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

Abstract

ABSTRACT 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.