Connexin 40, a Target of Transcription Factor Tbx5, Patterns Wrist, Digits, and Sternum

Pizard, Anne; Burgon, Patrick G.; Paul, David L.; Bruneau, Benoit G.; Seidman, Christine E.

doi:10.1128/mcb.25.12.5073-5083.2005

Cited by 39 publications

(31 citation statements)

References 48 publications

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“…27 The subsequent patterning of the digits, wrist bones, and sternum occurs via Cx40-containing gap junctions, again regulated by TBX5. 28 Because both FGF10 and Cx40 are highly sensitive to TBX5 dosage, it is not surprising that the skeletal phenotypes of the family reported here reflects the underlying mutation, namely a mild skeletal phenotype as a result of a gain-of-function mutation, in which the core functionality of TBX5 is retained, in contrast with the more severe phenotypes caused by the common loss-of-function TBX5 mutations. 13 We also investigated whether the prevalent paroxysmal AF in this family could be the consequence of a change in expression levels of genes that are known to be associated with AF.…”

Section: Discussionmentioning

confidence: 80%

A Gain-of-Function TBX5 Mutation Is Associated With Atypical Holt–Oram Syndrome and Paroxysmal Atrial Fibrillation

Postma

Meerakker

Mathijssen

et al. 2008

Circulation Research

156

106

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Abstract-Holt-Oram syndrome (HOS) is a heart/hand syndrome clinically characterized by upper limb and cardiac malformations. Mutations in T-box transcription factor 5 (TBX5) underlie this syndrome. Here, we describe a large atypical HOS family in which affected patients have mild skeletal deformations and paroxysmal atrial fibrillation, but few have congenital heart disease. Sequencing of TBX5 revealed a novel mutation, c.373GϾA, resulting in the missense mutation p.Gly125Arg, in all investigated affected family members, cosegregating with the disease. We demonstrate that the mutation results in normal Nkx2-5 interaction, is correctly targeted to the nucleus, has significantly enhanced DNA binding and activation of both the Nppa(Anf) and Cx40 promoter, and significantly augments expression of Nppa, Cx40, Kcnj2, and Tbx3 in comparison with wild-type TBX5. Thus, contrary to previously published HOS mutations, the p.G125R TBX5 mutation results in a gain-of-function. We speculate that the gain-of-function mechanism underlies the mild skeletal phenotype and paroxysmal atrial fibrillation and suggest a possible role of TBX5 in the development of (paroxysmal) atrial fibrillation based on a gain-of-function either through a direct stimulation of target genes via TBX5 or indirectly via TBX5 stimulated TBX3. These findings may warrant a renewed look at the phenotypes of families and individuals hitherto not classified as HOS or as atypical but presenting with paroxysmal atrial fibrillation, because these may possibly be the result of additional TBX5 gain-of-function mutations. Key Words: atrial fibrillation Ⅲ congenital heart defects Ⅲ transcription factor Ⅲ TBX5 Ⅲ Holt-Oram syndrome C ongenital heart defects are among the most common congenital defects in children, occurring in 1% to 2% of live births and in Ϸ5% of stillbirths. 1 Congenital heart defects can either appear as a spontaneous defect or as part of a syndrome. One such syndrome is the Holt-Oram Syndrome (HOS) (Online Mendelian Inheritance in Man [OMIM] no. 142900), 2 appearing in 1 of 100 000 live births 3 and segregating in an autosomal dominant fashion. It is characterized by bilateral forelimb deformities and congenital heart defects. Clinically, there are 3 variations of HOS: affected individuals may have only skeletal anomalies (27.4%), only cardiac defects (3.9%), or both (68.7%). 4 The limb and heart malformations can vary from mild to severe, even within families, and no correlation exists between the severity of the cardiac and skeletal abnormalities of the patient. 5 The congenital heart malformations are generally secundum atrial septal defects (ASD II) or ventricular septal defects, but others, such as mitral valve defects and cardiac conduction defects, most notably atrioventricular block, have also been reported. 3,6 Single-gene mutations were identified in the T-box transcription factor 5 (TBX5) in multiple HOS patients. 7 TBX5 is a member of the T-box transcription factor family that regulates a wide variety of developmental processes in ...

