| Summary: | Choroideremia (CHM) is a X-linked recessive chorioretinal dystrophy due to deficiency of the <i>CHM</i> gene product, i.e., Rab escort protein isoform 1 (REP1). To date, gene therapy for CHM has shown variable effectiveness, likely because the underlying pathogenic mechanisms as well as genotype-phenotype correlation are not yet fully known. Small nucleotide variants leading to premature termination codons (PTCs) are a major cause of CHM, but about 20% of patients has <i>CHM</i> gene deletions. To improve understanding of the disease mechanisms, we analyzed molecular features of seven deletions involving the <i>CHM</i> gene sequence. We mapped the deletion breakpoints by using polymerase chain reaction, sequencing and array comparative genomic hybridization; to identify rearrangement-promoting DNA sequences, we analyzed genomic architecture surrounding the breakpoint regions. Moreover, in some CHM patients with different mutation types, we measured transcript level of <i>CHM</i> and of <i>CHML</i>, encoding the REP2 isoform. Scattered along the whole <i>CHM</i> gene and in close proximity to the deletion breakpoints we found numerous repeat elements that generate a locus-specific rearrangement hot spot. Unexpectedly, patients with non-PTC variants had increased expression of the aberrant <i>CHM</i> mRNA; <i>CHML</i> expression was higher than normal in a patient lacking <i>CHM</i> and its putative regulatory sequences. This latest evidence suggests that mechanisms regulating <i>CHM</i> and <i>CHML</i> gene expression are worthy of further study, because their full knowledge could be also useful for developing effective therapies for this hitherto untreatable inherited retinal degeneration.
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