Molecular characterization of a de novo t (11;18) translocation associated with Peter´s anomaly

Dissertação para obtenção do grau de Mestre em Genética Molecular e Biomedicina

Peter’s 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 Peter´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 of first protein homolog 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 proband´s lymphoblastoid cell line (LCL). Cell adhesion protein Nectin 1 or PVRL1, located 500 kb upstream from 11q23.3 breakpoint, reveal 3.5 fold increase in proband’s LCL. Expression levels of additional genes from breakpoint regions are not significantly different. Furthermore, RT-qPCR confirmed that expression level CYP1B1 from chromosome 2p22.2, and EDIL3 from chromosome 5q14 are significantly changed in proband´s LCL, 16.5 fold decrease and 126 fold increase, 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 and CYP1B1 or EDIL3, localized outside of the breakpoint regions, in the underlying molecular pathogenesis of syndromic PA remains to be determined.