Histochem Cell Biol (2012) 138:643–651 DOI 10.1007/s00418-012-0977-5 O R I G I N A L P A P E R Altered chromatin organization and SUN2 localization in mandibuloacral dysplasia are rescued by drug treatment Daria Camozzi • Maria Rosaria D’Apice • Elisa Schena • Vittoria Cenni • Marta Columbaro • Cristina Capanni • Nadir M. Maraldi • Stefano Squarzoni • Michela Ortolani • Giuseppe Novelli • Giovanna Lattanzi Accepted: 20 May 2012 / Published online: 17 June 2012 The Author(s) 2012. This article is published with open access at Springerlink.com Abstract Mandibuloacral dysplasia type A (MADA) is a rare laminopathy characterized by growth retardation, craniofacial anomalies, bone resorption at speciﬁc sites including clavicles, phalanges and mandibula, mottled cutaneous pigmentation, skin rigidity, partial lipodystro- phy, and insulin resistance. The disorder is caused by recessive mutations of the LMNA gene encoding for A-type lamins. The molecular feature of MADA consists in the accumulation of the unprocessed lamin A precursor, which is detected at the nuclear rim and in intranuclear aggre- gates. Here, we report the characterization of prelamin A post-translational modiﬁcations in MADA cells that induce Electronic supplementary material The online version of this article (doi:10.1007/s00418-012-0977-5) contains supplementary material, which is available to authorized users. D. Camozzi V. Cenni C. Capanni N. M. Maraldi S. Squarzoni M. Ortolani G. Lattanzi (&) Institute of Molecular Genetics, Unit of Bologna IOR, National Research Council of Italy - CNR, Via di Barbiano 1/10, 40136 Bologna, Italy e-mail: lattanzi@area.bo.cnr.it; giovanna.lattanzi@cnr.it M. R. D’Apice G. Novelli Department of Biopathology and Diagnostic Imaging, University of Tor Vergata, Rome, Italy E. Schena M. Columbaro N. M. Maraldi Laboratory of Musculoskeletal Cell Biology, RAMSES, Rizzoli Orthopedic Institute, Via di Barbiano 1/10, 40136 Bologna, Italy G. Novelli National Agency for the Evaluation of Universities and Research (ANVUR), Rome, Italy G. Novelli St. Peter Fatebenefratelli Hospital, Rome, Italy alterations in the chromatin arrangement and dislocation of nuclear envelope-associated proteins involved in correct nucleo-cytoskeleton relationships. We show that protein post-translational modiﬁcations change depending on the passage number, suggesting the onset of a feedback mechanism. Moreover, we show that treatment of MADA cells with the farnesyltransferase inhibitors is effective in the recovery of the chromatin phenotype, altered in MADA, provided that the cells are at low passage number, while at high passage number, the treatment results inef- fective. Moreover, the distribution of the lamin A interac- tion partner SUN2, a constituent of the nuclear envelope, is altered by MADA mutations, as argued by the formation of a highly disorganized lattice. Treatment with statins par- tially rescues proper SUN2 organization, indicating that its alteration is caused by farnesylated prelamin A accumu- lation. Given the major role of SUN1 and SUN2 in the nucleo-cytoskeleton interactions and in regulation of nuclear positioning in differentiating cells, we hypothesise that mechanisms regulating nuclear membrane–centrosome interplay and nuclear movement may be affected in MADA ﬁbroblasts. Keywords Mandibuloacral dysplasia type A (MADA) Prelamin A forms SUN2 Heterochromatin defects Statins Trichostatin A Introduction Mandibuloacral dysplasia type A [MADA; Online Men- delian Inheritance in Man (OMIM) no. 248370] is a rare and complex laminopathy characterized by postnatal growth retardation, craniofacial anomalies, bone resorption at speciﬁc sites including clavicles, phalanges and 123