Disease relevance of EMD

• Emerin is the gene product of STA whose mutations cause Emery-Dreifuss muscular dystrophy [1].
• Mouse embryo fibroblasts ablated for emerin protein through gene knockout support the same level of HIV-1 infection as cells derived from wild-type littermate control animals [2].
• Wild-type levels of human immunodeficiency virus type 1 infectivity in the absence of cellular emerin protein [2].
• Mutations in emerin and nuclear lamins have been associated with muscular dystrophies and lipodystrophy, raising new questions about the functions of inner nuclear membrane proteins [3].
• Loss of emerin, a nuclear membrane protein, causes Emery-Dreifuss muscular dystrophy (EDMD), characterized by muscle weakening, contractures of major tendons and potentially lethal cardiac conduction system defects [4].
• Mutations in EMD may indicate a limb-girdle muscular dystrophy phenotype [5].

Psychiatry related information on EMD

• RESULTS: After EMD, rapid eye movement (REM) sleep was nearly totally abolished [6].
• In view of the only moderate antipsychotic efficacy in acute schizophrenia and the fact that antidepressant and anxiolytic effects were also observed, a clinical investigation of EMD 49980 in affective disorders and in schizophrenia with depression or anergia should be performed [7].
• Pretreatment with EMD 281014 prevented the DOI-induced increase of waking and light sleep and the reduction of slow wave sleep [8].
• Psychometric analysis demonstrated that EMD was superior to placebo in regard to general, associative and numeric memory, concentration and attention variability, psychomotor activity, affect and mood, while the Benton test and attention showed opposite findings [9].
• In a clinical trial of 30 patients suffering from psychovegetative disorders and anxiety neuroses, Mepiprazol (test designation: EMD 16-923; supplier: E. Merck, Darmstadt, FRG) was proven in a treatment period of 14 days to be an effective, well-tolerated medication [10].

High impact information on EMD

• Together with mutations in EMD (refs 5,6), they underscore the potential importance of the nuclear envelope components in the pathogenesis of neuromuscular disorders [11].
• We have mapped the locus for EDMD-AD to an 8-cM interval on chromosome 1q11-q23 in a large French pedigree, and found that the EMD phenotype in four other small families was potentially linked to this locus [11].
• The emerin gene, located in human Xq28, is approximately 2 kb in length, is composed of 6 exons and falls within a 219-kb region that has been completely sequenced [12].
• The high level of genomic detail in this region allowed us to characterize the first complete emerin gene deletion mutation that also involved a partial duplication of the nearby FLN1 gene [12].
• Emerin deletion reveals a common X-chromosome inversion mediated by inverted repeats [12].

Chemical compound and disease context of EMD

• The Emery-Dreifuss muscular dystrophy associated-protein emerin is phosphorylated on serine 49 by protein kinase A [13].
• Prosthetic heart valve sewing rings were impregnated with gentamicin crobefat (EMD 46217), a poorly soluble gentamicin salt, gentamicin sulfate, and clindamycin palmitate to prevent early prosthetic endocarditis [14].
• We hypothesized that ET(A) blockers (EMD 122946 and BQ 610) would reduce hypoxia-induced (HYP) but not group B streptococcal infusion (GBS)-induced pulmonary hypertension in a juvenile whole animal model [15].
• Phase I study of the humanised anti-EGFR monoclonal antibody matuzumab (EMD 72000) combined with gemcitabine in advanced pancreatic cancer [16].
• Treatment of Parkinson's disease with the partial dopamine agonist EMD 49980 [17].

Biological context of EMD

• However, the means of phosphorylation of emerin are poorly understood [1].
• Emerin binding to Btf, a death-promoting transcriptional repressor, is disrupted by a missense mutation that causes Emery-Dreifuss muscular dystrophy [18].
• MAN1 and emerin have overlapping function(s) essential for chromosome segregation and cell division in Caenorhabditis elegans [19].
• Biochemical roles for emerin in gene expression are discussed [20].
• During telophase, emerin accumulates briefly at the 'core' region of telophase chromosomes, and later distributes over the entire nuclear rim [21].

