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

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.

• Authors: 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
• Journal: European journal of human genetics : EJHG (Eur J Hum Genet) Vol. 23 Issue 8 Pg. 1051-61 (Aug 2015) ISSN: 1476-5438 [Electronic] England
• PMID: 25649378 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• LMNA protein, human
• Lamin Type A
• Protein Precursors
• RNA Splice Sites

Topics

• Aging, Premature (genetics, pathology)
• Female
• Fibroblasts
• Gene Expression Regulation
• Humans
• Lamin Type A (biosynthesis, genetics)
• Male
• Mutation
• Pedigree
• Progeria (genetics, pathology)
• Protein Precursors (genetics)
• RNA Splice Sites (genetics)
• RNA Splicing
• Transcription, Genetic