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

Abstract

Keratolenticular 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 poliovirus 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.

• Authors: Dezső David, Deepti Anand, Carlos Araújo, Brian Gloss, Joana Fino, Marcel Dinger, Päivi Lindahl, Minna Pöyhönen, Laivuori Hannele, João Lavinha
• Journal: Experimental eye research (Exp Eye Res) Vol. 168 Pg. 161-170 (03 2018) ISSN: 1096-0007 [Electronic] England
• PMID: 29305299 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 Elsevier Ltd. All rights reserved.

Chemical References

• Membrane Glycoproteins
• Nectins
• CYP1B1 protein, human
• Cytochrome P-450 CYP1B1

Topics

• Animals
• Anterior Eye Segment (abnormalities)
• Axial Length, Eye (pathology)
• Cornea (pathology)
• Corneal Opacity (genetics)
• Cytochrome P-450 CYP1B1 (genetics)
• Ectopia Lentis (genetics)
• Eye Abnormalities (genetics)
• Gene Expression Profiling
• Humans
• Lens, Crystalline (pathology)
• Membrane Glycoproteins (genetics)
• Mice
• Nectins (genetics)
• Translocation, Genetic