Skip to Main content Skip to Navigation
Journal articles

Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells

Abstract : Progeroid laminopathies, including Hutchinson-Gilford Progeria Syndrome (HGPS, OMIM #176670), are premature and accelerated aging diseases caused by defects in nuclear A-type Lamins. Most HGPS patients carry a de novo point mutation within exon 11 of the LMNA gene encoding A-type Lamins. This mutation activates a cryptic splice site leading to the deletion of 50 amino acids at its carboxy-terminal domain, resulting in a truncated and permanently farnesylated Prelamin A called Prelamin A ∆50 or Progerin. Some patients carry other LMNA mutations affecting exon 11 splicing and are named " HGPS-like " patients. They also produce Progerin and/or other truncated Prelamin A isoforms (∆35 and ∆90) at the transcriptional and/or protein level. The results we present show that morpholino antisense oligonucleotides (AON) prevent pathogenic LMNA splicing, markedly reducing the accumulation of Progerin and/or other truncated Prelamin A isoforms (Prelamin A ∆35, Prelamin A ∆90) in HGPS-like patients' cells. Finally, a patient affected with Mandibuloacral Dysplasia type B (MAD-B, carrying a homozygous mutation in ZMPSTE24, encoding an enzyme involved in Prelamin A maturation, leading to accumulation of wild type farnesylated Prelamin A), was also included in this study. These results provide preclinical proof of principle for the use of a personalized antisense approach in HGPS-like and MAD-B patients, who may therefore be eligible for inclusion in a therapeutic trial based on this approach, together with classical HGPS patients.
Document type :
Journal articles
Complete list of metadatas

Cited literature [43 references]  Display  Hide  Download

https://hal-amu.archives-ouvertes.fr/hal-01769404
Contributor : Administrateur Hal Amu <>
Submitted on : Wednesday, April 18, 2018 - 9:20:50 AM
Last modification on : Wednesday, August 19, 2020 - 12:08:15 PM

File

cells-05-00031-v2.pdf
Publication funded by an institution

Licence


Distributed under a Creative Commons Attribution 4.0 International License

Identifiers

Collections

Citation

Karim Harhouri, Claire Navarro, Camille Baquerre, Nathalie da Silva, Catherine Bartoli, et al.. Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells. Cells, MDPI, 2016, 5 (3), pp.31. ⟨10.3390/cells5030031⟩. ⟨hal-01769404⟩

Share

Metrics

Record views

178

Files downloads

246