Cells 2016, 5(3), 31; https://doi.org/10.3390/cells5030031
Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells
Karim Harhouri 1, Claire Navarro 1
, Camille Baquerre 1, Nathalie Da Silva 1, Catherine Bartoli 1, Frank Casey 2, Guedenon Koffi Mawuse 3, Yassamine Doubaj 4, Nicolas Lévy 1,5 and Annachiara De Sandre-Giovannoli 1,5,*
, Camille Baquerre 1, Nathalie Da Silva 1, Catherine Bartoli 1, Frank Casey 2, Guedenon Koffi Mawuse 3, Yassamine Doubaj 4, Nicolas Lévy 1,5 and Annachiara De Sandre-Giovannoli 1,5,*
1
Aix Marseille Université, INSERM, GMGF UMR_S 910, 13385 Marseille, France
2
Royal Belfast, Pediatric Cardiology, Hospital for Sick Children, Belfast BT9 7AB, Northern Ireland
3
CHU Sylvanus Olympio de Lomé, Unité de Génétique Humaine, Lomé BP 1515, Togo
4
Département de Génétique Médicale, Institut National d’Hygiène, 11400 Rabat, Morocco
5
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)
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 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-TextKeywords:
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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