Alterations of nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy

Ilaria Filesi, Francesca Gullotta, Giovanna Lattanzi, Maria Rosaria D'Apice, Cristina Capanni, Anna Maria Nardone, Marta Columbaro, Gioacchino Scarano, Elisabetta Mattioli, Patrizia Sabatelli, Nadir M. Maraldi, Silvia Biocca, Giuseppe Novelli

Research output: Contribution to journalArticlepeer-review

Abstract

Autosomal recessive mandibuloacral dysplasia [mandibuloacral dysplasia type A (MADA); Online Mendelian Inheritance in Man (OMIM) no. 248370] is caused by a mutation in LMNA encoding lamin A/C. Here we show that this mutation causes accumulation of the lamin A precursor protein, a marked alteration of the nuclear architecture and, hence, chromatin disorganization. Heterochromatin domains are altered or completely lost in MADA nuclei, consistent with the finding that heterochromatin-associated protein HP1β and histone H3 methylated at lysine 9 and their nuclear envelope partner protein lamin B receptor (LBR) are delocalized and solubilized. Both accumulation of lamin A precursor and chromatin defects become more severe in older patients. These results strongly suggest that altered chromatin remodeling is a key event in the cascade of epigenetic events causing MADA and could be related to the premature-aging phenotype.

Original languageEnglish
Pages (from-to)150-158
Number of pages9
JournalPhysiol Genomics
Volume23
Issue number2
DOIs
Publication statusPublished - Oct 17 2005

Keywords

  • Heterochromatin
  • Heterochromatin protein-1β
  • LMNA
  • Prelamin A

ASJC Scopus subject areas

  • Physiology
  • Genetics

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