Alterations of nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy
Alterations of nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy
复制标题
DOI：
10.1152/physiolgenomics.00060.2005
复制
发表时间：
2005-10-17
影响因子：
4.6
通讯作者：
Novelli, G
中科院分区：
文献类型：
--
作者：
Filesi, I;Gullotta, F;Novelli, G
常染色体隐性下颌肢发育不良[下颌肢发育不良A型（MADA）；人类孟德尔遗传在线（OMIM）248370]是由编码层粘连蛋白a /C的LMNA突变引起的。在这里，我们表明这种突变导致层粘胶蛋白A前体蛋白的积累，核结构的显著改变，因此，染色质解体。异染色质结构域在MADA细胞核中发生改变或完全丢失，这与异染色质相关蛋白HP1 β和组蛋白H3在赖氨酸9位点甲基化及其核膜伴侣蛋白层蛋白B受体（LBR）脱位和溶解的发现一致。层粘连蛋白A前体的积累和染色质缺陷在老年患者中变得更加严重。这些结果强烈表明，染色质重塑改变是导致MADA的一系列表观遗传事件中的一个关键事件，并可能与过早衰老表型有关。
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.