Alterations of nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy.
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 HP1beta 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.
Filesi
Ilaria
I
Laboratory of Clinical Biochemistry and Department of Neuroscience, University of Roma Tor Vergata, Rome, Italy.
Gullotta
Francesca
F
Lattanzi
Giovanna
G
D'Apice
Maria Rosaria
MR
Capanni
Cristina
C
Nardone
Anna Maria
AM
Columbaro
Marta
M
Scarano
Gioacchino
G
Mattioli
Elisabetta
E
Sabatelli
Patrizia
P
Maraldi
Nadir M
NM
Biocca
Silvia
S
Novelli
Giuseppe
G
D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D005147:Facial Bones / Q000002:abnormalities*; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000473:pathology / Q000648:ultrastructure; D006570:Heterochromatin / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D034904:Lamin Type A / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009685:Nuclear Envelope / Q000378:metabolism* / Q000648:ultrastructure; D009687:Nuclear Proteins / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D013194:Staining and Labeling; D000097682:Lamin B Receptor
D000090266:Chromobox Protein Homolog 5; D002868:Chromosomal Proteins, Non-Histone; D006570:Heterochromatin; D006657:Histones; D034904:Lamin Type A; D009687:Nuclear Proteins; D011498:Protein Precursors; D018160:Receptors, Cytoplasmic and Nuclear; D000097682:Lamin B Receptor; C000715593:CBX1 protein, human; C090764:prelamin A