A De Novo Missense Mutation in IFT122 Confers a Genetic Susceptibility Factor of Idiopathic Pediatric Uveitis via Trio-based Whole-Exome Sequencing [CHIP_FRA1_seq]

Herein, trio-based whole-exome sequencing was performed in 28 affected families and targeted sequencing in 1953 sporadic cases from a Han Chinese cohort, identifying a rare missense mutation A773E in intraflagellar transport 122 (IFT122). Functional assays showed deleterious IFT122-E773 increased inflammatory factors secretion and exacerbated barrier function damage both in vivo and vitro.

Further studies using proteomics found that IFT122-E773 increased AP-1 transcription factor subunit (FRA1) expression. In addition, the IFT122-E773 substitution enhanced the interaction with IFT43, thereby activating the MEK/ERK signaling axis. Collectively, this study suggested that IFT122-E773 may increase susceptibility to IPU through activation of the IFT122-MEK/ERK/FRA1 axis.