Personalized models reveal mechanistic and therapeutic insights into CEP290-associated Leber congenital amaurosis
Lebers congenital amaurosis (LCA) is an early onset form of retinal degeneration, commonly known as childhood blindness, which manifests via mutations in genes required for functional or structural maintenance of photoreceptors. Eighteen genes are currently recognized as causative for disease progression with the largest percentage of confirmed clinical cases occurring due to defects in CEP290. This gene encodes the centrosomal protein of 290 kilodaltons (CEP290), which is an evolutionarily conserved component from green algae to modern vertebrates that participates in cellular processes associated with primary cilium assembly/stability, cell cycle control, and DNA replication (1-3). Photoreceptors are particularly vulnerable to deficits in ciliogenesis as their structure includes a ciliary axoneme that connects the major segments. Loss of CEP290 disrupts several functions of the connecting cilium with respect to intraflagellar trafficking and structural stability, thereby prompting a rapid course of photoreceptor degeneration that culminates in a phenotype of severe vision loss (2,4).