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Article

Molecular Characterization of Choroideremia-Associated Deletions Reveals an Unexpected Regulation of CHM Gene Transcription

by
Tiziana Fioretti
1,†,
Valentina Di Iorio
2,†,
Barbara Lombardo
1,3,
Francesca De Falco
1,
Armando Cevenini
1,3,
Fabio Cattaneo
3,
Francesco Testa
2,
Lucio Pastore
1,3,
Francesca Simonelli
2 and
Gabriella Esposito
1,3,*
1
CEINGE-Biotecnologie Avanzate s.c. a r.l., Via G. Salvatore 486, 80145 Naples, Italy
2
Eye Clinic, Multidisciplinary Department of Medical, Surgical and Dental Sciences, University of Campania Luigi Vanvitelli, Via S. Pansini 5, 80131 Naples, Italy
3
Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Genes 2021, 12(8), 1111; https://doi.org/10.3390/genes12081111
Submission received: 15 June 2021 / Revised: 16 July 2021 / Accepted: 19 July 2021 / Published: 22 July 2021
(This article belongs to the Special Issue Genetics in Inherited Retinal Diseases)
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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.
Keywords: CHM; choroideremia; deletion breakpoint; inherited retinal degeneration; REP1; REP2; repeat elements; transcriptional regulation CHM; choroideremia; deletion breakpoint; inherited retinal degeneration; REP1; REP2; repeat elements; transcriptional regulation

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MDPI and ACS Style

Fioretti, T.; Di Iorio, V.; Lombardo, B.; De Falco, F.; Cevenini, A.; Cattaneo, F.; Testa, F.; Pastore, L.; Simonelli, F.; Esposito, G. Molecular Characterization of Choroideremia-Associated Deletions Reveals an Unexpected Regulation of CHM Gene Transcription. Genes 2021, 12, 1111. https://doi.org/10.3390/genes12081111

AMA Style

Fioretti T, Di Iorio V, Lombardo B, De Falco F, Cevenini A, Cattaneo F, Testa F, Pastore L, Simonelli F, Esposito G. Molecular Characterization of Choroideremia-Associated Deletions Reveals an Unexpected Regulation of CHM Gene Transcription. Genes. 2021; 12(8):1111. https://doi.org/10.3390/genes12081111

Chicago/Turabian Style

Fioretti, Tiziana, Valentina Di Iorio, Barbara Lombardo, Francesca De Falco, Armando Cevenini, Fabio Cattaneo, Francesco Testa, Lucio Pastore, Francesca Simonelli, and Gabriella Esposito. 2021. "Molecular Characterization of Choroideremia-Associated Deletions Reveals an Unexpected Regulation of CHM Gene Transcription" Genes 12, no. 8: 1111. https://doi.org/10.3390/genes12081111

APA Style

Fioretti, T., Di Iorio, V., Lombardo, B., De Falco, F., Cevenini, A., Cattaneo, F., Testa, F., Pastore, L., Simonelli, F., & Esposito, G. (2021). Molecular Characterization of Choroideremia-Associated Deletions Reveals an Unexpected Regulation of CHM Gene Transcription. Genes, 12(8), 1111. https://doi.org/10.3390/genes12081111

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