Original Investigation

Human Genetics

, Volume 113, Issue 3, pp 268-275

Novel types of mutation in the choroideremia (CHM) gene: a full-length L1 insertion and an intronic mutation activating a cryptic exon

  • José A. J. M. van den HurkAffiliated withDepartment of Human Genetics, University Medical Center Nijmegen Email author 
  • , Dorien J. R. van de PolAffiliated withDepartment of Human Genetics, University Medical Center Nijmegen
  • , Bernd WissingerAffiliated withUniversity Eye Hospital
  • , Marc A. van DrielAffiliated withCenter for Molecular and Biomolecular Informatics, University of Nijmegen
  • , Lies H. HoefslootAffiliated withDepartment of Human Genetics, University Medical Center Nijmegen
  • , Ilse J. de WijsAffiliated withDepartment of Human Genetics, University Medical Center Nijmegen
  • , L. Ingeborgh van den BornAffiliated withThe Rotterdam Eye Hospital
  • , John R. HeckenlivelyAffiliated withJules Stein Eye Institute, UCLA School of Medicine
  • , Han G. BrunnerAffiliated withDepartment of Human Genetics, University Medical Center Nijmegen
    • , Eberhart ZrennerAffiliated withUniversity Eye Hospital
    • , Hans-Hilger RopersAffiliated withMax Planck Institute for Molecular Genetics
    • , Frans P. M. CremersAffiliated withDepartment of Human Genetics, University Medical Center Nijmegen

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Abstract

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.