(last modified November 12, 2005)
epsilon-Sarcoglycan (Gene Symbol SGCE) was first characterized by Ettinger et al. (1997) and McNally et al (1998). The gene contains 12 exons and covers 71 kb of genomic DNA on humane chromosome 7q21.3 (mouse chromosome 6), between markers D7S644 and WI-5810 (McNally et al ). A processed epsilon-sarcoglycan pseudogene (SGCEP) maps to chromosome 2q22.3. The mouse genome does not contain a pseudogene. The structure of the epsilon-sarcoglycan gene is similar to that of alpha-sarcoglycan, with nearly identical placement of intro/exon borders (McNally et al ).
The gene produces a major 1.7 kb mRNA, containing a 437 amino acid open reading frame which encodes a typical sarcolgycan protein. Expression of the SGCE gene is maternally imprinted. At its N-terminus it contains a hydrophobic signal sequence, followed by a large extracellular domain, a hydrophobic transmembrane region and a cytoplasmic domain. The extra-cellular domain contains conserved sites for asparagine-linked N-glycosolation and four conserved Cysteine residues. The cytoplasmic domain contains three phosphorylation consensus sites.
On Northern blot, both Ettinger et al. (1997) and McNally et al (1998) detected expression in all tissues examined. Levels were moderate in brain, heart, lung, placenta and skeletal muscle and low in kidney, liver and pancreas. Using a polyclonal antibody, Ettinger et al. (1997) detected a 45 kDa sarcolemmal protein (in heart, kidney, liver, lung and skeletal muscle). Expression in mouse embryos was detectable as early as tested, i.e. from E8.5 onwards (Straub et al. ). Straub et al. (1999) characterized the DGC-complex in smooth muscle and show that epsilon-sarcoglycan is an integral pasrt of the DGC, replacing alpha-sarcoglycan (SGCA). A tight interaction of beta-, delta- and epsilon-sarcoglycan is also indicated by the loss of Sgcb- and Sgce-expression due to a Sgcd mutation in the BIO14.6 hamster (Straub et al. ).
Zimprich et al. (2001) identified sequence variations in SGCE in families with myoclonus-dystonia (MDS, DYT11 [OMIM:159900]). The mode of inheritance is autosomal dominant with reduced penetrance upon maternal transmission, caused by a maternal imprinting mechanism.
Links to other databases:
Gene Symbol nomenclature LocusLink db OMIM Gene Map GenBank sequence
The human epsilon-Sarcoglycan gene (Gene Symbol SGCE) was characterized by McNally et al (1998). The gene was isolated by screening a genomic phage clone library with an sarcoglycan epsilon-cDNA probe. The gene contains 12 exons and covers 71 kb of genomic DNA (GenBank AC069292). One differentially spliced exon has been detected (exon 9b), which is present rarely. McNally et al (1998) identified a polymorphic CA-repeat in intron 3, which was polymorphic in 49% of the individuals tested.
The SGCE-gene was originally mapped to human chromosome 7q21 using the Genebridge 4 radiation hybrid panel, between markers D7S644 (8.45 cR centromeric) and WI-5810 and D7S657 (4.2 and 7.0 cR telomeric resp., McNally et al ). On the human genome map the SGCE gene localizes to 7q21.3, it is transcribed from telomere to centromere and flanked centromeric by the CAS1 gene and telomeric by the PEG10 gene.
A processed epsilon-sarcoglycan pseudogene was identified by FISH, mapping to human chromosome 2q21. This localization, between WI-3579 (3.8 cR) and WI-4650 (5.4 cR), was confirmed by radiation hybrid mapping and from the humane genome sequence (GenBank AC023128 from 2q22.3). The pseudogene, SGCEP, contains no introns and no intact open reading frame. The mouse genome does not contain a similar pseudogene. The murine Sgce gene maps to chromosome 6, close to the telomere, between Pon1/Pon3 (1.06 cM) and Pon 2 (2.13 cM) resp.
