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

Gabriella Esposito, Francesca De Falco, Nadia Tinto, Francesco Testa, Luigi Vitagliano, Igor Cristian Maria Tandurella, Lucio Iannone, Settimio Rossi, Ernesto Rinaldi, Francesca Simonelli, Adriana Zagari, Francesco Salvatore

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)1460-1469
Number of pages10
JournalHuman Mutation
Volume32
Issue number12
DOIs
Publication statusPublished - Dec 2011

Keywords

  • CHM
  • Choroideremia
  • Modeling
  • Rab proteins
  • REP1

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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