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

作者：Filesi I; Gullotta F; Lattanzi G; D'Apice MR; Capanni C; Nardone AM; Columbaro M; Scarano G; Mattioli E; Sabatelli P; Maraldi NM; Biocca S; Novelli G^*

来源：Physiological Genomics, 2005, 23(2): 150-158.

DOI：10.1152/physiolgenomics.00060.2005

• LMNA
• heterochromatin
• heterochromatin protein-1 beta
• prelamin A

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.

• 出版日期2005-10-17