Publication
Molecular characterization of a de novo t(11;18) translocation associated with a syndromic form of PeterĀ“s anomaly
| dc.contributor.advisor | David, Dezso | |
| dc.contributor.author | Carlos, AraĆŗjo | |
| dc.date.accessioned | 2015-02-17T11:39:20Z | |
| dc.date.available | 2015-02-17T11:39:20Z | |
| dc.date.issued | 2014 | |
| dc.description | DissertaĆ§Ć£o de mestrado em GenĆ©tica Molecular e Biomedicina apresentado Ć Faculdade de CiĆŖncias e Tecnologia da Universidade Nova de Lisboa, 2013 | por |
| dc.description | Dezso David, investigador do Departamento de GenƩtica Humana do INSA. | |
| dc.description.abstract | [ENG] Peterās anomaly (PA) is a congenital defect of the anterior chamber of the eye. The aim of this study is molecular characterization of a de novo balanced chromosome translocation [t(11;18)(q23.3;q11.2)] identified in a proband with syndromic form of PeterĀ“s anomaly (ectopia lentis and mild CNS abnormalities). Chromosome breakpoints were identified at nucleotide resolution. The 11q23.3 breakpoint is at position 120,097,868 (genome assembly GRCh37/hg19) within intron 3 of out at first (OAF) homolog (Drosophila) gene (OAF) while, 18q11.2 breakpoint in the intergenic region between CTAGE1 and RBBP8 genes, at position 20,220,714. Although OAF is disrupted, its expression level is unchanged in probandĀ“s lymphoblastoid cell line (LCL). Cell adhesion protein Nectin 1 or PVRL1, located 500 kb upstream from the 11q23.3 breakpoint, reveal 3.5 fold increase in probandās LCL. Expression levels of additional genes from breakpoint regions are not significantly different. Furthermore, RT-qPCR confirmed that expression level of CYP1B1 from chromosome 2p22.2, and EDIL3 from chromosome 5q14 are significantly changed in probandĀ“s LCL, 16.5 fold decreased and 126 fold increased, respectively. Alterations in CYP1B1 have been reported as PA causing mutations. Therefore, mutation screening of CYP1B1 was performed and no pathogenic mutation was identified in the proband, although, a disease-causing 13 bp, homozygous deletion was identified in a Portuguese patient with PA. In conclusion, we hypothesize that PVRL1 is a candidate gene for at least some of the observed clinical features, which is elicited in mouse models by association of its paralog Pvrl3 to lens and other ocular defects involving the ciliary body. Furthermore, the involvement of the POU family domain containing transcription factor (POU2F3) from 11q23.3, CYP1B1 and/or EDIL3, localized outside of the breakpoint regions, in the molecular pathogenesis of syndromic PA remains to be determined. | por |
| dc.description.abstract | [PT] A anomalia de Peters Ć© um defeito congĆ©nito da camara anterior do olho. Este estudo tem como objetivo caracterizar molecularmente uma translocaĆ§Ć£o cromossĆ³mica equilibrada de novo [t(11;18)(q23.3;q11.2)] identificada num proband com forma sindrĆ³mica de Peters, (ectopia lentis e ligeiras anomalias do SNS). Os pontos de quebra foram identificados ao nĆvel da resoluĆ§Ć£o nucleotĆdica. O ponto de quebra 11q23.3 estĆ” na posiĆ§Ć£o g.120,097,868_120,097,869 (GRCh37/hg), no intrĆ£o 3 do out of first protein homolog (OAF) enquanto o ponto de quebra 18q11.2, regiĆ£o intergĆ©nica entre o CTAGE1 e o RBBP8 encontra-se na posiĆ§Ć£o g.20,220,714_20,220,715. Apesar do OAF estar interrompido, o nĆvel de expressĆ£o estĆ” inalterado em linha linfoblastĆ³ide (LCL) do proband. O PVRL1, localizado a 500 kb a montante do ponto de quebra 11q23.3, revelou um aumento de 3.5 vezes no proband. Os nĆveis de expressĆ£o dos genes adicionais aos pontos de quebra nĆ£o foram significativamente diferentes. Confirmou-se por RT-qPCR que os nĆveis de expressĆ£o do CYP1B1 (2p22.2), e EDIL3 (5q14) estĆ£o significativamente alterados em LCL do proband, com reduĆ§Ć£o de 16,5 vezes e aumento de 126 vezes, respetivamente. AlteraƧƵes no CYP1B1 tĆŖm sido descritas como mutaƧƵes causadoras de PA. Desta forma, a pesquisa de mutaƧƵes no CYP1B1 nĆ£o encontraram mutaƧƵes patogĆ©nicas no proband, no entanto foi identificado uma deleĆ§Ć£o em homozigotia com13 nucleĆ³tidos causador de doenƧa num paciente PortuguĆŖs com PA. Em conclusĆ£o, sugerimos que o PVRL1 Ć© o principal gene candidato para parte da clĆnica descrita, o qual Ć© sustentado por modelos de murganho pela associaĆ§Ć£o com o seu parĆ”logo PVRL3 para o cristalino e para outros defeitos oculares no corpo ciliar. Por outro lado, o envolvimento com o factor de transcriĆ§Ć£o, contendo o domĆnio da famĆlia POU, da regiĆ£o do ponto de quebra 11q23.3 e o CYP1B1 ou EDIL3, subjacente Ć patogĆ©nese molecular do fenĆ³tipo observado contĆnua por ser determinado. | por |
| dc.description.sponsorship | FCT | por |
| dc.identifier.uri | http://hdl.handle.net/10400.18/2860 | |
| dc.language.iso | eng | por |
| dc.relation | PTDC/SAU-GMG/118140/2010 - PatogĆ©nese molecular de ādoenƧas de cis-rupĆ§Ć£oā associadas a translocaƧƵes cromossĆ³micas | por |
| dc.relation.publisherversion | http://run.unl.pt/handle/10362/11893 | por |
| dc.subject | TranslocaƧƵes CromossĆ³micas Equilibradas | por |
| dc.subject | Anomalia de Peters | por |
| dc.subject | Ectopia Lentis | por |
| dc.subject | PVRL1 | por |
| dc.subject | CYP1B1 | por |
| dc.subject | EDIL3 | por |
| dc.subject | DoenƧas GenƩticas | por |
| dc.subject | Chromosome Balanced Translocation | por |
| dc.subject | PeterĀ“s Anomaly | por |
| dc.subject | Ectopia Lentis | por |
| dc.title | Molecular characterization of a de novo t(11;18) translocation associated with a syndromic form of PeterĀ“s anomaly | por |
| dc.type | master thesis | |
| dspace.entity.type | Publication | |
| rcaap.rights | embargoedAccess | por |
| rcaap.type | masterThesis | por |