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.
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Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, Bork P, Kondrashov AS, Sunyaev SR (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249
Ahn JW, Mann K, Walsh S, Shehab M, Hoang S, Docherty Z, Mohammed S, Mackie Ogilvie C (2010) Validation and implementation of array comparative genomic hybridisation as a first line test in place of postnatal karyotyping for genome imbalance. Mol Cytogenet 3:9
Bakrania P, Robinson DO, Bunyan DJ, Salt A, Martin A, Crolla JA, Wyatt A, Fielder A, Ainsworth J, Moore A, Read S, Uddin J, Laws D, Pascuel-Salcedo D, Ayuso C, Allen L, Collin JR, Ragge NK (2007) SOX2 anophthalmia syndrome: 12 new cases demonstrating broader phenotype and high frequency of large gene deletions. Br J Ophthalmol 91(11):1471–1476
Bakrania P, Efthymiou M, Klein JC, Salt A, Bunyan DJ, Wyatt A, Ponting CP, Martin A, Williams S, Lindley V, Gilmore J, Restori M et al (2008) Mutations in BMP4 cause eye, brain, and digit developmental anomalies: overlap between the BMP4 and hedgehog signaling pathways. Am J Hum Genet 82:304–319
Bakrania P, Ugur Iseri SA, Wyatt AW, Bunyan DJ, Lam WW, Salt A, Ramsay J, Robinson DO, Ragge NK (2010) Sonic hedgehog mutations are an uncommon cause of developmental eye anomalies. Am J Med Genet A. 152A(5):1310–1313
Campbell H, Holmes E, MacDonald S, Morrison D, Jones I (2002) A capture-recapture model to estimate prevalence of children born in Scotland with developmental eye defects. J Cancer Epidemiol Prev 7:21–28
Fang M, Adams JS, Mcmahan BL, Brown RJ, Oxford JT (2010) The expression patterns of minor fibrillar collagens during development in zebrafish. Gene Expr Patterns 10(7–8):315–322
Fantes J, Ragge NK, Lynch SA, McGill NI, Collin JR, Howard-Peebles PN, Hayward C, Vivian AJ, Williamson K, van Heyningen V, FitzPatrick DR (2003) Mutations in SOX2 cause anophthalmia. Nat Genet 33:461–463
Funayama T, Mashima Y, Ohtake Y, Ishikawa K, Fuse N, Yasuda N, Fukuchi T, Murakami A, Hotta Y, Shimada N, Glaucoma Gene Research Group (2006) SNPs and interaction analyses of noelin 2, myocilin, and optineurin genes in Japanese patients with open-angle glaucoma. Invest Ophthalmol Vis Sci 47(12):5368–5375
Gautier M, Flori L, Riebler A, Jaffrézic F, Laloé D, Gut I, Moazami-Goudarzi K, Foulley JL (2009) A whole genome Bayesian scan for adaptive genetic divergence in West African cattle. BMC Genom 21(10):550
Hever AM, Williamson KA, van Heyningen V (2006) Developmental malformations of the eye: the role of PAX6, SOX2 and OTX2. Clin Genet 69(6):459–470
Hoffman GG, Dodson GE, Cole WG, Greenspan DS (2008) Absence of apparent disease causing mutations in COL5A3 in 13 patients with hypermobility Ehlers-Danlos syndrome. Am J Med Genet A 146A(24):3240–3241
Imamura Y, Scott IC, Greenspan DS (2000) The Pro-α3(V) Collagen Chain: complete primary structure, expression domains in adult and developing tissues, and comparison to the structures and expression domains of the other types V and XI procollagen chains. J Bio Chem 275(12):8749–8759
Iseri SU, Osborne RJ, Farrall M, Wyatt AW, Mirza G, Nürnberg G, Kluck C, Herbert H, Martin A, Hussain MS, Collin JR, Lathrop M, Nürnberg P, Ragoussis J, Ragge NK (2009) Seeing clearly: the dominant and recessive nature of FOXE3 in eye developmental anomalies. Hum Mutat 30(10):1378–1386
Lee JA, Anholt RRH, Cole GJ (2008) Olfactomedin-2 mediates development of the anterior central nervous system and head structures in zebrafish. Mech Dev 125:167–181
Lovicu FJ, McAvoy JW, de Iongh RU (2011) Understanding the role of growth factors in embryonic development: insights from the lens. Philos Trans R Soc Lond B Biol Sci 366(1568):1204–1218
Mark PR, Torres-Martinez W, Lachman RS, Weaver DD (2011) Association of a p.Pro786Leu variant in COL2A1 with mild spondyloepiphyseal dysplasia congenita in a three-generation family. Am J Med Genet A 155A(1):174–179
