Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
The Francis Crick Institute, London NW1 1AT, UK.
Int J Mol Sci. 2021 Feb 22;22(4):2190. doi: 10.3390/ijms22042190.
EPHA2 is a transmembrane tyrosine kinase receptor that, when disrupted, causes congenital and age-related cataracts. Cat-Map reports 22 pathogenic 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 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 / 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 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 with microphthalmia, suggesting further analysis of pathogenic variants in unsolved microphthalmia cohorts may increase molecular diagnostic rates.
Epha2 是一种跨膜酪氨酸激酶受体，如果发生突变，会导致先天性和年龄相关性白内障。Cat-Map 报告了 22 种与先天性白内障、可变小角膜和晶状体锥形有关的致病性变异，但与小眼球（眼睛小、发育不良，眼轴长度低于正常 2 个标准差以上）无关。小眼球是由眼发育异常引起的，有超过 90 种单基因病因，可能包括复杂的眼部表型。在本文中，我们报告了两个无关联家族的致病性变异，这些家族表现为双侧小眼球和先天性白内障。通过 10 万基因组计划和白内障相关靶向基因panel 测试进行全基因组测序，发现了与疾病共分离的常染色体显性杂合突变：（i）错义 c.1751C>T，p.(Pro584Leu) 和（ii）剪接位点 c.2826-9G>A。为了功能验证致病性，在斑马鱼中进行 / 的 morpholino 敲低导致眼睛大小显著减小±白内障形成。在 knockdown 形态发生突变鱼的发育晶状体中观察到 N-钙粘蛋白的异位表达和纤维细胞核的保留，这表明通过破坏钙粘蛋白介导的黏附连接来破坏小眼发生的潜在机制，阻止晶状体成熟和刺激眼生长的关键信号。这项研究表明 与小眼球之间存在新的关联，提示对未解决的小眼球队列中的致病性变异进一步分析可能会提高分子诊断率。
