<i>EPHA2</i> Segregates with Microphthalmia and Congenital Cataracts in Two Unrelated Families
EPHA2 is a transmembrane tyrosine kinase receptor that, when disrupted, causes congenital and age-related cataracts. Cat-Map reports 22 pathogenic <i>EPHA2</i> variants associated with congenital cataracts, variable microcornea, and lenticonus, but no previous association with microphtha...
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MDPI AG
2021-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/4/2190 |
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| author | Philippa Harding Maria Toms Elena Schiff Nicholas Owen Suzannah Bell Ian Christopher Lloyd Mariya Moosajee |
| author_facet | Philippa Harding Maria Toms Elena Schiff Nicholas Owen Suzannah Bell Ian Christopher Lloyd Mariya Moosajee |
| author_sort | Philippa Harding |
| collection | DOAJ |
| description | EPHA2 is a transmembrane tyrosine kinase receptor that, when disrupted, causes congenital and age-related cataracts. Cat-Map reports 22 pathogenic <i>EPHA2</i> 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 <i>EPHA2</i> 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 <i>epha2a</i>/<i>epha2b</i> 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 <i>epha2b</i> 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 <i>EPHA2</i> with microphthalmia, suggesting further analysis of pathogenic variants in unsolved microphthalmia cohorts may increase molecular diagnostic rates. |
| first_indexed | 2024-03-09T00:37:28Z |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T00:37:28Z |
| publishDate | 2021-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-63dca7666c9d444a8e6b6dff49f473a92023-12-11T18:02:19ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-02-01224219010.3390/ijms22042190<i>EPHA2</i> Segregates with Microphthalmia and Congenital Cataracts in Two Unrelated FamiliesPhilippa Harding0Maria Toms1Elena Schiff2Nicholas Owen3Suzannah Bell4Ian Christopher Lloyd5Mariya Moosajee6Institute of Ophthalmology, University College London, London EC1V 9EL, UKInstitute of Ophthalmology, University College London, London EC1V 9EL, UKMoorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UKInstitute of Ophthalmology, University College London, London EC1V 9EL, UKMoorfields Eye Hospital NHS Foundation Trust, London EC1V 2PD, UKGreat Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UKInstitute of Ophthalmology, University College London, London EC1V 9EL, UKEPHA2 is a transmembrane tyrosine kinase receptor that, when disrupted, causes congenital and age-related cataracts. Cat-Map reports 22 pathogenic <i>EPHA2</i> 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 <i>EPHA2</i> 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 <i>epha2a</i>/<i>epha2b</i> 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 <i>epha2b</i> 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 <i>EPHA2</i> with microphthalmia, suggesting further analysis of pathogenic variants in unsolved microphthalmia cohorts may increase molecular diagnostic rates.https://www.mdpi.com/1422-0067/22/4/2190<i>EPHA2</i>microphthalmiacataractscongenitaleyedevelopment |
| spellingShingle | Philippa Harding Maria Toms Elena Schiff Nicholas Owen Suzannah Bell Ian Christopher Lloyd Mariya Moosajee <i>EPHA2</i> Segregates with Microphthalmia and Congenital Cataracts in Two Unrelated Families International Journal of Molecular Sciences <i>EPHA2</i> microphthalmia cataracts congenital eye development |
| title | <i>EPHA2</i> Segregates with Microphthalmia and Congenital Cataracts in Two Unrelated Families |
| title_full | <i>EPHA2</i> Segregates with Microphthalmia and Congenital Cataracts in Two Unrelated Families |
| title_fullStr | <i>EPHA2</i> Segregates with Microphthalmia and Congenital Cataracts in Two Unrelated Families |
| title_full_unstemmed | <i>EPHA2</i> Segregates with Microphthalmia and Congenital Cataracts in Two Unrelated Families |
| title_short | <i>EPHA2</i> Segregates with Microphthalmia and Congenital Cataracts in Two Unrelated Families |
| title_sort | i epha2 i segregates with microphthalmia and congenital cataracts in two unrelated families |
| topic | <i>EPHA2</i> microphthalmia cataracts congenital eye development |
| url | https://www.mdpi.com/1422-0067/22/4/2190 |
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