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1 Laboratory of Clinical Biochemistry and Department of Neuroscience, University of Roma Tor Vergata, Roma, Italy
2 Laboratory of Medical Genetics, University of Roma Tor Vergata, Roma, Italy
3 CNR, Unit of Bologna, ITOI, Bologna, Italy
4 Cell Biology, Istituti Ortopedici Rizzoli, Bologna, Italy
5 Medical Genetics, Hospital of Benevento, Benevento, Italy
6 CNR, Unit of Bologna, ITOI, Bologna, Italy; Cell Biology, Istituti Ortopedici Rizzoli, Bologna, Italy
* To whom correspondence should be addressed. E-mail: novelli{at}med.uniroma2.it.
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 HP1
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.
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