title: Comprehensive mutation analysis (20 families) of the choroideremia gene reveals a missense variant that prevents the binding of REP1 with Rab geranylgeranyl transferase.
abstract: 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, nine of which are new. In most cases, we analyzed the effect of the mutations at the mRNA level. Furthermore, we demonstrated, by in vitro trancription/translation assays, that the mutated mRNAs produced truncated proteins in all cases but one. In fact, we also identified a novel REP1 missense variant (c.1520A>G; p.H507R) associated to CHM. Thus far, only two other CHM-associated missense mutations have been identified, one of which was a splicing alteration. We investigated the impact of the p.H507R amino acid change on REP1 structure and function, thus providing 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.
authors: CEINGE-Biotecnologie Avanzate S.C.a r.l., Naples, Italy.
authors: Gabriella
authors: G
authors: Esposito
authors: Francesca
authors: F
authors: De Falco
authors: Nadia
authors: N
authors: Tinto
authors: Francesco
authors: F
authors: Testa
authors: Luigi
authors: L
authors: Vitagliano
authors: Igor Cristian Maria
authors: IC
authors: Tandurella
authors: Lucio
authors: L
authors: Iannone
authors: Settimio
authors: S
authors: Rossi
authors: Ernesto
authors: E
authors: Rinaldi
authors: Francesca
authors: F
authors: Simonelli
authors: Adriana
authors: A
authors: Zagari
authors: Francesco
authors: F
authors: Salvatore
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism*; D000328:Adult; D019883:Alkyl and Aryl Transferases / Q000378:metabolism*; D002675:Child, Preschool; D015794:Choroideremia / Q000235:genetics* / Q000503:physiopathology; D004252:DNA Mutational Analysis / Q000379:methods*; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D055815:Young Adult
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C081787:CHM protein, human; D019883:Alkyl and Aryl Transferases; C075607:Rab geranylgeranyltransferase