Loss of RPGR glutamylation underlies the pathogenic mechanism of retinal dystrophy caused by TTLL5 mutations

Significance Mutations affecting two unrelated genes, retinitis pigmentosa GTPase regulator ( RPGR ) and tubulin tyrosine ligase like 5 ( TTLL5 ), lead to photoreceptor degeneration and blindness in humans. We find that RPGR function in photoreceptor cilia requires glutamylation by TTLL5. Glutamylation is a poorly understood posttranslational modification that consists of the addition of glutamates to target proteins. Moreover, we find that mice lacking RPGR or TTLL5 exhibit similar phenotypes characterized by photoreceptor degeneration and opsin mislocalization. Our work identifies a novel essential regulator of RPGR and demonstrates that disease-causing mutations in these two genes share a common pathogenic pathway in humans.