RGD Reference Report - A gain-of-function TBX5 mutation is associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillation. - Rat Genome Database

Send us a Message
Submit Data |  Help |  Video Tutorials |  News |  Publications |  Download |  REST API |  Citing RGD |  Contact   
Search RGD Grant Resources Citing RGD About Us Contact Us
Genes Variants Community Projects QTLs Strains Markers Genome Information Ontologies Cell Lines References Download Submit Data
OntoMate (Literature Search) JBrowse (Genome Browser) Synteny Browser (VCMap) Variant Visualizer Multi-Ontology Enrichment (MOET) Gene-Ortholog Location Finder (GOLF) InterViewer (Protein-Protein Interactions) PhenoMiner (Quatitative Phenotypes) Gene Annotator OLGA (Gene List Generator) AllianceMine GViewer (Genome Viewer)
Aging & Age-Related Disease Cancer & Neoplastic Disease Cardiovascular Disease Coronavirus Disease Developmental Disease Diabetes Hematologic Disease Immune & Inflammatory Disease Infectious Disease Liver Disease Neurological Disease Obesity & Metabolic Syndrome Renal Disease Respiratory Disease Sensory Organ Disease
Find Models   new Genetic Models Autism Models Rat PhenoMiner (Quantitative Phenotypes) Chinchilla PhenoMiner Expected Ranges (Quantitative Phenotype) PhenoMiner Term Comparison Hybrid Rat Diversity Panel Phenotypes Phenotypes in Other Animal Models Animal Husbandry Strain Medical Records Phylogenetics Strain Availability Calendar Rats 101 Submissions Photo Archive
Pathways
Rat Community Forum Directory of Rat Laboratories Video Tutorials News RGD Publications RGD Presentations Archive Nomenclature Guidelines Resource Links Laboratory Resources Employment Resources

A gain-of-function TBX5 mutation is associated with atypical Holt-Oram syndrome and paroxysmal atrial fibrillation.

Authors: Postma, AV  Van de Meerakker, JB  Mathijssen, IB  Barnett, P  Christoffels, VM  Ilgun, A  Lam, J  Wilde, AA  Lekanne Deprez, RH  Moorman, AF 
Citation: Postma AV, etal., Circ Res. 2008 Jun 6;102(11):1433-42. doi: 10.1161/CIRCRESAHA.107.168294. Epub 2008 May 1.
RGD ID: 7327219
Pubmed: PMID:18451335   (View Abstract at PubMed)
DOI: DOI:10.1161/CIRCRESAHA.107.168294   (Journal Full-text)

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.373G>A, 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Holt-Oram syndrome  IAGP 7327219DNA:missense mutation:cds:p.G125R (human)RGD 
Holt-Oram syndrome  ISOTBX5 (Homo sapiens)7327219; 7327219DNA:missense mutation:cds:p.G125R (human)RGD 

Objects Annotated

Genes (Rattus norvegicus)
Tbx5  (T-box transcription factor 5)

Genes (Mus musculus)
Tbx5  (T-box 5)

Genes (Homo sapiens)
TBX5  (T-box transcription factor 5)


Additional Information