Distinct regions specify the nuclear membrane targeting of emerin, the responsible protein for Emery-Dreifuss muscular dystrophy. (1/97)

Emery-Dreifuss muscular dystrophy is a neuromuscular disorder that has three characteristics: (a) early contracture of the elbows, Achilles tendons and postcervical muscles; (b) slowly progressive wasting and weakness of skeletal muscle; and (c) cardiomyopathy with severe conduction block. The responsible gene for the X-linked recessive form of this disease encodes an inner nuclear membrane protein named emerin. Although emerin is absent in tissues from patients with this disorder, it remains obscure why the loss of this widely expressed protein affects selectively skeletal muscle, heart and joints. As the first step to address this question, we examined the molecular regions of emerin that are essential for nuclear membrane targeting and stability of the protein. We found that the C-terminal hydrophobic region was necessary, but not sufficient, for nuclear membrane anchoring and stability of the protein. In the absence of this transmembrane domain, the upstream nucleoplasmic domain showed no firm association with the nuclear rim, but showed the tendency to accumulate at the nucleolus-like structures. Furthermore, proper targeting of emerin to the nuclear membrane required the latter half of the nucleoplasmic domain. These characteristics are distinct from those of lamina-associated polypeptide 2. Our findings indicate that emerin has distinct interactions with the inner nuclear membrane components that may be required for the stability and function of rigorously moving nuclei in tissues such as skeletal muscle, heart and joints.  (+info)

Intracellular trafficking of emerin, the Emery-Dreifuss muscular dystrophy protein. (2/97)

Emerin is an integral protein of the inner nuclear membrane that is mutated or not expressed in patients with Emery-Dreifuss muscular dystrophy. Confocal immunofluorescence microscopy studies of the intracellular targeting of truncated forms of emerin, some of which are found in patients with Emery-Dreifuss muscular dystrophy, show that the nucleoplasmic, amino-terminal domain is necessary and sufficient for nuclear retention. When this domain is fused to a transmembrane segment of an integral membrane protein of the ER/plasma membrane, the chimeric protein is localized in the inner nuclear membrane. The transmembrane segment of emerin is not targeted to the inner nuclear membrane. Fluorescence photobleaching experiments of emerin fused to green fluorescent protein demonstrate that the diffusional mobility (D) of emerin is decreased in the inner nuclear membrane (D=0.10+/-0.01 microm2/second) compared to the ER membrane (D=0.32+/-0.01 microm2/second). This is in agreement with a model where integral proteins reach the inner nuclear membrane by lateral diffusion and are retained there by association with nucleoplasmic components. Some overexpressed emerin-green fluorescent protein also reaches the plasma membrane of transfected cells, where its diffusion is similar to that in the inner nuclear membrane, suggesting that emerin may also associate with non-nuclear structures.  (+info)

Cardiac involvement in Emery Dreifuss muscular dystrophy: a case series. (3/97)

Three patients with Emery Dreifuss muscular dystrophy are reported. Emery Dreifuss muscular dystrophy is an X linked muscular dystrophy, in which locomotor involvement is characteristically mild and slowly progressive. The effect on the heart becomes apparent in the teenage years and is characterised by cardiac conduction defects and infiltration of the myocardium by fibrous and adipose tissue. It first affects the atria, which results in atrial paralysis; treatment with ventricular pacing is usually needed. Female carriers can develop heart problems and are at risk of sudden death. Relatives of affected patients should be offered screening with electrocardiography and echocardiography.  (+info)

The Emery-Dreifuss muscular dystrophy phenotype arises from aberrant targeting and binding of emerin at the inner nuclear membrane. (4/97)

The product of the X-linked Emery-Dreifuss muscular dystrophy gene is a single-membrane-spanning protein called emerin, which is localized to the inner nuclear membrane of all tissues studied. To examine whether a number of the mutant forms of emerin expressed in patients are mislocalized, we transfected GFP-emerin cDNA constructs reflecting these mutations into undifferentiated C2C12 myoblasts and showed that both wild type and all the mutant emerins are targeted to the nuclear membrane, but the mutants to a lesser extent. Mutant Del236-241 (deletion in transmembrane region) was mainly expressed as cytoplasmic aggregates, with only trace amounts at the nuclear envelope. Complete removal of the transmembrane region and C-terminal tail relocated emerin to the nucleoplasm. Mutations in emerin's N-terminal domain had a less severe effect on disrupting nuclear envelope targeting. This data suggests that emerin contains multiple non-overlapping nuclear-membrane-targeting determinants. Analysis of material immunoisolated using emerin antibodies, from either undifferentiated C2C12 myoblasts or purified hepatocyte nuclei, demonstrated that both A- and B-type lamins and nuclear actin interact with emerin. This is the first report of proteins interacting with emerin. The EDMD phenotype can thus arise by either the absence or a reduction in emerin at the nuclear envelope, and both of these disrupt its interactions with that of structural components of the nucleus. We propose that an emerin-nuclear protein complex exists at the nuclear envelope and that one of its primary roles is to stabilize the nuclear membrane against the mechanical stresses that are generated in muscle cells during contraction.  (+info)

