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

Author:

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

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.

Publisher

American Physiological Society

Subject

Genetics,Physiology

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