Mukhopadhyay A, Talukdar S, Bhattacharjee A, Ray K (2004) Bioinformatic approaches for identification and characterization of olfactomedin related genes with a potential role in pathogenesis of ocular disorders. Mol Vis 10:304–314
Ng PC, Henikoff S (2003) SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 31:3812–3814
Piri N, Gao YQ, Danciger M, Mendoza E, Fishman GA, Farber DB (2005) A substitution of G to C in the cone cGMP-phosphodiesterase gamma subunit gene found in a distinctive form of cone dystrophy. Ophthalmology 112(1):159–166
Ragge NK, Brown AG, Poloschek CM, Lorenz B, Henderson RA, Clarke MP, Russell-Eggitt I, Fielder A, Gerrelli D, Martinez-Barbera JP, Ruddle P, Hurst J et al (2005) Heterozygous mutations of OTX2 cause severe ocular malformations. Am J Hum Genet 76:1008–1022
Shaikh TH, Gai X, Perin JC, Glessner JT, Xie H, Murphy K, O’Hara R, Casalunovo T, Conlin LK, D’Arcy M, Frackelton EC, Geiger EA et al (2009) High-resolution mapping and analysis of copy number variations in the human genome: a data resource for clinical and research applications. Genome Res 19(9):1682–1690
Shi N, Guo X, Chen SY (2014) Olfactomedin 2, a novel regulator for transforming growth factor-β–induced smooth muscle differentiation of human embryonic stem cell–derived mesenchymal cells. Mol Biol Cell 25(25):4106–4114
Sultana A, Nakaya N, Senatorov VV, Tomarev SI (2011) Olfactomedin 2: expression in the eye and interaction with other olfactomedin domain-containing proteins. Invest Ophthalmol Vis Sci 52(5):2584–2592
Tomarev SI, Nakaya N (2009) Olfactomedin domain-containing proteins: possible mechanisms of action and functions in normal development and pathology. Mol Neurobiol 40(2):122–138
Tsunoda T, Takagi T (1999) Estimating transcription factor bindability on DNA. Bioinformatics 15(7/8):622–630
Wong KK, deLeeuw RJ, Dosanjh NS, Kimm LR, Cheng Z, Horsman DE, MacAulay C, Ng RT, Brown CJ, Eichler EE, Lam WL (2007) A comprehensive analysis of common copy-number variations in the human genome. Am J Hum Genet 80(1):91–104
Wyatt AW, Osborne RJ, Stewart H, Ragge NK (2010) Bone morphogenetic protein 7 (BMP7) mutations are associated with variable ocular, brain, ear, palate, and skeletal anomalies. Hum Mutat 31(7):781–787
Zhou J, Kherani F, Bardakjian TM, Katowitz J, Hughes N, Schimmenti LA, Schneider A, Young TL (2008) Identification of novel mutations and sequence variants in the SOX2 and CHX10 genes in patients with anophthalmia/microphthalmia. Molecular Vision 14:583–592
We would like to thank the patients and their families for their participation in our study. We are grateful to the following: Youming Zhang, Imperial College London, for contributing vectors; Stephanie Halford, University of Oxford, for providing cDNA and cell lines; Andrew Gallagher (paediatrician), Worcestershire Royal Hospital for initial patient referral; Electrophysiology Department, Great Ormond St Hospital, for electrophysiology studies; M Parulekar (Birmingham Children’s Hospital), K Nischal, Y Abou-Rayyah for clinical care; Thalia Antoniadi (West Midlands Regional Genetics Laboratory) for assistance with the gene panel sequencing. This work was supported by grants from Baillie Gifford, Visually Impaired Children Taking Action (VICTA) (http://www.victa.org.uk/) and Microphthalmia, Anophthalmia and Coloboma Support (MACS) (http://www.macs.org.uk). The human embryonic and fetal material was provided by the Joint Medical Research Council (MRC)/Wellcome Trust (Grant #099175/Z/12/Z) Human Developmental Biology Resource (http://www.hdbr.org).
Conflict of interest
On behalf of all authors, the corresponding author states that there is no conflict of interest.
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Holt, R., Ugur Iseri, S.A., Wyatt, A.W. et al. Identification and functional characterisation of genetic variants in OLFM2 in children with developmental eye disorders. Hum Genet 136, 119–127 (2017). https://doi.org/10.1007/s00439-016-1745-8
- Open Angle Glaucoma
- Lens Vesicle
- OLFM2 Expression