title: Loss of A-type lamin expression compromises nuclear envelope integrity leading to muscular dystrophy.
abstract: The nuclear lamina is a protein meshwork lining the nucleoplasmic face of the inner nuclear membrane and represents an important determinant of interphase nuclear architecture. Its major components are the A- and B-type lamins. Whereas B-type lamins are found in all mammalian cells, A-type lamin expression is developmentally regulated. In the mouse, A-type lamins do not appear until midway through embryonic development, suggesting that these proteins may be involved in the regulation of terminal differentiation. Here we show that mice lacking A-type lamins develop to term with no overt abnormalities. However, their postnatal growth is severely retarded and is characterized by the appearance of muscular dystrophy. This phenotype is associated with ultrastructural perturbations to the nuclear envelope. These include the mislocalization of emerin, an inner nuclear membrane protein, defects in which are implicated in Emery-Dreifuss muscular dystrophy (EDMD), one of the three major X-linked dystrophies. Mice lacking the A-type lamins exhibit tissue-specific alterations to their nuclear envelope integrity and emerin distribution. In skeletal and cardiac muscles, this is manifest as a dystrophic condition related to EDMD.
authors.affiliation: Advanced BioScience Laboratories-Basic Research Program, National Cancer Institute-Frederick Cancer Research and Development Center, Maryland 21702, USA.
authors.forename: T
authors.initials: T
authors.lastname: Sullivan
authors.forename: D
authors.initials: D
authors.lastname: Escalante-Alcalde
authors.forename: H
authors.initials: H
authors.lastname: Bhatt
authors.forename: M
authors.initials: M
authors.lastname: Anver
authors.forename: N
authors.initials: N
authors.lastname: Bhat
authors.forename: K
authors.initials: K
authors.lastname: Nagashima
authors.forename: C L
authors.initials: CL
authors.lastname: Stewart
authors.forename: B
authors.initials: B
authors.lastname: Burke
mesh_terms: D000818:Animals; D005347:Fibroblasts / Q000473:pathology; D018390:Gene Targeting; D006580:Genetic Carrier Screening; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D034882:Lamins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009136:Muscular Dystrophies / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D016297:Mutagenesis, Site-Directed; D009685:Nuclear Envelope / Q000378:metabolism* / Q000473:pathology*; D009687:Nuclear Proteins / Q000096:biosynthesis* / Q000172:deficiency* / Q000235:genetics; D017384:Sequence Deletion; D014162:Transfection
chemical_list: D034882:Lamins; D009687:Nuclear Proteins