Repository logo
 
Publication

Functional analysis of two novel TBX5 variants present in individuals with Holt-Oram syndrome with different clinical manifestations

2021Journal article Restricted access
Simple item page
dc.contributor.authorVarela, Debora
dc.contributor.authorVarela, Tatiana
dc.contributor.authorConceição, Natércia
dc.contributor.authorFerreira, Angela
dc.contributor.authorMarques, Nuno
dc.contributor.authorSilva, Ana Paula
dc.contributor.authorAzevedo, Pedro
dc.contributor.authorPereira, Salome
dc.contributor.authorCamacho, Ana
dc.contributor.authorde Jesus, Ilidio
dc.contributor.authorCancela, M. Leonor
dc.date.accessioned2021-09-08T10:57:58Z
dc.date.available2021-09-08T10:57:58Z
dc.date.issued2021
dc.description.abstractHolt-Oram syndrome (HOS) is a rare disorder characterized by cardiac and upper-limb defects. Pathogenic variants in TBX5-a gene encoding a transcription factor important for heart and skeletal development-are the only known cause of HOS. Here, we present the identification and functional analysis of two novel TBX5 pathogenic variants found in two individuals with HOS presenting distinct phenotypes. The individual with the c.905delA variant has a severe cardiac phenotype but mild skeletal defects, unlike the individual with the c.246_249delGATG variant who has no cardiac problems but severe upper limbs malformations, including phocomelia. Both frameshift variants, c.246_249delGATG and c.905delA, generate mRNAs harbouring premature stop codons which, if not degraded by nonsense mediated decay, will lead to the production of shorter TBX5 proteins, p.Gln302Argfs*92 and p.Met83Phefs*6, respectively. Immunocytochemistry results suggest that both mutated proteins are produced and furthermore, like the wild-type protein, p.Gln302Argfs*92 mutant appears to be mainly localized in the nucleus, in contrast with p.Met83Phefs*6 mutant that displays a higher level of cytoplasmic localization. In addition, luciferase activity analysis revealed that none of the TBX5 mutants are capable of transactivating the NPPA promoter. In conclusion, our results provide evidence that both pathogenic variants cause a severe TBX5 loss-of-function, dramatically reducing its biological activity. The absence of cardiac problems in the individual with the p.Met83Phefs*6 variant supports the existence of other mechanisms/genes underlying the pathogenesis of HOS and/or the existence of an age-related delay in the development of a more serious cardiac phenotype. Further studies are required to understand the differential effects observed in the phenotypes of both individuals.
dc.description.sponsorshipFoundation for Science and Technology (FCT)Portuguese Foundation for Science and TechnologyEuropean Commission [UIDB/04326/2020]; FCTPortuguese Foundation for Science and TechnologyEuropean Commission [SFRH/BD/141918/2018, SFRH/BD/144230/2019]
dc.description.versioninfo:eu-repo/semantics/publishedVersion
dc.identifier.doi10.1007/s00438-021-01781-2
dc.identifier.issn1617-4615
dc.identifier.urihttp://hdl.handle.net/10400.1/16991
dc.language.isoeng
dc.peerreviewedyes
dc.publisherSPRINGER HEIDELBERG
dc.relationAlgarve Centre for Marine Sciences
dc.relationEpigenetic regulation of ZNF687 in bone cells: elucidation of its role in the progression of Paget’s disease towards giant cell tumor of bone
dc.relationIdentification of novel CDKL5 molecular targets/pathways associated with skeletal defects present in CDKL5 associated disorders
dc.subjectHolt–Oram syndrome
dc.subjectHeart–upper limb defects
dc.subjectTBX5
dc.subjectFrameshift variant
dc.subjectLoss-of function
dc.subject.otherBiochemistry & Molecular Biology; Genetics & Heredity
dc.titleFunctional analysis of two novel TBX5 variants present in individuals with Holt-Oram syndrome with different clinical manifestations
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleAlgarve Centre for Marine Sciences
oaire.awardTitleEpigenetic regulation of ZNF687 in bone cells: elucidation of its role in the progression of Paget’s disease towards giant cell tumor of bone
oaire.awardTitleIdentification of novel CDKL5 molecular targets/pathways associated with skeletal defects present in CDKL5 associated disorders
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/6817 - DCRRNI ID/UIDB%2F04326%2F2020/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT//SFRH%2FBD%2F141918%2F2018/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/OE/SFRH%2FBD%2F144230%2F2019/PT
oaire.citation.titleMolecular Genetics and Genomics
oaire.fundingStream6817 - DCRRNI ID
oaire.fundingStreamOE
person.familyNameConceição
person.familyNameMarques
person.familyNameCancela
person.givenNameNatércia
person.givenNameNuno
person.givenNameM. Leonor
person.identifier.ciencia-id7C11-760D-F425
person.identifier.orcid0000-0002-5057-0912
person.identifier.orcid0000-0003-0275-2807
person.identifier.orcid0000-0003-3114-6662
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.identifierhttp://doi.org/10.13039/501100001871
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
project.funder.nameFundação para a Ciência e a Tecnologia
rcaap.rightsrestrictedAccess
rcaap.typearticle
relation.isAuthorOfPublication62064ac0-1f34-407d-96b7-b7074325a84e
relation.isAuthorOfPublication1b66ba1f-d295-4211-b41e-c0f0b622eea0
relation.isAuthorOfPublicationb9bbfe32-3dfe-4131-ad14-a4394008447f
relation.isAuthorOfPublication.latestForDiscoveryb9bbfe32-3dfe-4131-ad14-a4394008447f
relation.isProjectOfPublicationfafa76a6-2cd2-4a6d-a3c9-772f34d3b91f
relation.isProjectOfPublication7baff70a-818d-4310-8373-6b29231dc0c3
relation.isProjectOfPublication2ba66e2a-4b86-4dd8-a39c-edd428810146
relation.isProjectOfPublication.latestForDiscoveryfafa76a6-2cd2-4a6d-a3c9-772f34d3b91f

Files

Original bundle
Now showing 1 - 1 of 1
No Thumbnail Available
Name:
Varela2021_Article_FunctionalAnalysisOfTwoNovelTB.pdf
Size:
1.44 MB
Format:
Adobe Portable Document Format
Download

Collections

ULS_10.1-MED-Artigos
ABC2-Artigos (em revistas ou actas indexadas)
CCM2-Artigos (em revistas ou actas indexadas)
FCB2-Artigos (em revistas ou actas indexadas)