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Section: Discussionmentioning

confidence: 80%

A Gain-of-Function TBX5 Mutation Is Associated With Atypical Holt–Oram Syndrome and Paroxysmal Atrial Fibrillation

Postma

Meerakker

Mathijssen

et al. 2008

Circulation Research

156

106

View full text Add to dashboard Cite

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“…Skulls from newborn mice were fixed in 95% ethanol, stained with Alcian blue solution, washed in 95% ethanol, and stained in alizarin red solution (44).…”

Section: Methodsmentioning

confidence: 99%

“…A 720-bp probe for Eya1 was amplified using the following primers: Eya1, forward, ATG-GAAATGCAGGATCTAACCAGC; and Eya1, reverse, CGTCATGTAGTGT-GCTGGATAC. Fragments were cloned into pCR4Blunt-TOPO (Invitrogen) plasmid, transcribed as described for Eya4 probes, and hybridized to either whole mouse E12.5 embryos or to 10-μm paraffin-embedded sections (44).…”

Section: Methodsmentioning

confidence: 99%

Eya4-deficient mice are a model for heritable otitis media

Depreux¹,

Darrow²,

Conner³

et al. 2008

J. Clin. Invest.

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Otitis media is an extremely common pediatric inflammation of the middle ear that often causes pain and diminishes hearing. Vulnerability to otitis media is due to eustachian tube dysfunction as well as other poorly understood factors, including genetic susceptibility. As EYA4 mutations cause sensorineural hearing loss in humans, we produced and characterized Eya4-deficient (Eya4 -/-) mice, which had severe hearing deficits. In addition, all Eya4 -/-mice developed otitis media with effusion. Anatomic studies revealed abnormal middle ear cavity and eustachian tube dysmorphology; thus, Eya4 regulation is critical for the development and function of these structures. We suggest that some human otitis media susceptibility reflects underlying genetic predisposition in genes like EYA4 that regulate middle ear and eustachian tube anatomy.

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“…Other connexins are also expressed in bone, specifically Cx45 and Cx46, though their functions in these cells remain unknown [22;23]. Cx40 is also present in developing limbs ribs and sternum [27], but its expression in the adult skeleton has never been documented. Earlier studies using antisense nucleotide strategies demonstrated severe limb malformations upon inhibition of Cx43 gene (Gja1) expression [28;29].…”

Section: Connexins In Skeletal Developmentmentioning

confidence: 99%

Cell–cell communication in the osteoblast/osteocyte lineage

Civitelli

2008

Archives of Biochemistry and Biophysics

228

176

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Skeletal development (bone modeling) and its maintenance in post-natal life in response to local and systemic stimuli (bone remodeling) require coordinated activity among osteoblasts (bone forming cells), osteocytes (cells embedded in bone) and osteoclasts (bone resorbing cells), in order to meet the needs of structural integrity, mechanical competence and maintenance of mineral homeostasis. One mechanism of cell-cell interaction is via direct cell-cell communication via gap junctions. These are transmembrane channels that allow continuity of cytoplasms between communicating cells. The biologic importance of connexin43 (Cx43), the most abundant gap junction protein in the skeleton is demonstrated by the skeletal malformations present in oculodentodigital dysplasia (ODDD), a disease linked to Cx43 gene (GJA1) mutations, and by the low bone mass and osteoblast dysfunction in Gja1 ablated mice. The presence of Cx43 is required for osteoblast differentiation and function, and by forming either gap junctions or "hemichannels" Cx43 allows participation of cell networks to responses to extracellular stimuli, via propagation of specific signals converging upon connexin sensitive transcriptional units. Hence, Cx43 is involved in skeletal responsiveness to anabolic signals, as those provided by parathyroid hormone and physical load, the latter function probably involving osteocyte-osteoblast communication.

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Connexin 40, a Target of Transcription Factor Tbx5, Patterns Wrist, Digits, and Sternum

Cited by 39 publications

References 48 publications

A Gain-of-Function TBX5 Mutation Is Associated With Atypical Holt–Oram Syndrome and Paroxysmal Atrial Fibrillation

A Gain-of-Function TBX5 Mutation Is Associated With Atypical Holt–Oram Syndrome and Paroxysmal Atrial Fibrillation

Eya4-deficient mice are a model for heritable otitis media

Cell–cell communication in the osteoblast/osteocyte lineage

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