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.
Pubmed ID: 27409638 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
The mission of the Arabidopsis Biological Resource Center (ABRC) is to acquire, preserve and distribute seed and DNA resources that are useful to the Arabidopsis research community. More than 100,000 stocks are shipped annually to researchers in more than 60 countries, and modest fees for stocks are charged. The ABRC database functions and ordering system are incorporated into The Arabidopsis Information Resource (TAIR). Researchers can obtain information about Arabidopsis, perform stock searches, order stocks, and view current and past orders. Sponsors: ABRC is supported by the National Science Foundation under Grant No. 0542034.
View all literature mentionsThe mission of The Progeria Research Foundation is to discover treatments and the cure for Progeria, and its aging related disorders. Progeria is a rare and fatal genetic disease characterized by an appearance of accelerated aging in children. Without the discovery of new treatments, all children with Progeria will die of heart disease at an average age of 13 years. The Progeria Research Foundation (PRF) was founded in 1999 in response to the complete lack of progress being made to help children with Progeria. We have filled a void, taking these children out of the background where they had been for over 100 years and putting them and Progeria at the forefront of scientific efforts. In just 11.5 years, we have achieved extraordinary progress towards our mission: the Progeria gene discovery in 2003, first-ever clinical drug trials initiated in 2007, extensive global awareness of the disease and PRF''s work, and discovery of critical biological links between Progeria, heart disease and aging we all experience.
View all literature mentions