Discordant Gene Expression Signatures and Related Phenotypic Differences in Lamin A- and A/C-Related Hutchinson-Gilford Progeria Syndrome (HGPS)

• DOI: 10.1371/journal.pone.0021433
• Publication Date: 2011-06-27T21:52:01Z
• Authors: Martina Plasilova; Chandon Chattopad...; Apurba Ghosh; Friedel Wenzel; Philippe Demougin; Christoph Noppen; Nathalie Schaub; Gabor Szinnai; Luigi Terracciano; Karl Heinimann
• Keywords: LMNA; Progeria; Nuclear lamina; Premature aging; Molecular Genetics

Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disorder displaying features reminiscent of premature senescence caused by germline mutations in the LMNA gene encoding lamin A and C, essential components nuclear lamina. By studying family with homozygous mutation (K542N), we showed that HGPS can also be affecting both isoforms, C. Here, aimed to elucidate molecular mechanisms underlying pathogenesis both, A- (sporadic) C-related (hereditary) HGPS. For this, performed detailed studies on primary fibroblasts hetero- K542N carriers, accompanied clinical examinations related findings. assessing global expression found substantial overlap altered transcription profiles (13.7%; 90/657) sporadic hereditary HGPS, 83.3% (75/90) concordant 16.7% (15/90) discordant transcriptional changes. Among ones observed down-regulation TWIST2, whose inactivation mice humans leads loss subcutaneous fat dermal appendages, periadnexial cells from LMNAK542N/K542N patient further confirming its pivotal role skin development. identified two key mediators vascular calcification bone metabolism, ENPP1 OPG, which offer explanation for major phenotypic differences disease Finally, this study correlates reduced TWIST2 OPG increased osteocalcin levels, thereby linking remodeling energy homeostasis