RGD Reference Report - Functional analysis of novel TBX5 T-box mutations associated with Holt-Oram syndrome. - Rat Genome Database

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

Authors: Boogerd, CJ  Dooijes, D  Ilgun, A  Mathijssen, IB  Hordijk, R  Van de Laar, IM  Rump, P  Veenstra-Knol, HE  Moorman, AF  Barnett, P  Postma, AV 
Citation: Boogerd CJ, etal., Cardiovasc Res. 2010 Oct 1;88(1):130-9. doi: 10.1093/cvr/cvq178. Epub 2010 Jun 2.
RGD ID: 7327217
Pubmed: PMID:20519243   (View Abstract at PubMed)
DOI: DOI:10.1093/cvr/cvq178   (Journal Full-text)

AIMS: 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, the majority of which lead to premature stops. In this study, we present our functional analyses of five (novel) missense TBX5 mutations identified in HOS patients, most of whom presented with severe cardiac malformations. METHODS AND RESULTS: Functional characterization of mutant proteins shows a dramatic loss of DNA-binding capacity, as well as diminished binding to known cardiac interaction partners NKX2-5 and GATA4. The disturbance of these interactions leads to a loss of function, as measured by the reduced activation of Nppa and FGF10 in rat heart derived cells, although with variable severity. Two out of the five mutations are peculiar: one, p.H220del, is associated with additional extra-cardiac defects, perhaps by interfering with other T-box dependant pathways, and another, p.I106V, leads to limb defects only, which is supported by its normal interaction with cardiac-specific interaction partners. CONCLUSION: 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.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
Holt-Oram syndrome  IAGP 7327217DNA:missense mutations and deletion:cds:multipleRGD 
Holt-Oram syndrome  ISOTBX5 (Homo sapiens)7327217; 7327217DNA:missense mutations and deletion:cds:multipleRGD 

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