emerin and Lipodystrophy--Familial-Partial

Higher-eukaryotic membrane compartmentalization of different processes provides the control of functional activity in cells. The nuclear envelope that consists of outer and inner nuclear membranes, lamina, and nuclear pore complexes is one of the most significant and complex cell compartments. It separates DNA replication and transcription in the nucleus from RNA translation in the cytoplasm and regulates the nuclear-cytoplasmic transport of different molecules. This review describes and discusses the structural organization and biochemical composition of different nuclear envelope components (except nuclear pore complexes, which were discussed in our previous review) as well as its dynamics during mitosis in vitro and in vivo. Special attention is given to the role of lamina in a group of human genetic diseases, collectively referred to as laminopathies.

Topics: Animals; Chordata; Drosophila; Eukaryotic Cells; Humans; Lamin Type A; Lipodystrophy, Familial Partial; Membrane Proteins; Mitosis; Muscular Dystrophy, Emery-Dreifuss; Mutation; Nuclear Envelope; Nuclear Lamina; Nuclear Proteins

Lamin A/C proteins are the major components of a thin proteinaceous filamentous meshwork, the lamina, that underlies the inner nuclear membrane. A few specific mutations in the lamin A/C gene cause a disease with remarkably different clinical features: FPLD, or familial partial lipodystrophy (Dunnigan-type), which mainly affects adipose tissue. Lamin A/C mutant R482W is the key variant that causes FPLD. Biomolecular interaction and molecular dynamics (MD) simulation analysis were performed to understand dynamic behavior of native and mutant structures at atomic level. Mutant lamin A/C (R482W) showed more interaction with its biological partners due to its expansion of interaction surface and flexible nature of binding residues than native lamin A/C. MD simulation clearly indicates that the flexibility of interacting residues of mutant are mainly due to less involvement in formation of inter and intramolecular hydrogen bonds. Our analysis of native and Mutant lamin A/C clearly shows that the structural and functional consequences of the mutation R482W causes FPLD. Because of the pivotal role of lamin A/C in maintaining dynamics of nuclear function, these differences likely contribute to or represent novel mechanisms in laminopathy development.

Topics: Amino Acid Substitution; Humans; Hydrogen Bonding; Hydrophobic and Hydrophilic Interactions; Lamin Type A; Lipodystrophy, Familial Partial; Membrane Proteins; Molecular Dynamics Simulation; Nuclear Proteins; Principal Component Analysis; Protein Binding; Protein Structure, Secondary; Protein Structure, Tertiary; Sterol Regulatory Element Binding Protein 1; Thermodynamics

Prelamin A processing impairment is a common feature of a restricted group of rare genetic alterations/disorders associated with a wide range of clinical phenotypes. Changes in histone posttranslational modifications, alterations in non-histone chromatin proteins and chromatin disorganization have been specifically linked to impairment of specific, distinct prelamin A processing steps, but the molecular mechanism involved in these processes is not yet understood . In this study, we show that the accumulation of wild-type prelamin A detected in restrictive dermopathy (RD), as well as the accumulation of mutated forms of prelamin A identified in familial partial lipodystrophy (FPLD) and mandibuloacral dysplasia (MADA), affect the nuclear localization of barrier-to-autointegration factor (BAF), a protein able to link lamin A precursor to chromatin remodeling functions. Our findings, in accordance with previously described results, support the hypothesis of a prelamin A involvement in BAF nuclear recruitment and suggest BAF-prelamin A complex as a protein platform usually activated in prelamin A-accumulating diseases. Finally, we demonstrate the involvement of the inner nuclear membrane protein emerin in the proper localization of BAF-prelamin A complex.

Topics: Acro-Osteolysis; Adult; Animals; Cell Nucleus; Contracture; DNA-Binding Proteins; HEK293 Cells; Humans; Infant, Newborn; Lamin Type A; Lipodystrophy; Lipodystrophy, Familial Partial; Mandible; Membrane Proteins; Mutant Proteins; Nuclear Proteins; Protein Binding; Protein Precursors; Protein Transport; Rats; Skin Abnormalities; Transfection

A number of diseases associated with specific tissue degeneration and premature aging have mutations in the nuclear envelope proteins A-type lamins or emerin. Those diseases with A-type lamin mutation are inclusively termed laminopathies. Due to various hypothetical roles of nuclear envelope proteins in genome function we investigated whether alterations to normal genomic behaviour are apparent in cells with mutations in A-type lamins and emerin. Even though the distributions of these proteins in proliferating laminopathy fibroblasts appear normal, there is abnormal nuclear positioning of both chromosome 18 and 13 territories, from the nuclear periphery to the interior. This genomic organization mimics that found in normal nonproliferating quiescent or senescent cells. This finding is supported by distributions of modified pRb in the laminopathy cells. All laminopathy cell lines tested and an X-linked Emery-Dreifuss muscular dystrophy cell line also demonstrate increased incidences of apoptosis. The most extreme cases of apoptosis occur in cells derived from diseases with mutations in the tail region of the LMNA gene, such as Dunningan-type familial partial lipodystrophy and mandibuloacral dysplasia, and this correlates with a significant level of micronucleation in these cells.

Topics: Aging, Premature; Apoptosis; Cell Line; Cell Proliferation; Fibroblasts; Genome, Human; Humans; Lamin Type A; Lipodystrophy, Familial Partial; Membrane Proteins; Muscular Dystrophy, Emery-Dreifuss; Nuclear Envelope; Nuclear Proteins