Journal
PHYSIOLOGICAL GENOMICS
Volume 23, Issue 2, Pages 150-158Publisher
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/physiolgenomics.00060.2005
Keywords
LMNA; heterochromatin; heterochromatin protein-1 beta; prelamin A
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Funding
- Telethon [GGP030213] Funding Source: Medline
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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 HP1 beta 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.
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