Anatomical context of EMD

• Direct binding of nuclear membrane protein MAN1 to emerin in vitro and two modes of binding to barrier-to-autointegration factor [22].
• We investigated the regulation mechanism for the binding of emerin to chromatin, focusing on its cell cycle-dependent phosphorylation in a Xenopus egg cell-free system [1].
• In a yeast two-hybrid screen, we found that emerin interacts with Btf, a death-promoting transcriptional repressor, which is expressed at high levels in skeletal muscle [18].
• In contrast, lamin B1 was absent from cardiomyocyte nuclei, showing that lamin B1 is not essential for localization of emerin to the nuclear lamina [23].
• Although emerin was abundant in the membranes of cardiomyocyte nuclei, it was absent from many non-myocyte cells in the heart [23].

Associations of EMD with chemical compounds

• Using a collection of 21 clustered alanine-substitution mutations in emerin, the residues required for binding to Btf mapped to two regions of emerin that flank its lamin-binding domain [18].
• Biochemical fractionation of brain and liver tissues showed that emerin was present in nuclei purified by centrifugation through 65% sucrose and was absent from soluble fractions (post-100,000 g) [24].
• The emerin gene has been mapped to Xq28 and encodes a 34-kDa serine-rich protein, emerin, which has been localized to the nuclear envelope in a wide variety of tissues, including skeletal and cardiac muscle [25].
• These studies demonstrate the importance of proline 183 for the proper structure/function of emerin [25].
• Tyrosine Y-94/Y-95 is located adjacent to a five-residue motif in human emerin, whose deletion has been associated with X-linked Emery-Dreifuss muscle dystrophy [26].
• Some emerin hyperphosphorylation can be inhibited by the protein kinase Cdelta (PKCdelta) inhibitor rottlerin [27].

Physical interactions of EMD

• Biochemical analysis showed that emerin binds Btf with an equilibrium affinity (KD) of 100 nm [18].
• GCL co-immunoprecipitates with emerin from HeLa cells [20].
• MAN1 is an integral protein of the inner nuclear membrane that interacts with nuclear lamins and emerin, thus playing a role in nuclear organization [28].
• Binding was optimal for full nucleoplasmic dimers of nesprin-1alpha, since nesprin fragments SR1-5 and SR5-7 bound emerin as monomers with affinities of 53 nM and 250 mM, respectively [29].
• We then used a synthetic flavonoid (EMD) that competitively inhibits binding of T4 to serum TTR and transiently increases serum free T4 to determine the role of choroid plexus TTR and CSF TTR in the transport of T4 from serum to brain [30].

Regulatory relationships of EMD

• Dissociation of emerin from barrier-to-autointegration factor is regulated through mitotic phosphorylation of emerin in a xenopus egg cell-free system [1].
• The inner nuclear membrane protein emerin regulates beta-catenin activity by restricting its accumulation in the nucleus [31].

Other interactions of EMD

• The other region, MAN1-N, bound directly to BAF, lamin A, and lamin B1, supporting functional overlap with emerin [22].
• Proposed MAN1-emerin complexes are discussed in the context of EDMD disease mechanisms and potential in vivo functions [22].
• Two disease-causing mutations in emerin, S54F and Delta95-99, disrupted binding to Btf [18].
• The Delta95-99 mutation was relatively uninformative, as this mutation also disrupts emerin binding to lamin A and a different transcription repressor named germ cell-less (GCL) [18].
• Inhibition by emerin of YT521-B-dependent splice site selection in vivo suggests that the interaction is physiologically significant [32].

Analytical, diagnostic and therapeutic context of EMD

• We used a high-stringency yeast two-hybrid method to screen a human heart cDNA library, with full-length emerin as bait [32].
• We used site-directed mutagenesis and biochemical analysis to map functionally important residues in human BAF, including those required for direct binding to DNA or emerin [33].
• A muscle biopsy from an Emery-Dreifuss muscular dystrophy (EMDM) patient showed complete absence of emerin by both Western blotting and immunohistochemistry, suggesting a simple diagnostic antibody test for EDMD families [24].
• Immunofluorescence microscopy showed that emerin is located at the nuclear rim in all tissues examined [24].
• A large fragment of emerin cDNA was prepared by PCR and expressed as a recombinant protein in Escherichia coli [24].

References