Truncated prelamin A expression in HGPS-like patients: a transcriptional study.
Τίτλος | Truncated prelamin A expression in HGPS-like patients: a transcriptional study. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Barthélémy, F., Navarro C., Fayek R., Da Silva N., Roll P., Sigaudy S., Oshima J., Bonne G., Papadopoulou-Legbelou K., Evangeliou A. E., Spilioti M., Lemerrer M., Wevers R. A., Morava E., Robaglia-Schlupp A., Lévy N., Bartoli M., & De Sandre-Giovannoli A. |
Journal | Eur J Hum Genet |
Volume | 23 |
Issue | 8 |
Pagination | 1051-61 |
Date Published | 2015 Aug |
ISSN | 1476-5438 |
Abstract | Premature aging syndromes are rare genetic disorders mimicking clinical and molecular features of aging. A recently identified group of premature aging syndromes is linked to mutation of the LMNA gene encoding lamins A and C, and is associated with nuclear deformation and dysfunction. Hutchinson-Gilford progeria syndrome (HGPS) was the first premature aging syndrome linked to LMNA mutation and its molecular bases have been deeply investigated. It is due to a recurrent de novo mutation leading to aberrant splicing and the production of a truncated and toxic nuclear lamin A precursor (prelamin AΔ50), also called progerin. In this work and based on the literature data, we propose to distinguish two main groups of premature aging laminopathies: (1) HGPS and HGP-like syndromes, which share clinical features due to hampered processing and intranuclear toxic accumulation of prelamin A isoforms; and (2) APS (atypical progeria syndromes), due to dominant or recessive missense mutations affecting lamins A and C. Among HGPS-like patients, several deleted prelamin A transcripts (prelamin AΔ50, AΔ35 and AΔ90) have been described. The purpose of this work was to characterize those transcripts in eight patients affected with HGP-like rare syndromes. When fibroblasts were available, the relationships between the presence and ratios of these transcripts and other parameters were studied, aiming to increase our understanding of genotype-phenotype relationships in HGPS-like patients. Altogether our results evidence that progerin accumulation is the major pathogenetic mechanism responsible for HGP-like syndromes due to mutations near the donor splice site of exon 11. |
DOI | 10.1038/ejhg.2014.239 |
Alternate Journal | Eur. J. Hum. Genet. |
PubMed ID | 25649378 |
PubMed Central ID | PMC4795109 |
Grant List | R24 AG042328 / AG / NIA NIH HHS / United States R24AG042328 / AG / NIA NIH HHS / United States |