Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells
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 mutati...
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MDPI AG
2016-07-01
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| Series: | Cells |
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| Online Access: | http://www.mdpi.com/2073-4409/5/3/31 |
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| author | Karim Harhouri Claire Navarro Camille Baquerre Nathalie Da Silva Catherine Bartoli Frank Casey Guedenon Koffi Mawuse Yassamine Doubaj Nicolas Lévy Annachiara De Sandre-Giovannoli |
| author_facet | Karim Harhouri Claire Navarro Camille Baquerre Nathalie Da Silva Catherine Bartoli Frank Casey Guedenon Koffi Mawuse Yassamine Doubaj Nicolas Lévy Annachiara De Sandre-Giovannoli |
| author_sort | Karim Harhouri |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T09:07:52Z |
| format | Article |
| id | doaj.art-528d9dadacbd4b30b7e1ac3dea03165c |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T09:07:52Z |
| publishDate | 2016-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-528d9dadacbd4b30b7e1ac3dea03165c2023-09-02T15:10:33ZengMDPI AGCells2073-44092016-07-01533110.3390/cells5030031cells5030031Antisense-Based Progerin Downregulation in HGPS-Like Patients’ CellsKarim Harhouri0Claire Navarro1Camille Baquerre2Nathalie Da Silva3Catherine Bartoli4Frank Casey5Guedenon Koffi Mawuse6Yassamine Doubaj7Nicolas Lévy8Annachiara De Sandre-Giovannoli9Aix Marseille Université, INSERM, GMGF UMR_S 910, 13385 Marseille, FranceAix Marseille Université, INSERM, GMGF UMR_S 910, 13385 Marseille, FranceAix Marseille Université, INSERM, GMGF UMR_S 910, 13385 Marseille, FranceAix Marseille Université, INSERM, GMGF UMR_S 910, 13385 Marseille, FranceAix Marseille Université, INSERM, GMGF UMR_S 910, 13385 Marseille, FranceRoyal Belfast, Pediatric Cardiology, Hospital for Sick Children, Belfast BT9 7AB, Northern IrelandCHU Sylvanus Olympio de Lomé, Unité de Génétique Humaine, Lomé BP 1515, TogoDépartement de Génétique Médicale, Institut National d’Hygiène, 11400 Rabat, MoroccoAix Marseille Université, INSERM, GMGF UMR_S 910, 13385 Marseille, FranceAix Marseille Université, INSERM, GMGF UMR_S 910, 13385 Marseille, FranceProgeroid 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.http://www.mdpi.com/2073-4409/5/3/31HGPS-likeMAD-Bantisense oligonucleotidesProgerinPrelamin A Δ90Prelamin A Δ35 |
| spellingShingle | Karim Harhouri Claire Navarro Camille Baquerre Nathalie Da Silva Catherine Bartoli Frank Casey Guedenon Koffi Mawuse Yassamine Doubaj Nicolas Lévy Annachiara De Sandre-Giovannoli Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells Cells HGPS-like MAD-B antisense oligonucleotides Progerin Prelamin A Δ90 Prelamin A Δ35 |
| title | Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells |
| title_full | Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells |
| title_fullStr | Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells |
| title_full_unstemmed | Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells |
| title_short | Antisense-Based Progerin Downregulation in HGPS-Like Patients’ Cells |
| title_sort | antisense based progerin downregulation in hgps like patients cells |
| topic | HGPS-like MAD-B antisense oligonucleotides Progerin Prelamin A Δ90 Prelamin A Δ35 |
| url | http://www.mdpi.com/2073-4409/5/3/31 |
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