Department of Cellular Biology and Anatomy, Augusta University, Augusta, GA, USA.
Department of Biochemistry, Faculty of Pharmacy, Cairo University, Cairo, Egypt.
Sci Rep. 2019 Dec 18;9(1):19406. doi: 10.1038/s41598-019-55866-5.
Keratoconus (KC) is the most common corneal ectatic disorder affecting >300,000 people in the US. KC normally has its onset in adolescence, progressively worsening through the third to fourth decades of life. KC patients report significant impaired vision-related quality of life. Genetic factors play an important role in KC pathogenesis. To identify novel genes in familial KC patients, we performed whole exome and genome sequencing in a four-generation family. We identified potential variants in the PPIP5K2 and PCSK1 genes. Using in vitro cellular model and in vivo gene-trap mouse model, we found critical evidence to support the role of PPIP5K2 in normal corneal function and KC pathogenesis. The gene-trap mouse showed irregular corneal surfaces and pathological corneal thinning resembling KC. For the first time, we have integrated corneal tomography and pachymetry mapping into characterization of mouse corneal phenotypes which could be widely implemented in basic and translational research for KC diagnosis and therapy in the future.
圆锥角膜（KC）是最常见的角膜扩张性疾病，影响美国超过 30 万人。KC 通常在青春期发病，在第三至第四十年逐渐恶化。KC 患者报告视力相关的生活质量显著受损。遗传因素在 KC 的发病机制中起重要作用。为了在家族性 KC 患者中鉴定新的基因，我们对一个四代同堂的家庭进行了全外显子和全基因组测序。我们在 PPIP5K2 和 PCSK1 基因中发现了潜在的变异。通过体外细胞模型和体内基因捕获小鼠模型，我们发现了支持 PPIP5K2 在正常角膜功能和 KC 发病机制中起作用的关键证据。基因捕获小鼠表现出不规则的角膜表面和病理性角膜变薄，类似于 KC。我们首次将角膜断层扫描和角膜测厚图整合到小鼠角膜表型的特征描述中，这在未来的 KC 诊断和治疗的基础和转化研究中可能得到广泛应用。
