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EMERIN; EMD

EMERIN; EMD

Alternative titles; symbolsSTAHGNC Approved Gene Symbol: EMDCytogenetic location: Xq28 Genomic coordinates (GRCh38): X:154,379,235-154,381,522 (from NCBI)▼ D...

Alternative titles; symbols

  • STA

HGNC Approved Gene Symbol: EMD

Cytogenetic location: Xq28 Genomic coordinates (GRCh38): X:154,379,235-154,381,522 (from NCBI)

▼ Description
The EMD gene encodes a ubiquitous protein, emerin, that is found along the nuclear rim of many cell types and is a member of the nuclear lamina-associated protein family. Mutation in the EMD gene has been found to cause the Emery-Dreifuss type of muscular dystrophy (EDMD; 310300).

▼ Cloning and Expression
Bione et al. (1993) constructed a transcriptional map of the 2-Mb region of Xq28 to which the Emery-Dreifuss muscular dystrophy locus had been mapped by linkage studies. Within this region, they identified the STA gene. Bione et al. (1994) determined that STA (EMD) encodes a 254-amino acid protein, termed emerin, which lacks a signal peptide, contains a long N-terminal domain, and is hydrophilic except for a highly hydrophobic 20-amino acid sequence at the C-terminal region. It has several putative phosphorylation sites and 1 potential glycosylation site. Northern blot analysis demonstrated ubiquitous expression of a major, approximately 1-kb transcript, with highest expression in skeletal muscle and heart and abundant expression in other tissues, including colon, testis, ovary, and placenta. Bione et al. (1994) suggested that emerin belongs to a class of tail-anchored membrane proteins of the secretory pathway involved in vesicular transport.

Manilal et al. (1996) developed a panel of 12 monoclonal antibodies to a large fragment of emerin cDNA prepared by PCR and expressed as a recombinant protein in E. coli. These antibodies detected 4 different epitopes on emerin. All monoclonal antibodies recognized a 34-kD protein in all tissues tested. Immunofluorescence and cell fractionation studies confirmed that emerin is located in the nuclear membrane. Amino acid sequence similarities and cellular localization suggested that emerin is a member of the nuclear lamina-associated protein family.

Small et al. (1997) isolated and characterized the complete mouse emerin gene. The 2.9-kb mouse emerin gene comprises 6 exons and encodes a protein 73% identical to that of the human protein. As in the human, the gene encodes a serine-rich protein similar to lamina-associated protein-2 (LAP2; 188380) and shows critical LAP2 phosphorylation sites.

▼ Gene Structure
Bione et al. (1995) reported the sequence of the EMD gene, which is 2,100 bp long. The gene contains 6 exons.

▼ Mapping
Bione et al. (1994) identified the EMD gene on a transcriptional map of Xq28.

▼ Gene Function
Cartegni et al. (1997) reported that emerin localizes to the inner nuclear membrane via its hydrophobic C-terminal domain, but that in heart and cultured cardiomyocytes, it is also associated with the intercalated discs. They proposed a general role for emerin in membrane anchorage to the cytoskeleton. In the nuclear envelope, emerin plays a ubiquitous and indispensable role in association of the nuclear membrane with the lamina. In heart, it is specifically located to desmosomes and fasciae adherentes. Desmosomes and fasciae adherentes anchor desmin-containing intermediate filaments and the bundles of sarcomeric myofilaments, respectively. They consist of transmembrane adhesive glycoproteins, members of the cadherin superfamily, and of cytoplasmic proteins such as vinculin (193065), catenins, and actin-binding proteins. Different assortments of the same or similar proteins in desmosomes, fasciae adherentes, focal adhesions, and other adhesive junctions seem to confer specific functions to ensure cell-cell communication and tight adhesion between cells and to the extracellular matrix. The role of this complex assortment of proteins is best demonstrated by the existence of many genetic diseases that perturb adhesion and in the heart by the dramatic consequences of plakoglobin (gamma-catenin) knockout (Ruiz et al., 1996): plakoglobin -/- mice die at midgestation due to rupture of the ventricles. In heart, the specific localization of emerin to desmosomes and fasciae adherentes could account for the characteristic conduction defects described in patients with Emery-Dreifuss muscular dystrophy.

