Molecular Characterization of Choroideremia-Associated Deletions Reveals an Unexpected Regulation of CHM Gene Transcription
Open Access
- 22 July 2021
- Vol. 12 (8), 1111
- https://doi.org/10.3390/genes12081111
Abstract
Choroideremia (CHM) is a X-linked recessive chorioretinal dystrophy due to deficiency of the CHM 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 CHM gene deletions. To improve understanding of the disease mechanisms, we analyzed molecular features of seven deletions involving the CHM 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 CHM and of CHML, encoding the REP2 isoform. Scattered along the whole CHM 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 CHM mRNA; CHML expression was higher than normal in a patient lacking CHM and its putative regulatory sequences. This latest evidence suggests that mechanisms regulating CHM and CHML 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.This publication has 49 references indexed in Scilit:
- Choroideremia: Effect of age on visual acuity in patients and female carriersOphthalmic Genetics, 2011
- Choroideremia: A review of general findings and pathogenesisOphthalmic Genetics, 2011
- A Functional Link between the Histone Demethylase PHF8 and the Transcription Factor ZNF711 in X-Linked Mental RetardationMolecular Cell, 2010
- Loss-of-Function Mutations in Rab Escort Protein 1 (REP-1) Affect Intracellular Transport in Fibroblasts and Monocytes of Choroideremia PatientsPLOS ONE, 2009
- CHM gene molecular analysis and X‐chromosome inactivation pattern determination in two families with choroideremiaAmerican Journal of Medical Genetics Part A, 2009
- A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardationNature Genetics, 2009
- New Type of Mutations in Three Spanish Families with ChoroideremiaInvestigative Ophthalmology & Visual Science, 2008
- Molecular basis of choroideremia (CHM): Mutations involving the rab escort protein-1 (REP-1) geneHuman Mutation, 1997
- Mutation spectrum in the CHM gene of Danish and Swedish choroideremia patientsHuman Molecular Genetics, 1994
- Physical fine mapping of the choroideremia locus using Xq21 deletions associated with complex syndromesGenomics, 1989