Novel non‐contiguous exon duplication in choroideremia

Abstract

The importance of establishing a genetic diagnosis in patients with a choroideremia phenotype has been underscored by the advent of gene replacement therapy for this condition. Here, we describe a complex imbalance at the CHM locus in a male patient with classical disease. At the DNA level, this imbalance consists of 2 non‐contiguous duplications (exons 1‐2 and 9‐12). Further characterization suggests the generation of 2 independent CHM transcriptional units, one of which may produce a deleted form of the Rab escort protein 1 protein. Expression of such a type of aberrant protein in photoreceptors may have important implications when considering gene therapy for this disorder.

Choroideremia: molecular mechanisms and development of AAV gene therapy

“…Fibroblasts grown from a skin biopsy cultured in vitro constitute an alternative source of cells obtained by minimally invasive methods. Immunoblot analysis of REP1 expression in cells from choroideremia patients, either PMBCs and/or fibroblasts, has been used to validate the diagnosis of choroideremia, regardless the mutation [13][14][15]18,19,55,[57][58][59][60][61][62][63]. All these reports showed absence of REP1 expression in the cell type analysed, except for the three missense mutations, which showed reduced expression of REP1 [13][14][15], and an in-frame deletion (c.117_314del; R40_S105del), where a truncated protein would be predicted.…”

Choroideremia: from genetic and clinical phenotyping to gene therapy and future treatments

“…17 A variety of mutations have been implicated including deletions, insertions, duplications, translocations, nonsense, splice site, frameshift, missense and deep intronic variants. 1,[18][19][20] Most of the mutations in the CHM gene are null, either through deletions (25-50%) or nonsense mutations (30%). 1 Deletions may involve either a few kilobases or the entire length of the gene resulting in a dysfunctional or completely absent protein, while nonsense mutations introduce premature stop codons in the coding sequence signalling abrupt disruption of the translational process.…”

Expression of Rab Prenylation Pathway Genes and Relation to Disease Progression in Choroideremia

“…This patient has a pathological noncontiguous duplication in CHM resulting in 2 transcripts: the first comprises exons 1 to 12 without exons 13 to 15 or a termination or polyadenylation signal; the second unit arises from a duplication event and comprises the exons 1 to 2 and exons 9 to 15. 30 The primer set used in this study binds within exon 3, and so detects the expression of the first transcriptional unit. This transcript does not lead to the translation of detectable or functional REP1 protein.…”