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

• Published in: Human genetics Vol. 113; no. 3; pp. 268 - 275
• Main Authors: VAN DEN HURK, José A. J. M, VAN DE POL, Dorien J. R, ROPERS, Hans-Hilger, CREMERS, Frans P. M, WISSINGER, Bernd, VAN DRIEL, Marc A, HOEFSLOOT, Lies H, DE WIJS, Ilse J, VAN DEN BORN, L. Ingeborgh, HECKENLIVELY, John R, BRUNNER, Han G, ZRENNER, Eberhart
• Format: Journal Article
• Language: English
• Published: Heidelberg Springer 01.08.2003; Berlin Springer Nature B.V; New York, NY
• Subjects: Adaptor Proteins, Signal Transducing; Alkyl and Aryl Transferases; Amino Acid Sequence; Base Sequence; Biological and medical sciences; CHM gene; Choroideremia; Choroideremia - genetics; Codon, Nonsense; DNA; DNA Mutational Analysis; Errors of metabolism; Exons; G proteins; Gene Deletion; Genes; Genetic aspects; Genetic research; Genetic transcription; Humans; Introns; Male; Medical sciences; Messenger RNA; Metabolic diseases; Miscellaneous hereditary metabolic disorders; Molecular Sequence Data; Mutagenesis, Insertional; Mutation; Ophthalmology; Protein Splicing; Proteins; Rab escort protein; rab GTP-Binding Proteins - genetics; rab protein; Retinopathies; Reverse Transcriptase Polymerase Chain Reaction; Exon; Gene; Length; Choroideremia; Insertion mutation
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-003-0970-0

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.