Truncated prelamin A expression in HGPS-like patients: A transcriptional study

Florian Barthélémy, Claire Navarro, Racha Fayek, Nathalie Da Silva, Patrice Roll, Sabine Sigaudy, Junko Oshima, Gisèle Bonne, Kyriaki Papadopoulou-Legbelou, Athanasios E. Evangeliou, Martha Spilioti, Martine Lemerrer, Ron A. Wevers, Eva Morava, Andrée Robaglia-Schlupp, Nicolas Lévy, Marc Bartoli, Annachiara De Sandre-Giovannoli

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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.

Original languageEnglish (US)
Pages (from-to)1051-1061
Number of pages11
JournalEuropean Journal of Human Genetics
Volume23
Issue number8
DOIs
StatePublished - Aug 21 2015

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

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. (2015). Truncated prelamin A expression in HGPS-like patients: A transcriptional study. European Journal of Human Genetics, 23(8), 1051-1061. https://doi.org/10.1038/ejhg.2014.239