Choroideremia (CHM) is a progressive chorioretinal degeneration caused by mutations in the widely expressed CHM gene on chromosome Xq21. The product of this gene, Rab escort
protein (REP)-1, is involved in the posttranslational
lipid modification and subsequent membrane targeting of Rab
proteins,
small GTPases that play a key role in intracellular trafficking. We have searched for mutations of the CHM gene in patients with
choroideremia by analysis of individual CHM exons and adjacent intronic sequences PCR-amplified from genomic
DNA and by reverse transcription (RT)-PCR analysis of the coding region of the CHM
mRNA. In 35 patients, at least 21 different causative CHM defects were identified. These included two partial CHM gene deletions and an insertion of a full-length L1
retrotransposon into the coding region of the CHM gene, a type of mutation that has not been previously reported as a cause of CHM. We also detected nine different
nonsense mutations, five of which are recurrent, a small deletion, a small insertion, and at least five distinct splice site mutations, one of which has been described previously. Moreover, we report for the first time the identification of an intronic mutation remote from the exon-intron junctions that creates a strong acceptor splice site and leads to the inclusion of a cryptic exon into the CHM
mRNA. Finally, in an affected male who did not have a mutation in any of the CHM exons or their splice sites, the deletion of a complete exon from the CHM
mRNA was observed.