Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, UK.
Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Sci Rep. 2017 Aug 11;7(1):7975. doi: 10.1038/s41598-017-08397-w.
YAP1, which encodes the Yes-associated protein 1, is part of the Hippo pathway involved in development, growth, repair and homeostasis. Nonsense YAP1 mutations have been shown to co-segregate with autosomal dominantly inherited coloboma. Therefore, we screened YAP1 for variants in a cohort of 258 undiagnosed UK patients with developmental eye disorders, including anophthalmia, microphthalmia and coloboma. We identified a novel 1 bp deletion in YAP1 in a boy with bilateral microphthalmia and bilateral chorioretinal coloboma. This variant is located in the coding region of all nine YAP1 spliceforms, and results in a frameshift and subsequent premature termination codon in each. The variant is predicted to result in the loss of part of the transactivation domain of YAP1, and sequencing of cDNA from the patient shows it does not result in nonsense mediated decay. To investigate the role of YAP1 in human eye development, we performed in situ hybridisation utilising human embryonic tissue, and observed expression in the developing eye, neural tube, brain and kidney. These findings help confirm the role of YAP1 and the Hippo developmental pathway in human eye development and its associated anomalies and demonstrate its expression during development in affected organ systems.
YAP1 编码 Yes 相关蛋白 1，是参与发育、生长、修复和内稳态的 Hippo 通路的一部分。无义 YAP1 突变已被证明与常染色体显性遗传的眼眶脑裂畸形共分离。因此，我们在一个包括无眼症、小眼症和眼眶脑裂畸形的 258 名英国未确诊的发育性眼部疾病患者队列中对 YAP1 进行了变体筛查。我们在一名双侧小眼症和双侧脉络膜视网膜脑裂畸形的男孩中发现了 YAP1 中的一个新的 1bp 缺失。该变体位于所有九个 YAP1 剪接体的编码区域，导致每个剪接体的移码和随后的提前终止密码子。该变体预计会导致 YAP1 的转录激活域部分丢失，并且对患者 cDNA 的测序表明它不会导致无义介导的降解。为了研究 YAP1 在人类眼睛发育中的作用，我们利用人类胚胎组织进行了原位杂交，并观察到其在发育中的眼睛、神经管、大脑和肾脏中的表达。这些发现有助于确认 YAP1 和 Hippo 发育途径在人类眼睛发育及其相关异常中的作用，并证明其在受影响的器官系统中的发育过程中的表达。