Heart to heart: from nuclear proteins to Emery-Dreifuss muscular dystrophy. (5/97)

Emery-Dreifuss muscular dystrophy has some remarkably specific features, with only cardiac and skeletal tissues being affected. Equally remarkably, the disease is caused by mutations in widely expressed genes for the nuclear membrane/lamina proteins, emerin and lamin A/C. How do mutations in proteins at the heart of the cell lead to stiff joints and sudden heart failure? This and related questions are the subject of this review.  (+info)

Live fluorescence imaging reveals early recruitment of emerin, LBR, RanBP2, and Nup153 to reforming functional nuclear envelopes. (6/97)

We determined the times when the nuclear membrane, nuclear pore complex (NPC) components, and nuclear import function were recovered during telophase in living HeLa cells. Simultaneous observation of fluorescently-labeled NLS-bearing proteins, lamin B receptor (LBR)-GFP, and Hoechst33342-stained chromosomes revealed that nuclear membranes reassembled around chromosomes by 5 minutes after the onset of anaphase (early telophase) whereas nuclear import function was recovered later, at 8 minutes. GFP-tagged emerin also accumulated on chromosomes 5 minutes after the onset of anaphase. Interestingly, emerin and LBR initially accumulated at distinct, separate locations, but then became uniform 8 minutes after the onset of anaphase, concurrent with the recovery of nuclear import function. We further determined the timing of NPC assembly by immunofluorescence staining of cells fixed at precise times after the onset of anaphase. Taken together, these results showed that emerin, LBR, and several NPC components (RanBP2, Nup153, p62), but not Tpr, reconstitute around chromosomes very early in telophase prior to the recovery of nuclear import activity.  (+info)

MAN1, an inner nuclear membrane protein that shares the LEM domain with lamina-associated polypeptide 2 and emerin. (7/97)

The "MAN antigens" are polypeptides recognized by autoantibodies from a patient with a collagen vascular disease and localized to the nuclear envelope. We now show that one of the human MAN antigens termed MAN1 is a 82.3-kDa protein with an amino-terminal domain followed by two hydrophobic segments and a carboxyl-terminal tail. The MAN1 gene contains seven protein-coding exons and is assigned to human chromosome 12q14. Its mRNA is approximately 5.5 kilobases and is detected in several different cell types that were examined. Cell extraction experiments show that MAN1 is an integral membrane protein. When expressed in transfected cells, MAN1 is exclusively targeted to the nuclear envelope, consistent with an inner nuclear membrane localization. Protein sequence analysis reveals that MAN1 shares a conserved globular domain of approximately 40 amino acids, which we term the LEM module, with inner nuclear membrane proteins lamina-associated polypeptide 2 and emerin. The LEM module is also present in two proteins of Caenorhabditis elegans. These results show that MAN1 is an integral protein of the inner nuclear membrane that shares the LEM module with other proteins of this subcellular localization.  (+info)

Linkage of X-linked myopathy with excessive autophagy (XMEA) to Xq28. (8/97)

X-linked myopathy with excessive autophagy (XMEA, MIM 310440) is a rare inherited mild myopathy. We have used 32 polymorphic markers spanning the entire X chromosome to exclude most of the chromosome except the Xq28 region in a large XMEA family. Using three additional families for linkage analysis, we have obtained a significant two-point lod score with marker DXS1183 (Z = 2.69 at theta = 0). Multipoint linkage analysis confirmed the assignment of the disease locus with a maximal lod score of 2.74 obtained at recombination fraction zero. Linkage of XMEA to the Xq28 region is thus firmly established. In addition, we have ruled out the Emery-Dreifuss muscular dystrophy to be allelic with XMEA by direct sequencing of the emerin gene in three of our families.  (+info)

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