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

The autosomal recessive mandibuloacral dysplasia (MADA; OMIM #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 proteins HP1beta and histone H3 methylated at lysine 9 and their nuclear envelope partner protein lamin B receptor (LBR) are delocalised and solubilised. Both accumulation of lamin A precursor and chromatin defects become more severe in older patients. These results strongly suggest that altered chromatin remodelling is a key event in the cascade of epigenetic events causing MADA and could be related to the premature aging phenotype.