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Identification of OAF and PVRL1 as candidate genes for an ocular anomaly characterized by Peters anomaly type 2 and ectopia lentis

2018-03Journal article Restricted access
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dc.contributor.authorDavid, Dezso
dc.contributor.authorAnand, D.
dc.contributor.authorAraújo, C.
dc.contributor.authorGloss, B.
dc.contributor.authorFino, J.
dc.contributor.authorDinger, M.
dc.contributor.authorLindahl, P.
dc.contributor.authorPöyhönen, M.
dc.contributor.authorHannele, L.
dc.contributor.authorLavinha, J.
dc.date.accessioned2018-03-28T15:46:31Z
dc.date.available2018-03-28T15:46:31Z
dc.date.issued2018-03
dc.description.abstractKeratolenticular dysgenesis (KLD) and ectopia lentis are congenital eye defects. The aim of this study is the identification of molecular genetic alterations responsible for those ocular anomalies with neurologic impairment in an individual with a de novo balanced chromosome translocation t(11;18)(q23.3;q11.2)dn. Disruption of OAF, the human orthologue of the Drosophila oaf, by the 11q23.3 breakpoint results in reduced expression of this transcriptional regulator. Furthermore, four most likely nonfunctional chimeric transcripts comprising up to OAF exon 3, derived from the der(11) allele, have also been identified. This locus has been implicated by publicly available genome-wide association data in corneal disease and corneal topography. The expression of the poliovírus receptor-related 1(PVRL1) or nectin cell adhesion molecule 1 (NECTIN1), a paralogue of nectin cell adhesion molecule 3 (PVRL3) associated with congenital ocular defects, situated 500 kb upstream from 11q23.3 breakpoint, is increased. The 18q11.2 breakpoint is localized between cutaneous T-cell lymphoma-associated antigen 1(CTAGE1) and retinoblastoma binding protein 8 (RBBP8) genes. Genomic imbalance that could contribute to the observed phenotype was excluded. Analysis of gene expression datasets throughout normal murine ocular lens embryogenesis suggests that OAF expression is significantly enriched in the lens from early stages of development through adulthood, whereas PVRL1 is lens-enriched until E12.5 and then down-regulated. This contrasts with the observation that the proposita's lymphoblastoid cell lines exhibit low OAF and high PVRL1 expression as compared to control, which offers further support that the alterations described above are most likely responsible for the clinical phenotype. Finally, gene interaction topology data for PVRL1 also agree with our proposal that disruption of OAF by the translocation breakpoint and misregulation of PVRL1 due to a position effect contribute to the observed ocular and neurological phenotype.pt_PT
dc.description.sponsorshipCA was supported by a Ricardo Jorge Research Fellowship from Instituto Nacional de Saúde Dr Ricardo Jorge I.P. (Ref. BRJ/01/DG/2009). This research is supported by Fundação para a Ciência e a Tecnologia Research Grants PTDC/SAU-GMG/118140/2010 and HMSP-ICT/0016/2013.pt_PT
dc.description.versioninfo:eu-repo/semantics/publishedVersionpt_PT
dc.identifier.citationExp Eye Res. 2018 Mar;168:161-170. doi: 10.1016/j.exer.2017.12.012. Epub 2018 Jan 2.pt_PT
dc.identifier.doi10.1016/j.exer.2017pt_PT
dc.identifier.issn0014-4835
dc.identifier.urihttp://hdl.handle.net/10400.18/5484
dc.language.isoengpt_PT
dc.peerreviewedyespt_PT
dc.publisherElsevierpt_PT
dc.relationThe molecular pathogenesis of chromosome translocation-associated “cis-ruption” disorders
dc.relation.publisherversionhttps://www.sciencedirect.com/science/article/pii/S0014483517303007?via%3Dihubpt_PT
dc.subjectBalanced Chromosome Translocationpt_PT
dc.subjectEctopia Lentispt_PT
dc.subjectKeratolenticular Dysgenesispt_PT
dc.subjectNECTIN1pt_PT
dc.subjectOAFpt_PT
dc.subjectPVRL1pt_PT
dc.subjectTopologically Associated Domains (TADs)pt_PT
dc.subjectType 2 Peters Anomalypt_PT
dc.subjectDoenças Genéticaspt_PT
dc.titleIdentification of OAF and PVRL1 as candidate genes for an ocular anomaly characterized by Peters anomaly type 2 and ectopia lentispt_PT
dc.typejournal article
dspace.entity.typePublication
oaire.awardTitleThe molecular pathogenesis of chromosome translocation-associated “cis-ruption” disorders
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FSAU-GMG%2F118140%2F2010/PT
oaire.awardURIinfo:eu-repo/grantAgreement/FCT/3599-PPCDT/HMSP-ICT%2F0016%2F2013/PT
oaire.citation.endPage170pt_PT
oaire.citation.startPage161pt_PT
oaire.citation.titleExperimental Eye Researchpt_PT
oaire.citation.volume168pt_PT
oaire.fundingStream3599-PPCDT
oaire.fundingStream3599-PPCDT
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
rcaap.rightsembargoedAccesspt_PT
rcaap.typearticlept_PT
relation.isProjectOfPublicationbfe30e6a-27f3-4fef-abe7-61feea3fc38c
relation.isProjectOfPublication55f3392d-71be-4224-bedd-9feb4a06c428
relation.isProjectOfPublication.latestForDiscovery55f3392d-71be-4224-bedd-9feb4a06c428

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