Human Genetics

, Volume 136, Issue 1, pp 119–127 | Cite as

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

  • R. Holt
  • S. A. Ugur Iseri
  • A. W. Wyatt
  • D. A. Bax
  • D. Gold Diaz
  • C. Santos
  • S. Broadgate
  • R. Dunn
  • J. Bruty
  • Y. Wallis
  • D. McMullan
  • C. Ogilvie
  • D. Gerrelli
  • Y. Zhang
  • Nicola Ragge
Original Investigation

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.

Supplementary material

439_2016_1745_MOESM1_ESM.docx (17 kb)
Supplementary material 1 (DOCX 17 kb)
439_2016_1745_MOESM2_ESM.docx (14 kb)
Supplementary material 2 (DOCX 14 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • R. Holt
    • 1
  • S. A. Ugur Iseri
    • 2
  • A. W. Wyatt
    • 3
  • D. A. Bax
    • 1
  • D. Gold Diaz
    • 4
  • C. Santos
    • 4
  • S. Broadgate
    • 1
    • 5
  • R. Dunn
    • 6
  • J. Bruty
    • 7
  • Y. Wallis
    • 7
  • D. McMullan
    • 7
  • C. Ogilvie
    • 8
  • D. Gerrelli
    • 4
  • Y. Zhang
    • 1
  • Nicola Ragge
    • 1
    • 9
  1. 1.Faculty of Health and Life SciencesOxford Brookes UniversityOxfordUK
  2. 2.Department of Genetics, Aziz Sancar Institute of Experimental MedicineIstanbul UniversityIstanbulTurkey
  3. 3.Department of Urologic SciencesUniversity of British ColumbiaVancouverCanada
  4. 4.Developmental Biology & Cancer ProgrammeUCL Great Ormond Street Institute of Child HealthLondonUK
  5. 5.Nuffield Department of Clinical NeurosciencesUniversity of OxfordOxfordUK
  6. 6.Department of Genetics, ViapathGuy’s HospitalLondonUK
  7. 7.West Midlands Regional Genetics LaboratoryBirmingham Women’s HospitalBirminghamUK
  8. 8.Department of CytogeneticsLondonUK
  9. 9.Clinical Genetics Unit, West Midlands Regional Genetics ServiceBirmingham Women’s HospitalBirminghamUK

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