Identification and functional characterisation of genetic variants in OLFM2 in children with developmental eye disorders

Abstract

Anophthalmia, microphthalmia, and coloboma are a genetically heterogeneous spectrum of developmental eye disorders and affect around 30 per 100,000 live births. OLFM2 encodes a secreted glycoprotein belonging to the noelin family of olfactomedin domain-containing proteins that modulate the timing of neuronal differentiation during development. OLFM2 SNPs have been associated with open angle glaucoma in a case-control study, and knockdown of Olfm2 in zebrafish results in reduced eye size. From a cohort of 258 individuals with developmental eye anomalies, we identified two with heterozygous variants in OLFM2: an individual with bilateral microphthalmia carrying a de novo 19p13.2 microdeletion involving OLFM2 and a second individual with unilateral microphthalmia and contralateral coloboma who had a novel single base change in the 5' untranslated region. Dual luciferase assays demonstrated that the latter variant causes a significant decrease in expression of OLFM2. Furthermore, RNA in situ hybridisation experiments using human developmental tissue revealed expression in relevant structures, including the lens vesicle and optic cup. Our study indicates that OLFM2 is likely to be important in mammalian eye development and disease and should be considered as a gene for human ocular anomalies.

PITX2 deficiency and associated human disease: insights from the zebrafish model

“…Further analysis of these genes using publicly available resources ( http://biogps.org ; https://www.ncbi.nlm.nih.gov/pubmed/ ) revealed their expression in mouse ocular structures, with an enrichment in iris, cornea, eyecup and ciliary bodies similar to Pitx2 ( Supplementary Material , Fig. S3), as well as possible roles in anterior segment phenotypes ( 46–52 ). Genes associated with the strongest expression/possible function in anterior segment structures, including all identified WNT transcripts and four collagens, col1a1a, col1a2, col5a2b and col5a3b , were selected for further investigation ( Fig.…”

“…Interestingly, one case of OI with features of both EDS and ARS has been attributed to a frameshift c.3313delA mutation in COL1A1 ( 52 ), further linking these two phenotypes. Finally, a partial deletion involving another collagen gene, COL5A3 , and OLFM2 was recently identified in a patient with bilateral microphthalmia, sclerocornea, ptosis, small teeth, bifid uvula and hearing defects ( 46 ). Our work suggests that PITX2/pitx2 may regulate expression of genes encoding collagens I and V. With this, early deficiency in expression of corneal collagens is likely to contribute to the abnormal phenotypes associated with PITX2/pitx2 disruption.…”

Panel‐based whole exome sequencing identifies novel mutations in microphthalmia and anophthalmia patients showing complex Mendelian inheritance patterns

“…In this regard, WES strategy allows for rapid updating of the panel, as the inclusion of new genes is simply based on the modification of the filtering process during the bioinformatic analysis. In fact, two recently discovered MA genes, PTCH1 and OLFM2 (Chassaing et al 2016;Holt et al 2017), have already been added to a new version of the panel list.…”

Arginine to Glutamine Variant in Olfactomedin Like 3 (OLFML3) Is a Candidate for Severe Goniodysgenesis and Glaucoma in the Border Collie Dog Breed

“…In vitro experiments indicated that myocilin interacts with olfactomedin 3 (also known as optimedin, encoded by the OLFM3 gene) which was co-expressed with myocilin in the eye (Torrado et al 2002). A variant in another OLF family member, OLFM2 , has been associated with human open angle glaucoma in a small number of Japanese patients (rs779032127; p.Arg144Gln) (Funayama et al 2006) and identified as contributing to eye development (Holt et al 2017). These other OLF family members may compensate for olfactomedin like 3 abnormalities, or may interact with olfactomedin like 3 in the development of the eye.…”