title: Discordant gene expression signatures and related phenotypic differences in lamin A- and A/C-related Hutchinson-Gilford progeria syndrome (HGPS).
abstract: 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 of the nuclear lamina. By studying a family with homozygous LMNA mutation (K542N), we showed that HGPS can also be caused by mutations affecting both isoforms, lamin A and C. Here, we aimed to elucidate the molecular mechanisms underlying the pathogenesis in both, lamin A- (sporadic) and lamin A and C-related (hereditary) HGPS. For this, we performed detailed molecular studies on primary fibroblasts of hetero- and homozygous LMNA K542N mutation carriers, accompanied with clinical examinations related to the molecular findings. By assessing global gene expression we found substantial overlap in altered transcription profiles (13.7%; 90/657) in sporadic and hereditary HGPS, with 83.3% (75/90) concordant and 16.7% (15/90) discordant transcriptional changes. Among the concordant ones we observed down-regulation of TWIST2, whose inactivation in mice and humans leads to loss of subcutaneous fat and dermal appendages, and loss of expression in dermal fibroblasts and periadnexial cells from a LMNA(K542N/K542N) patient further confirming its pivotal role in skin development. Among the discordant transcriptional profiles we identified two key mediators of vascular calcification and bone metabolism, ENPP1 and OPG, which offer a molecular explanation for the major phenotypic differences in vascular and bone disease in sporadic and hereditary HGPS. Finally, this study correlates reduced TWIST2 and OPG expression with increased osteocalcin levels, thereby linking altered bone remodeling to energy homeostasis in hereditary HGPS.
authors: Research Group Human Genetics, Department of Biomedicine, University of Basel, and Division of Medical Genetics, University Children's Hospital, Basel, Switzerland. martina.plasilova@unibas.ch
authors: Martina
authors: M
authors: Plasilova
authors: Chandon
authors: C
authors: Chattopadhyay
authors: Apurba
authors: A
authors: Ghosh
authors: Friedel
authors: F
authors: Wenzel
authors: Philippe
authors: P
authors: Demougin
authors: Christoph
authors: C
authors: Noppen
authors: Nathalie
authors: N
authors: Schaub
authors: Gabor
authors: G
authors: Szinnai
authors: Luigi
authors: L
authors: Terracciano
authors: Karl
authors: K
authors: Heinimann
mesh_terms: D015153:Blotting, Western; D002478:Cells, Cultured; D002648:Child; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D006801:Humans; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism; D011371:Progeria / Q000235:genetics* / Q000378:metabolism*; D011755:Pyrophosphatases / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A; D053244:Osteoprotegerin; D012097:Repressor Proteins; C486274:TWIST2 protein, human; D051879:Twist-Related Protein 1; D010727:Phosphoric Diester Hydrolases; C065962:ectonucleotide pyrophosphatase phosphodiesterase 1; D011755:Pyrophosphatases