Yorifuji et al. (1997) likewise demonstrated that emerin is localized at the inner nuclear membrane. Studies for ultrastructural localization of the protein in human skeletal muscle and HeLa cells, using ultrathin cryosections, showed that immune-labeled colloidal gold particles were localized on the nucleoplasmic surface of the inner nuclear membrane, but not on the nuclear pore. They interpreted their results as indicating that emerin anchors at the inner nuclear membrane through the hydrophobic stretch and protrudes from the hydrophilic region to the nucleoplasm where it interacts with the nuclear lamina. They speculated that emerin contributes to maintenance of the nuclear structure and stability, as well as nuclear functions, particularly in muscle tissues that have severe stress with rigorous contraction-relaxation movements and calcium flux.

By mutation analysis, Lee et al. (2001) determined that several, but not all, disease mutations in emerin map to a central lamin A (LMNA; 150330)-binding domain, and that mutations in this region disrupt emerin-lamin A interaction. They also found that emerin binds directly to BAF (BANF1; 603811), a DNA-bridging protein, and this binding required conserved residues in the N-terminal LEM domain of emerin. The disease-linked emerin proteins all remained active for BAF binding both in vitro and in vivo.

Haraguchi et al. (2001) visualized colocalization between emerin and BAF at the 'core' region of chromosomes during telophase in HeLa cells. An emerin mutant defective in BAF binding in vitro failed to localize at the core in vivo and subsequently failed to localize at the reformed nuclear envelope. In HeLa cells expressing a BAF mutant that did not show core localization, endogenous emerin failed to localize at the core region during telophase and did not assemble into the nuclear envelope during the subsequent interphase. This BAF mutant also dominantly dislocalized LAP2-beta (188380) and lamin A from the nuclear envelope. Haraguchi et al. (2001) concluded that BAF is required for the assembly of emerin and A-type lamins at the reforming nuclear envelope during telophase and may mediate their stability in the subsequent interphase.

Using protein pull-down and coimmunoprecipitation assays, Libotte et al. (2005) found that a C-terminal region of the nuclear membrane scaffold protein nesprin-2 (SYNE2; 608442) bound directly to emerin in vitro and in vivo. Knockdown of nesprin-2 in COS-7 cells caused redistribution of emerin away from the nuclear envelope.

Jacque and Stevenson (2006) examined susceptibility of primary macrophages to human immunodeficiency virus (HIV)-1 infection following short interfering RNA (siRNA)-mediated silencing of nuclear lamins and several lamin-associated proteins. They found that silencing of emerin and BAF prevented infection with HIV-1, but not murine leukemia virus, by preventing integration of the virus into host DNA. Chromatin immunoprecipitation analysis identified emerin and BAF as cooperative cofactors of HIV-1, and mutation analysis showed that viral cDNA did not associate with BAF defective in emerin binding or with emerin lacking the LEM domain. Jacque and Stevenson (2006) concluded that HIV-1 cDNA, upon entering the nucleus, must interact with emerin to contact chromatin, and they suggested that molecules that prevent this interaction might promote abortive HIV-1 infection of a cell.

Using RNA interference, Huber et al. (2009) found that knockdown of Net25 (LEMD2; 616312) or emerin in C2C12 mouse myoblast cells inhibited myogenic differentiation upon shift to differentiation medium. Knockdown of either Net25 or emerin also resulted in elevated Erk1 (MAPK3; 601795) activation. Pharmacologic inhibition of Erk activation rescued myogenic differentiation in Net25- or emerin-knockdown cultures. Expression of human NET25 in mouse Net25 and emerin double-knockdown cultures also rescued differentiation, suggesting redundant roles for Net25 and emerin in C2C12 cell differentiation.

Ho et al. (2013) demonstrated that ectopic expression of emerin, which is mislocalized in Lmna-null and Lmna(N195K/N195K) (see 150330.0007) mutant cells, restored nuclear translocation of the mechanosensitive transcription factor megakaryoblastic leukemia-1 (MKL1; 606078) and rescued actin dynamics. These data indicated that emerin is a crucial modulator of actin polymerization and that loss of emerin from the nuclear envelope causes disturbed actin dynamics and impaired MKL1 signaling. Ho et al. (2013) concluded that these and other findings suggested a novel mechanism that could provide insight into the disease etiology for the cardiac phenotype in many laminopathies, whereby lamin A/C and emerin regulate gene expression through modulation of nuclear and cytoskeletal actin polymerization.

