A Rare De Novo Missense Mutation in IFT122 Confers a Genetic Susceptibility Factor of Idiopathic Pediatric Uveitis Via Trio-based Whole-Exome Sequencing.

Idiopathic pediatric uveitis (IPU) is a leading cause of irreversible vision loss in children; however, the genetic and molecular mechanisms underlying this condition remain unclear. Herein, trio-based whole-exome sequencing was performed in 28 affected families and targeted sequencing was performed in 1953 sporadic cases from a Han Chinese cohort. A rare missense mutation, A773E in intraflagellar transport 122 (IFT122), was identified in one trio and absent from sporadic cases. Functional assays showed that deleterious IFT122-A773E increased inflammatory factor secretion and exacerbated barrier function damage both in vivo and in vitro. Further studies using proteomics demonstrated that IFT122-A773E increased AP-1 transcription factor subunit (FRA1) expression. The IFT122-A773E substitution enhanced the interaction with IFT43 and up-regulated calcium channels, and in turn led to activation of the MEK/ERK signaling axis. Collectively, our findings suggest that IFT122-A773E may increase susceptibility to IPU through activation of the MEK/ERK/FRA1 axis.