Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0265264 (HOS)
 1,119 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Holt-Oram syndrome is an autosomal dominant disorder characterized by upper limb malformations in the preaxial radial ray and cardiac septation and/or a conduction abnormality. It has been demonstrated that Holt-Oram syndrome is caused by mutations in the T-box transcription factor gene TBX5. Numerous germline mutations (more than 90) of this gene have been reported; however, TBX5 mutations are only identified in up to 74% of typical Holt-Oram syndrome patients. We report a Japanese family with 2 affected individuals with the typical Holt-Oram syndrome phenotype, namely bilateral asymmetrical radial ray deformities and an atrial septal defect. An array-based comparative genomic hybridization study revealed an 11-kb duplication at 12q24.1. Moreover, a multiplex ligation-dependent probe amplification study confirmed the duplication of exons 1-6 of TBX5. Although a small duplication in TBX5 (6 bases) has been reported, a large duplication of this gene has not been described previously in typical Holt-Oram syndrome patients. All typical Holt-Oram syndrome cases in which a mutation is not identified should be screened for TBX5 exon duplications.
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PMID:Novel TBX5 duplication in a Japanese family with Holt-Oram syndrome. 2527 98

Holt-Oram syndrome is clinically characterized by morphological abnormalities of the upper limbs and congenital cardiac defects. Although the disease is congenital, the diagnosis may only be made later in life. It is a rare autosomal dominant disorder, caused by a mutation in the TBX5 gene located on chromosome 12, but sporadic cases have also been reported. We describe the case of a 75-year-old man with known morphological alterations of the upper limbs since birth and congenital cardiac defect (atrial septal defect), who later in life also manifested with advanced atrioventricular block.
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PMID:Holt-Oram syndrome: a case report. 2545 49

The sternum bone lies at the ventral midline of the thorax where it provides a critical attachment for the pectoral muscles that allow the forelimbs to raise the body from the ground. Among tetrapods, sternum morphology is correlated with the mode of locomotion: Avians that fly have a ventral extension, or keel, on their sterna, which provides an increased area for flight muscle attachment. The sternum is fused with the ribs attaching on either side; however, unlike the ribs, the sternal precursors do not originate from the somites. Despite the crucial role of the sternum in tetrapod locomotion, little attention has been given to its acquisition, evolution, and embryological development. We demonstrate an essential role for the T-box transcription factor gene Tbx5 in sternum and forelimb formation and show that both structures share an embryological origin within the lateral plate mesoderm. Consistent with this shared origin and role of Tbx5, sternum defects are a characteristic feature of Holt-Oram Syndrome (OMIM 142900) caused by mutations in TBX5. We demonstrate a link between sternum size and forelimb use across avians and provide evidence that modulation of Tbx5 expression underlies the reduction in sternum and wing size in a flightless bird, the emu. We demonstrate that Tbx5 is a common node in the genetic pathways regulating forelimb and sternum development, enabling specific adaptations of these features without affecting other skeletal elements and can also explain the linked adaptation of sternum and forelimb morphology correlated with mode of locomotion.
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PMID:Regulatory modulation of the T-box gene Tbx5 links development, evolution, and adaptation of the sternum. 2546 72

TBX5 is the gene mutated in Holt-Oram syndrome, an autosomal dominant disorder with complex heart and limb deformities. Its protein product is a member of the T-box family of transcription factors and an evolutionarily conserved dosage-sensitive regulator of heart and limb development. Understanding TBX5 regulation is therefore of paramount importance. Here we uncover the existence of novel exons and provide evidence that TBX5 activity may be extensively regulated through alternative splicing to produce protein isoforms with differing N- and C-terminal domains. These isoforms are also present in human heart, indicative of an evolutionarily conserved regulatory mechanism. The newly identified isoforms have different transcriptional properties and can antagonize TBX5a target gene activation. Droplet Digital PCR as well as immunohistochemistry with isoform-specific antibodies reveal differential as well as overlapping expression domains. In particular, we find that the predominant isoform in skeletal myoblasts is Tbx5c, and we show that it is dramatically up-regulated in differentiating myotubes and is essential for myotube formation. Mechanistically, TBX5c antagonizes TBX5a activation of pro-proliferative signals such as IGF-1, FGF-10, and BMP4. The results provide new insight into Tbx5 regulation and function that will further our understanding of its role in health and disease. The finding of new exons in the Tbx5 locus may also be relevant to mutational screening especially in the 30% of Holt-Oram syndrome patients with no mutations in the known TBX5a exons.
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PMID:Novel exons in the tbx5 gene locus generate protein isoforms with distinct expression domains and function. 2562 69

This paper reviews the 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. First, we review all previously reported cases with these mutations, and then describe the pathogenesis of the clinical features in the heart and upper limb. Special emphasis is given to 'non-classic' upper limb features which are known to occur with these mutations. Finally, the molecular basis of other concurrent anomalies (chest wall, craniofacial, vertebral, and lung anomalies) is reviewed.
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PMID: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. 2568 Feb 89

