title: 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.
authors.affiliation: Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK.
authors.forename: R
authors.initials: R
authors.lastname: Holt
authors.affiliation: Department of Genetics, Aziz Sancar Institute of Experimental Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: S A
authors.initials: SA
authors.lastname: Ugur Iseri
authors.affiliation: Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
authors.forename: A W
authors.initials: AW
authors.lastname: Wyatt
authors.affiliation: Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK.
authors.forename: D A
authors.initials: DA
authors.lastname: Bax
authors.affiliation: Developmental Biology & Cancer Programme, UCL Great Ormond Street Institute of Child Health, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Gold Diaz
authors.affiliation: Developmental Biology & Cancer Programme, UCL Great Ormond Street Institute of Child Health, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Santos
authors.affiliation: Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK.|Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
authors.forename: S
authors.initials: S
authors.lastname: Broadgate
authors.affiliation: Department of Genetics, Viapath, Guy's Hospital, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Dunn
authors.affiliation: West Midlands Regional Genetics Laboratory, Birmingham Women's Hospital, Birmingham, UK.
authors.forename: J
authors.initials: J
authors.lastname: Bruty
authors.affiliation: West Midlands Regional Genetics Laboratory, Birmingham Women's Hospital, Birmingham, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Wallis
authors.affiliation: West Midlands Regional Genetics Laboratory, Birmingham Women's Hospital, Birmingham, UK.
authors.forename: D
authors.initials: D
authors.lastname: McMullan
authors.affiliation: Department of Cytogenetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Ogilvie
authors.affiliation: Developmental Biology & Cancer Programme, UCL Great Ormond Street Institute of Child Health, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Gerrelli
authors.affiliation: Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK. nragge@brookes.ac.uk.|Clinical Genetics Unit, West Midlands Regional Genetics Service, Birmingham Women's Hospital, Birmingham, B15 2TG, UK. nragge@brookes.ac.uk.
authors.forename: Nicola
authors.initials: N
authors.lastname: Ragge
mesh_terms: D045744:Cell Line, Tumor; D015331:Cohort Studies; D016326:Extracellular Matrix Proteins / Q000235:genetics*; D005123:Eye / Q000196:embryology; D005124:Eye Abnormalities / Q000175:diagnosis / Q000235:genetics*; D005136:Eye Proteins / Q000235:genetics; D017353:Gene Deletion; D005786:Gene Expression Regulation; D005902:Glaucoma, Open-Angle / Q000175:diagnosis / Q000209:etiology / Q000235:genetics*; D006023:Glycoproteins / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D020641:Polymorphism, Single Nucleotide
chemical_list: D016326:Extracellular Matrix Proteins; D005136:Eye Proteins; D006023:Glycoproteins; C000600297:OLFM2 protein, human; C081451:olfactomedin