Microphthalmia, coloboma and cataract are part of a spectrum of developmental eye disorders in humans affecting ~ 12 per 100 000 live births. Currently, variants in over 100 genes are known to underlie these conditions. However, at least 40% of affected individuals remain without a clinical genetic diagnosis, suggesting variants in additional genes may be responsible. Calpain 15 (CAPN15) is an intracellular cysteine protease belonging to the non-classical Small Optic Lobe (SOL) family of calpains, an important class of developmental proteins, as yet uncharacterised in vertebrates. We identified five individuals with microphthalmia and/or coloboma from four independent families carrying homozygous or compound heterozygous predicted damaging variants in CAPN15. Several individuals had additional phenotypes including growth deficits, developmental delay and hearing loss. We generated Capn15 knockout mice that exhibited similar severe developmental eye defects, including anophthalmia, microphthalmia, and cataract, and diminished growth. We demonstrate widespread Capn15 expression throughout the brain and central nervous system, strongest during early development, and decreasing postnatally. Together, these findings demonstrate a critical role of CAPN15 in vertebrate developmental eye disorders, and may signify a new developmental pathway.

中文翻译：

---

小视叶钙蛋白酶 CAPN15 中的双等位基因变异与先天性眼异常、耳聋和其他神经发育缺陷有关。

小眼症、缺损和白内障是人类发育性眼部疾病的一部分，每 100 000 名活产婴儿中约有 12 人受到影响。目前，已知有 100 多个基因的变异是这些疾病的基础。然而，至少 40% 的受影响个体仍然没有临床基因诊断，这表明其他基因的变异可能是负责任的。钙蛋白酶 15 (CAPN15) 是一种细胞内半胱氨酸蛋白酶，属于非经典小视叶 (SOL) 钙蛋白酶家族，这是一类重要的发育蛋白，尚未在脊椎动物中表征。我们从携带 CAPN15 纯合子或复合杂合子预测损伤变异的四个独立家族中鉴定了五个患有小眼和/或缺损的个体. 几个人有额外的表型，包括生长缺陷、发育迟缓和听力损失。我们生成了Capn15基因敲除小鼠，它们表现出类似的严重发育性眼部缺陷，包括无眼症、小眼症和白内障，以及生长减慢。我们在整个大脑和中枢神经系统中表现出广泛的Capn15表达，在早期发育期间最强，并在出生后下降。总之，这些发现证明了CAPN15在脊椎动物发育性眼病中的关键作用，并且可能意味着一种新的发育途径。