Holt-Oram syndrome also known as heart and hand syndrome, first reported in 1960. It is a rare, inherited, an autosomal dominant disorder with mutation in TBX5. As the name suggests, the feature involves skeletal abnormality mainly involving upper limb, that is, upper-extremity malformations involving radial, thenar, or carpal bones; congenital heart diseases like, atrial-septal defect and ventricular septal defect and conduction problems. This syndrome may also involve other part of skeletal structure. We hereby report a case of a patient who was suffering from this syndrome scheduled for right radial head excision.
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PMID:Anesthetic management of a patient with Holt-Oram syndrome undergoing right radial head excision. 2588 10

Ventricular septal defects (VSDs) are the most commonly occurring congenital heart defect. They are regularly associated with complex syndromes, including DiGeorge syndrome and Holt-Oram syndrome, which are characterised by haploinsufficiency for the T-box transcription factors TBX1 and TBX5, respectively. The histone acetyltransferase monocytic leukaemia zinc finger protein, MOZ (MYST3/KAT6A), is required for the expression of the Tbx1 and Tbx5 genes. Homozygous loss of MOZ results in DiGeorge syndrome-like defects including VSD. The Moz gene is expressed in the ectodermal, mesodermal and endodermal aspects of the developing pharyngeal apparatus and heart; however it is unclear in which of these tissues MOZ is required for heart development. The role of MOZ in the activation of Tbx1 would suggest a requirement for MOZ in the mesoderm, because deletion of Tbx1 in the mesoderm causes VSDs. Here, we investigated the tissue-specific requirements for MOZ in the mesoderm. We demonstrate that Mesp1-cre-mediated deletion of Moz results in high penetrance of VSDs and overriding aorta and a significant decrease in MOZ-dependant Tbx1 and Tbx5 expression. Together, our data suggest that the molecular pathogenesis of VSDs in Moz germline mutant mice is due to loss of MOZ-dependant activation of mesodermal Tbx1 and Tbx5 expression.
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PMID:Mesodermal expression of Moz is necessary for cardiac septum development. 2591 87

We report on a Saudi infant with Holt-Oram syndrome caused by a de novo missense mutation of the TBX5 gene. The mutation (Thr72Lys) is novel and has not been previously reported. The cardiac and limb defects in our patient were both severe, and the infant also had micrognathia and cleft palate. Previously reported cases of the Holt-Oram syndrome caused by missense mutations were reviewed and their phenotypes were compared with the phenotype of our patient.
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PMID:A novel missense mutation in the TBX5 gene in a Saudi infant with Holt-Oram syndrome. 2621 50

Holt-Oram Syndrome (HOS) is an autosomal dominant heart-hand syndrome caused by mutations in the TBX5 gene, a transcription factor capable of regulating hundreds of cardiac-specific genes through complex transcriptional networks. Here we show that, in zebrafish, modulation of a single miRNA is sufficient to rescue the morphogenetic defects generated by HOS. The analysis of miRNA-seq profiling revealed a decreased expression of miR-19a in Tbx5-depleted zebrafish embryos compared to the wild type. We revealed that the transcription of the miR-17-92 cluster, which harbors miR-19a, is induced by Tbx5 and that a defined dosage of miR-19a is essential for the correct development of the heart. Importantly, we highlighted that miR-19a replacement is able to rescue cardiac and pectoral fin defects and to increase the viability of HOS zebrafish embryos. We further observed that miR-19a replacement shifts the global gene expression profile of HOS-like zebrafish embryos towards the wild type condition, confirming the ability of miR-19a to rescue the Tbx5 phenotype. In conclusion our data demonstrate the importance of Tbx5/miR-19a regulatory circuit in heart development and provide a proof of principle that morphogenetic defects associated with HOS can be rescued by transient miRNA modulation.
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PMID:MicroRNA 19a replacement partially rescues fin and cardiac defects in zebrafish model of Holt Oram syndrome. 2665 4

Limb reduction malformations are highly heterogeneous in their clinical presentation and so, predicting the underlying mutation on a clinical basis can be challenging. Molecular karyotyping is a powerful genomic tool that has quickly become the mainstay for the study of children with malformation syndromes. We describe three patients with major limb reduction anomalies in whom pathogenic copy number variants were identified on molecular karyotyping. These include a patient with hypoplastic phalanges and absent hallux bilaterally with de novo deletion of 11.9 Mb on 7p21.1-22.1 spanning 63 genes including RAC1, another patient with severe Holt-Oram syndrome and a large de novo deletion 2.2 Mb on 12q24.13-24.21 spanning 20 genes including TBX3 and TBX5, and a third patient with acheiropodia who had a nullizygous deletion of 102 kb on 7q36.3 spanning LMBR1. We discuss the potential of these novel genomic rearrangements to improve our understanding of limb development in humans.
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PMID:Novel copy number variants and major limb reduction malformation: Report of three cases. 2674 85


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