By mass spectrometric analysis, Shin et al. (2013) found that epitope-tagged human LAP1 (TOR1AIP1; 614512) interacted with emerin and lamin A in transfected HEK293 cells. Coimmunoprecipitation analysis confirmed interaction of endogenous LAP1 and emerin. Domain mapping revealed that emerin and LAP1 interacted via their nucleoplasmic domains. Use of knockout mouse fibroblasts showed that loss of Lap1 mislocalized emerin to distinct foci along the nuclear envelope, whereas loss of emerin had little effect on Lap1 localization in the nuclear envelope. Shin et al. (2013) concluded that LAP1 contributes to immobilization of emerin in the inner nuclear membrane.

▼ Molecular Genetics
In 5 patients with X-linked Emery-Dreifuss muscular dystrophy (EDMD1; 310300), Bione et al. (1994) identified mutations in the EMD gene (300384.0001-300384.0005). These mutations resulted in the loss of all or part of the protein.

Ellis et al. (1999) stated that more than 70 different mutations had been identified in the emerin gene. They described 2 missense mutations involving proline-183: P183H (300384.0008) and P183T (300384.0009). Biochemical analyses had demonstrated that the mobility and expression levels of the mutant forms of emerin are indistinguishable from those of wildtype emerin, but that they have weakened interactions with nuclear lamina components.

In a large consanguineous Algerian family segregating isolated atrial cardiac conduction defects and Emery-Dreifuss muscular dystrophy, Ben Yaou et al. (2007) identified a deletion of lys37 (delK37) in the EMD gene. Two men with EDMD were hemizygous for the mutation and homozygous for an LMNA mutation (150330.0020). Three males who were hemizygous for delK37 developed isolated atrial cardiac conduction defects in their forties; 1 asymptomatic male carrier was 32 years old. Three of 5 women heterozygous for delK37 also had cardiac disease. Ben Yaou et al. (2007) stated that this was the first report of an EMD mutation giving rise to isolated cardiac disease.

Brown et al. (2011) identified pathogenic mutations in the EMD gene in 23 (9.0%) of 255 North American patients referred for testing for EDMD. There were 8 novel and 10 recurrent mutations. Most (90.5%) of the mutations were predicted to result in a severely truncated or lack of protein. Analysis of 130 EMD mutations indicated that exon 2 may be a hotspot, perhaps owing to the high GC content.

▼ Animal Model
Frock et al. (2006) found that most cultured muscle cells from Lmna knockout mice exhibited impaired differentiation kinetics and reduced differentiation potential. Similarly, knockdown of Lmna or emerin expression by RNA interference in normal muscle cells impaired differentiation potential and reduced expression of muscle-specific genes, Myod (159970) and desmin (125660). To determine whether impaired myogenesis was linked to reduced Myod or desmin levels, Frock et al. (2006) individually expressed these proteins in Lmna-null myoblasts and found that both increased the differentiation potential of mutant myoblasts. Frock et al. (2006) concluded that LMNA and emerin are required for myogenic differentiation, at least in part, through an effect on expression of critical myoblast proteins.

Using Western blot analysis, Shin et al. (2013) confirmed that mouse skeletal muscle had diminished expression of emerin compared with human. Conversely, LAP1 expression was significantly higher in mouse than human striated muscle. Shin et al. (2013) stated that deletion of Lap1 in mice is perinatal lethal. They found that mice with conditional deletion of Lap1 in striated muscle were indistinguishable from controls at birth, but they developed progressive myopathy in several muscle groups that resulted in early death. Lap1 mutant mice also showed abnormal emerin localization in myofibers. Conditional deletion of Lap1 from liver caused no overt phenotype. Loss of emerin alone (Emd -/y mice) did not affect life span or cause any overt phenotype, but it exacerbated myopathy when combined with muscle-specific Lap1 knockout. Mice lacking striated muscle Lap1 or Lap1 and emerin also had significantly decreased left ventricular fractional shortening compared with controls. Shin et al. (2013) concluded that LAP1 and emerin interact physically and functionally in skeletal muscle maintenance, but that there are significant differences in the contributions of these proteins to myopathy in humans and mice.

▼ ALLELIC VARIANTS ( 10 Selected Examples):

.0001 EMERY-DREIFUSS MUSCULAR DYSTROPHY, X-LINKED
EMD, 2-BP DEL, NT564
Bione et al. (1994) described deletion of nucleotides 564 and 565 in the EMD gene in affected members of a family with Emery-Dreifuss muscular dystrophy (310300). This resulted in a frameshift and a stop codon after amino acid 207.

