Comprehensive mutation analysis (20 families) of the choroideremia gene reveals a missense variant that prevents the binding of REP1 with Rab geranylgeranyl transferase
Comprehensive mutation analysis (20 families) of the choroideremia gene reveals a missense variant that prevents the binding of REP1 with Rab geranylgeranyl transferase(1329 views) Esposito G, De Falco F, Tinto N, Testa F, Vitagliano L, Tandurella IC, Iannone L, Rossi S, Rinaldi E, Simonelli F, Zagari A, Salvatore F
Hum Mutat (ISSN: 1059-7794, 1098-1004, 1098-1004electronic), 2011 Dec; 32(12): 1460-1469.
Keywords: Chm, Choroideremia, Modeling, Rab Proteins, Amino Acid, Messenger Rna, Rab Escort Protein 1, Unclassified Drug, Alternative Rna Splicing, Article, Clinical Article, Controlled Study, Female, Human, Human Cell, Human Tissue, In Vitro Study, Italy, Missense Mutation, Mutational Analysis, Photoreceptor, Priority Journal, Protein Function, Protein Structure, Adaptor Proteins, Signal Transducing, Adult, Alkyl And Aryl Transferases, Child, Preschool, Dna Mutational Analysis, Middle Aged, Young Adult, Genetics, Metabolism, Physiopathology, Methods,
Affiliations: *** IBB - CNR ***
CEINGE-Biotecnologie Avanzate S.C.a r.l., Naples, Italy
Dipartimento di Biochimica e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy
IRCCS-Fondazione SDN, Via E. Gianturco, Naples, Italy
Dipartimento di Oftalmologia, Seconda Università di Napoli, Naples, Italy
Istituto di Biostrutture e Bioimmagini, CNR, Naples, Italy
Dipartimento delle Scienze Biologiche-Sezione Biostrutture, CNISM, Università di Napoli Federico II, Naples, Italy
References: Not available.
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, 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. 32:14601469, 2011. (C) 2011 Wiley Periodicals, Inc.
Comprehensive mutation analysis (20 families) of the choroideremia gene reveals a missense variant that prevents the binding of REP1 with Rab geranylgeranyl transferase
Comprehensive mutation analysis (20 families) of the choroideremia gene reveals a missense variant that prevents the binding of REP1 with Rab geranylgeranyl transferase
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