Comprehensive mutation analysis (20 families) of the choroideremia gene reveals a missense variant that prevents the binding of REP1 with rab geranylgeranyl transferase.

Choroideremia (CHM), an X-linked degeneration of the retinal pigmented epithelium (RPE), photoreceptors and choroid, ultimately leads to blindness. It is caused by loss-of-function of the CHM gene product, the Rab escort protein 1 (REP1) that is involved, together with its homologue REP2, in prenylation of Rab GTPases, key regulators of intracellular vesicular traffic. Here we report the molecular characterization of 20 unrelated Italian families affected by CHM. We identified 19 different mutations, ten of which are new. Among these, we identified a novel REP1 missense variant (c.1520A>G; p.H507R) associated to CHM. We investigated the impact of this amino acid change on REP1 structure and function. We provide the first experimental demonstration that correlates a missense mutation in CHM with a functional impairment of REP1. Overall, our results indicate that the REP1-Rab geranyl-geranyl transferase interaction and consequently REP1-mediated Rab prenylation is essential for RPE and photoreceptor function.