%

“…For example, the Ile106Val mutant protein retains the capacity to bind to NKX2-5 and has a slightly enhanced binding to GATA 4 (Boogerd et al, 2010). This is translated clinically in the absence of cardiac anomalies in patients with the Ile106Val mutation (Boogerd et al, 2010;McDermott et al, 2005). In contrast, the Met74Ile mutant protein shows a drastic reduction of binding capacity to both NKX2-5 and GATA 4; and affected patients have severe cardiac anomalies (Boogerd et al, 2010).…”

Section: Genotype-cardiac Phenotype Correlationsmentioning

confidence: 99%

See 4 more Smart Citations

Molecular basis of the clinical features of Holt–Oram syndrome resulting from missense and extended protein mutations of the TBX5 gene as well as TBX5 intragenic duplications

Al‐Qattan

Al-Shaar

2015

Gene

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Section: Tbx5 Mutations and Non-classic Upper Limb Phenotypesmentioning

confidence: 73%

Section: Tbx5 Mutations and Non-classic Upper Limb Phenotypesmentioning

confidence: 83%

Section: Literature Reviewmentioning

confidence: 99%

Section: Genotype-cardiac Phenotype Correlationsmentioning

confidence: 99%

Section: Genotype-cardiac Phenotype Correlationsmentioning

confidence: 99%

See 3 more Smart Citations

Molecular basis of the clinical features of Holt–Oram syndrome resulting from missense and extended protein mutations of the TBX5 gene as well as TBX5 intragenic duplications

Al‐Qattan

Al-Shaar

2015

Gene

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Molecular Genetics of Holt–Oram Syndrome

Barnett

Postma

2014

Encyclopedia of Life Sciences

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The Holt–Oram syndrome (HOS) is an autosomal‐dominant hand–heart syndrome characterised by malformations of the upper limbs, mainly involving the preaxial (radial) ray, and variable cardiac defects. Mutations in TBX5, a transcription factor that regulates a wide variety of developmental processes, underlie HOS. Thus far, more than a hundred TBX5 mutations have been identified in patients with HOS. However, only the application of stringent diagnostic criteria will lead to a high sensitivity and specificity in TBX5 mutation screening. Various pathogenic mechanisms that lead to HOS have been uncovered, ranging from loss‐of‐function to gain‐of‐function. Nonetheless, in a significant minority of HOS patients, who do fulfil the strict diagnostic criteria, no TBX5 mutation is identified. This suggests that mutations in regulatory parts of TBX5 could cause disease, or mutations in genes other than TBX5 could underlie HOS. Application of exome sequencing or even whole‐genome sequencing should be pursued in those cases. Key Concepts: Holt–Oram syndrome is caused by TBX5 mutations. The majority of TBX5 mutations lead to loss‐of‐function. Application of stringent diagnostic criteria increases the yield of TBX5 mutation screening in HOS patients. In a minority of HOS patients, who fulfil the stringent diagnostic criteria, no TBX5 mutation is identified. TBX5 is involved in the specification of the mesoderm and development of the heart, vasculature and limbs.

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An intragenic deletion of the gene MNAT1 in a family with pectus deformities

Heithaus

Davenport

Twyman

et al. 2014

American J of Med Genetics Pt A

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Pectus carinatum and excavatum have multiple genetic associations. We report on a novel association of these deformities in a 34-month-old male and his father, likely due to a small intragenic deletion of MNAT1 (ménage a trois 1 gene). Both individuals share a deletion of MNAT1 located at 14q23.1 and an interstitial duplication of CHRNA7 located at 15q13.3. Deletion of MNAT1 has been associated with connective tissue abnormalities and is likely the etiology of the malformations, whereas the duplication of CHNRA7 is unlikely related due to the lack of association with any such connective tissue abnormalities.

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Functional analysis of novel TBX5 T-box mutations associated with Holt-Oram syndrome

Abstract: Overall, our data are consistent with the hypothesis that these novel missense mutations in TBX5 lead to functional haploinsufficiency and result in a reduced transcriptional activation of target genes, which is likely central to the pathogenesis of HOS.

Cited by 43 publications

References 43 publications

Molecular basis of the clinical features of Holt–Oram syndrome resulting from missense and extended protein mutations of the TBX5 gene as well as TBX5 intragenic duplications

Molecular basis of the clinical features of Holt–Oram syndrome resulting from missense and extended protein mutations of the TBX5 gene as well as TBX5 intragenic duplications

Molecular Genetics of Holt–Oram Syndrome

An intragenic deletion of the gene MNAT1 in a family with pectus deformities

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