Discordant gene expression signatures and related phenotypic differences in lamin A- and A/C-related Hutchinson-Gilford progeria syndrome (HGPS)
| Autor: | Karl Heinimann, Martina Plasilova, Apurba Ghosh, Friedel Wenzel, Philippe Demougin, Christoph Noppen, Luigi Terracciano, Chandon Chattopadhyay, Gabor Szinnai, Nathalie Schaub |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Male
Anatomy and Physiology Fluorescent Antibody Technique Gene Expression lcsh:Medicine Biochemistry LMNA Progeria Endocrinology Gene expression Molecular Cell Biology Insulin Pyrophosphatases Child lcsh:Science Cells Cultured Genetics Multidisciplinary integumentary system Genetic disorder Lamin Type A Phenotype Nuclear lamina Medicine Research Article congenital hereditary and neonatal diseases and abnormalities Bone and Mineral Metabolism Blotting Western Endocrine System Dermatology Biology Real-Time Polymerase Chain Reaction Molecular Genetics Young Adult Germline mutation Rheumatology medicine Humans Clinical Genetics Diabetic Endocrinology Endocrine Physiology Phosphoric Diester Hydrolases Gene Expression Profiling Twist-Related Protein 1 lcsh:R Osteoprotegerin Personalized Medicine Computational Biology nutritional and metabolic diseases Human Genetics medicine.disease Repressor Proteins Metabolism Genetics of Disease Cancer research lcsh:Q Physiological Processes Lamin |
| Zdroj: | PLoS ONE, Vol 6, Iss 6, p e21433 (2011) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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