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Cells 2016, 5(3), 31;

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

Aix Marseille Université, INSERM, GMGF UMR_S 910, 13385 Marseille, France
Royal Belfast, Pediatric Cardiology, Hospital for Sick Children, Belfast BT9 7AB, Northern Ireland
CHU Sylvanus Olympio de Lomé, Unité de Génétique Humaine, Lomé BP 1515, Togo
Département de Génétique Médicale, Institut National d’Hygiène, 11400 Rabat, Morocco
Departement of Medical Genetics, la Timone Children’s Hospital, APHM, 13385 Marseille, France
Author to whom correspondence should be addressed.
Academic Editor: Thomas Dechat
Received: 28 April 2016 / Revised: 15 June 2016 / Accepted: 4 July 2016 / Published: 11 July 2016
(This article belongs to the Collection Lamins and Laminopathies)
Full-Text   |   PDF [2301 KB, uploaded 2 August 2016]   |  


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 Δ50 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 (Δ35 and Δ90) 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 Δ35, Prelamin A Δ90) 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. View Full-Text
Keywords: HGPS-like; MAD-B; antisense oligonucleotides; Progerin; Prelamin A Δ90; Prelamin A Δ35 HGPS-like; MAD-B; antisense oligonucleotides; Progerin; Prelamin A Δ90; Prelamin A Δ35

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Harhouri, K.; Navarro, C.; Baquerre, C.; Da Silva, N.; Bartoli, C.; Casey, F.; Mawuse, G.K.; Doubaj, Y.; Lévy, N.; De Sandre-Giovannoli, A. Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells. Cells 2016, 5, 31.

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