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.
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Acknowledgements
We acknowledge Danielle Depetris for her excellent technical assistance and Xavier Nissan (iSTEM, Paris) for kindly providing us with the real-time RT-PCR probe used to detect dermopathin. This work was supported by the Association Française contre les Myopathies (AFM), Institut National de la Santé et de la Recherche Médicale (INSERM) and a grant from NIH/NIA R24AG042328 (JO). FB and RF have received PhD fellowship grants from the Fondation pour la Recherche Médicale and INSERM regional fellowship, respectively.
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Barthélémy, F., Navarro, C., Fayek, R. et al. Truncated prelamin A expression in HGPS-like patients: a transcriptional study. Eur J Hum Genet 23, 1051–1061 (2015). https://doi.org/10.1038/ejhg.2014.239
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DOI: https://doi.org/10.1038/ejhg.2014.239
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