.0002 EMERY-DREIFUSS MUSCULAR DYSTROPHY, X-LINKED
EMD, MET1VAL
In affected members of a family with Emery-Dreifuss muscular dystrophy (310300), Bione et al. (1994) described an A-to-G transition at nucleotide 59 of the EMD gene, abolishing the ATG methionine initiator codon.

.0003 EMERY-DREIFUSS MUSCULAR DYSTROPHY, X-LINKED
EMD, 29-BP DEL, NT113
In the affected members of a family with Emery-Dreifuss muscular dystrophy (310300), Bione et al. (1994) found deletion of nucleotides 113 to 141 of the EMD gene, resulting in a frameshift and a stop codon after amino acid 21.

.0004 EMERY-DREIFUSS MUSCULAR DYSTROPHY, X-LINKED
EMD, 2-BP INS, NT198
In affected members of a family with Emery-Dreifuss muscular dystrophy (310300), Bione et al. (1994) found insertion of 2 basepairs after nucleotide 198 of the EMD gene, resulting in a frameshift and a stop codon after amino acid 64.

.0005 EMERY-DREIFUSS MUSCULAR DYSTROPHY, X-LINKED
EMD, IVSAS, A-G, -3, 214-BP INS
In affected members of a family with Emery-Dreifuss muscular dystrophy (310300), Bione et al. (1994) found an A-to-G transition at the -3 position in a 3-prime splice junction of the EMD gene. The mutation was first detected as an abnormality in the sequence of an RT-PCR product which showed insertion of 214 bp at nucleotide 324. The nucleotide sequence of the genomic fragments confirmed that the 214-bp insertion was an unspliced intron. In the presence of the mutation, alternative 3-prime splice junctions were used at position -87 of the same intron and position 365 in the next exon, giving 2 additional bands of size intermediate between the normal and the band reflecting the 214-bp insertion.

.0006 EMERY-DREIFUSS MUSCULAR DYSTROPHY, X-LINKED
EMD, GLN43TER
Klauck et al. (1995) identified novel mutations in 3 families with Emery-Dreifuss muscular dystrophy (310300). One of these was a C-to-T transition at nucleotide 188, resulting in a change of codon 43 from CAG (gln) to a stop codon.

.0007 EMERY-DREIFUSS MUSCULAR DYSTROPHY, X-LINKED
EMD, 1-BP DEL, FS236TER
In a patient with Emery-Dreifuss muscular dystrophy (310300), Yamada and Kobayashi (1996) found that the emerin gene carried a 1-bp deletion of C at nucleotide 672 or 673. This deletion caused a frameshift leading to change in the amino acid sequence (amino acids 206-235) and generating an early stop codon.

.0008 EMERY-DREIFUSS MUSCULAR DYSTROPHY, X-LINKED
EMD, PRO183HIS
In a man with Emery-Dreifuss muscular dystrophy (310300), Ellis et al. (1999) identified a pro183-to-his mutation in the EMD gene, which they called the STA gene. The patient was first referred to a neurologist at age 31 because of back pain, weakness in the legs greater than the arms, and leg numbness. As a child, he had been limited in his participation in athletics in school. Upper limb weakness was noticed in childhood, but no lower limb weakness was noted until age 25. He developed a burning-quality low back pain at age 27 which radiated into the posterior aspect of both legs. He had developed third-degree heart block requiring a pacemaker. There were mild contractures of both ankles but no elbow contractures.

.0009 EMERY-DREIFUSS MUSCULAR DYSTROPHY, X-LINKED
EMD, PRO183THR
In a family with 4 brothers and a maternal cousin with Emery-Dreifuss muscular dystrophy (310300), Ellis et al. (1999) identified a pro183-to-thr mutation in the EMD gene, which they referred to as the STA gene. Yates et al. (1999) identified the P183T mutation in a family with an unusually mild EDMD phenotype and normal amounts of emerin.

.0010 EMERY-DREIFUSS MUSCULAR DYSTROPHY, X-LINKED
EMD, 5-BP DEL, NT631
In 2 brothers with Emery-Dreifuss muscular dystrophy (310300), Manilal et al. (1998) identified a 5-bp deletion (TCTAC) spanning nucleotides 631-635 of the EMD gene.

Tags: Xq28