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Open AccessArticle

EPHA2 Segregates with Microphthalmia and Congenital Cataracts in Two Unrelated Families

1
Institute of Ophthalmology, University College London, London EC1V 9EL, UK
2
The Francis Crick Institute, London NW1 1AT, UK
3
Moorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UK
4
Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK
5
Manchester Academic Health Sciences Centre, University of Manchester, Manchester, M13 9PT, UK
6
Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UK
*
Author to whom correspondence should be addressed.
Academic Editor: Tomasz Żarnowski
Int. J. Mol. Sci. 2021, 22(4), 2190; https://doi.org/10.3390/ijms22042190
Received: 6 January 2021 / Revised: 12 February 2021 / Accepted: 18 February 2021 / Published: 22 February 2021
(This article belongs to the Special Issue Genetics of Eye Disease)
EPHA2 is a transmembrane tyrosine kinase receptor that, when disrupted, causes congenital and age-related cataracts. Cat-Map reports 22 pathogenic EPHA2 variants associated with congenital cataracts, variable microcornea, and lenticonus, but no previous association with microphthalmia (small, underdeveloped eye, ≥2 standard deviations below normal axial length). Microphthalmia arises from ocular maldevelopment with >90 monogenic causes, and can include a complex ocular phenotype. In this paper, we report two pathogenic EPHA2 variants in unrelated families presenting with bilateral microphthalmia and congenital cataracts. Whole genome sequencing through the 100,000 Genomes Project and cataract-related targeted gene panel testing identified autosomal dominant heterozygous mutations segregating with the disease: (i) missense c.1751C>T, p.(Pro584Leu) and (ii) splice site c.2826-9G>A. To functionally validate pathogenicity, morpholino knockdown of epha2a/epha2b in zebrafish resulted in significantly reduced eye size ± cataract formation. Misexpression of N-cadherin and retained fibre cell nuclei were observed in the developing lens of the epha2b knockdown morphant fish by 3 days post-fertilisation, which indicated a putative mechanism for microphthalmia pathogenesis through disruption of cadherin-mediated adherens junctions, preventing lens maturation and the critical signals stimulating eye growth. This study demonstrates a novel association of EPHA2 with microphthalmia, suggesting further analysis of pathogenic variants in unsolved microphthalmia cohorts may increase molecular diagnostic rates. View Full-Text
Keywords: EPHA2; microphthalmia; cataracts; congenital; eye; development; whole genome sequencing (WGS); next-generation sequencing (NGS); genetics; zebrafish EPHA2; microphthalmia; cataracts; congenital; eye; development; whole genome sequencing (WGS); next-generation sequencing (NGS); genetics; zebrafish
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MDPI and ACS Style

Harding, P.; Toms, M.; Schiff, E.; Owen, N.; Bell, S.; Lloyd, I.C.; Moosajee, M. EPHA2 Segregates with Microphthalmia and Congenital Cataracts in Two Unrelated Families. Int. J. Mol. Sci. 2021, 22, 2190. https://doi.org/10.3390/ijms22042190

AMA Style

Harding P, Toms M, Schiff E, Owen N, Bell S, Lloyd IC, Moosajee M. EPHA2 Segregates with Microphthalmia and Congenital Cataracts in Two Unrelated Families. International Journal of Molecular Sciences. 2021; 22(4):2190. https://doi.org/10.3390/ijms22042190

Chicago/Turabian Style

Harding, Philippa; Toms, Maria; Schiff, Elena; Owen, Nicholas; Bell, Suzannah; Lloyd, Ian C.; Moosajee, Mariya. 2021. "EPHA2 Segregates with Microphthalmia and Congenital Cataracts in Two Unrelated Families" Int. J. Mol. Sci. 22, no. 4: 2190. https://doi.org/10.3390/ijms22042190

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