Antisense oligonucleotides targeting exon 11 are able to partially rescue the NF2-related schwannomatosis phenotype in vitro
Por:
Catasús N, Rosas I, Bonache S, Negro A, Torres-Martin M, Plana-Pla A, Salvador-Hernandez H, Serra E, Blanco I and Castellanos E
Publicada:
13 dic 2022
Ahead of Print:
1 nov 2022
Resumen:
NF2-related schwannomatosis (NF2-related SWN) is an auto-somal dominant condition caused by loss of function variants in the NF2 gene, which codes for the protein Merlin and is char-acterized by the development of multiple tumors of the nervous system. The clinical presentation of the disease is variable and related to the type of the inherited germline variant. Here, we tested if phosphorodiamidate morpholino oligomers (PMOs) could be used to correct the splice signaling caused by variants at +/- 13 within the intron-exon boundary region and showed that the PMOs designed for these variants do not constitute a therapeutic approach. Furthermore, we evaluated the use of PMOs to decrease the severity of the effects of NF2 truncating variants with the aim of generating milder hypomorphic iso-forms in vitro through the induction of the in-frame deletion of the exon-carrying variant. We were able to specifically induce the skipping of exons 4, 8, and 11 maintaining the NF2 gene reading frame at cDNA level. Only the skipping of exon 11 produced a hypomorphic Merlin (Merlin-e11), which is able to partially rescue the observed phenotype in primary fibroblast cultures from NF2-related SWN patients, being encouraging for the treatment of patients harboring truncating variants located in exon 11.
Filiaciones:
Catasús N:
Clinical Genomics Research Group, Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Crta. Canyet, s/n. Badalona, Barcelona 08916, Spain
Rosas I:
Clinical Genomics Research Group, Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Crta. Canyet, s/n. Badalona, Barcelona 08916, Spain
Clinical Genetics Department, Germans Trias i Pujol University Hospital (HUGTP), Can Ruti Campus, Crta. Canyet, s/n. Badalona, Barcelona 08916, Spain
Bonache S:
Clinical Genomics Research Group, Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Crta. Canyet, s/n. Badalona, Barcelona 08916, Spain
Clinical Genetics Department, Germans Trias i Pujol University Hospital (HUGTP), Can Ruti Campus, Crta. Canyet, s/n. Badalona, Barcelona 08916, Spain
Negro A:
Clinical Genomics Research Group, Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Crta. Canyet, s/n. Badalona, Barcelona 08916, Spain
Clinical Genetics Department, Germans Trias i Pujol University Hospital (HUGTP), Can Ruti Campus, Crta. Canyet, s/n. Badalona, Barcelona 08916, Spain
Torres-Martin M:
Clinical Genomics Research Group, Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Crta. Canyet, s/n. Badalona, Barcelona 08916, Spain
Clinical Genetics Department, Germans Trias i Pujol University Hospital (HUGTP), Can Ruti Campus, Crta. Canyet, s/n. Badalona, Barcelona 08916, Spain
Plana-Pla A:
Dermatology Department, Germans Trias i Pujol University Hospital (HUGTP), Can Ruti Campus, Badalona, Barcelona 08916, Spain
Salvador-Hernandez H:
Pediatric Oncology Unit, Hospital Sant Joan de Déu, Esplugues, Barcelona, Spain
Serra E:
Hereditary Cancer Group, Germans Trias i Pujol Research Institute (IGTP-PMPPC), Can Ruti Campus, Badalona, Barcelona 08916, Spain
Blanco I:
Clinical Genomics Research Group, Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Crta. Canyet, s/n. Badalona, Barcelona 08916, Spain
Clinical Genetics Department, Germans Trias i Pujol University Hospital (HUGTP), Can Ruti Campus, Crta. Canyet, s/n. Badalona, Barcelona 08916, Spain
Castellanos E:
Clinical Genomics Research Group, Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Crta. Canyet, s/n. Badalona, Barcelona 08916, Spain
Clinical Genetics Department, Germans Trias i Pujol University Hospital (HUGTP), Can Ruti Campus, Crta. Canyet, s/n. Badalona, Barcelona 08916, Spain
Clinical Genomics Research Group, Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Crta. Canyet, s/n. Badalona, Barcelona 08916, Spain.; Clinical Genetics Department, Germans Trias i Pujol University Hospital (HUGTP), Can Ruti Campus, Crta. Canyet, s/n. Badalona, Barcelona 08916, Spain.; Dermatology Department, Germans Trias i Pujol University Hospital (HUGTP), Can Ruti Campus, Badalona, Barcelona 08916, Spain.; Pediatric Oncology Unit, Hospital Sant Joan de Deu, Esplugues, Barc
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