title: Alterations of nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy.
abstract: 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.
authors.affiliation: Laboratory of Clinical Biochemistry and Department of Neuroscience, University of Roma Tor Vergata, Rome, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Filesi
authors.forename: Francesca
authors.initials: F
authors.lastname: Gullotta
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lattanzi
authors.forename: Maria Rosaria
authors.initials: MR
authors.lastname: D'Apice
authors.forename: Cristina
authors.initials: C
authors.lastname: Capanni
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Nardone
authors.forename: Marta
authors.initials: M
authors.lastname: Columbaro
authors.forename: Gioacchino
authors.initials: G
authors.lastname: Scarano
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Mattioli
authors.forename: Patrizia
authors.initials: P
authors.lastname: Sabatelli
authors.forename: Nadir M
authors.initials: NM
authors.lastname: Maraldi
authors.forename: Silvia
authors.initials: S
authors.lastname: Biocca
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Novelli
mesh_terms: 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
chemical_list: 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