The structure of the epsilon-sarcoglycan gene is similar to that of alpha-sarcoglycan, with nearly identical placement of intron/exon borders (McNally et al ). The human SGCE gene contains an alternatively spliced exon, exon 9b. This exon shows homology with Alu-repetitive elements and is not present in the SGCE gene of other organisms.
|Exon||Exon size (bp)||Intron size (bp)||5' cDNA position||Splice after||Remarks|
|1||221||26,148||-111||1||5'UTR and ATG-codon, hydrophobic signal sequence|
|2||123||1,359||110||1|| hydrophobic signal
|5||199||15,305||464||2||extracellular domain; asparagine-linked N-glycosolation sites Asn168 and Asn200|
|6||163||2,432||663||0||extracellular domain; conserved Cys-residues Cys235, Cys248, Cys258 and Cys271|
|7||212||922||826||2|| extracellular domain,
transmembrane region; potential phosphorylation site Ser343
|9||189||10,042||1065||2||cytoplasmic domain; potential phosphorylation sites Leu377 and Thr408|
|9b||(75)||9,197||1254-875||2||diff. spliced - Alu homology
(McNally et al )
|11||292||-||1298||-||C-terminus protein and 3'UTR|
Exon: numbering of exons and intron/exon boundaries are according to McNally et al (1998), except for exons 9b-11 (designated 10-12 by McNally et al ). Exon size: size of exon indicated in base pairs. Intron size: size of intron indicated in base pairs. 5' cDNA position: first base of the exon (according to cDNA Reference Sequence, with the first base of the Met-codon counted as position 1. Splice after: splicing occurs in between of two coding triplets (0), after the first (1) or the second (2) base of a triplet. Remarks: 5'UTR = 5' untranslated region, 3'UTR = 3' untranslated region.
Links to other databases: RefSeq: NM_003919 UniGene: Hs.110708 + Mm.8739 + Rn.3825
The epsilon-sarcoglycan gene produces a major 1.7 kb mRNA, containing a 437 amino acid open reading frame. On Northern blot, both Ettinger et al. (1997) and McNally et al (1998) detected expression in all tissues examined. Levels were moderate in brain, heart, lung, placenta and skeletal muscle and low in kidney, liver and pancreas. Ettinger et al. (1997) also detected RNA-expression in E14 mouse embryos.
Early reports show maternal imprinting of the SGCE gene. Grabowski et al. (2003) studied the methylation pattern of CpG dinucleotides within the CpG island containing the promoter region and exon-1 of the SGCE gene. Their data revealed that in peripheral blood leukocytes the maternal allele is methylated, while the paternal allele is unmethylated. Most likely the maternal allele is completely methylated in brain tissue. Surprisingly, in one affected female that inherited the mutated allele from her mother, Grabowski et al. (2003) found in peripheral blood only the paternal wild type allele expressed.
Muller et al. (2002) described an apparently sporadic MDS case and two patients from an MDS family with seemingly autosomal recessive inheritance. In both families, an SGCE mutation was identified that was inherited from the patients' clinically unaffected fathers in an autosomal dominant fashion. In affected individuals from one family RNA expression of only the mutated allele could be detected while expression of exclusively the normal allele was found in unaffected mutation carriers. An affected individual of a second family expressed both alleles.
Links to other databases: RefSeq: NP_003910
epsilon-Sarcoglycan is a 437 amino acid protein, encoding a typical sarcolgycan protein. At its N-terminus it contains a 46 amino acid hydrophobic signal sequence (NOTE: numbering in McNally et al (1998) starts 24 amino acids later). This is followed by a large, 262 amino acid, extracellular domain (aa47-316) which contains a conserved site for asparagine-linked N-glycosolation (Asn200) and four conserved Cysteine residues (Cys235, Cys248, Cys258 and Cys271). Finally, SGCE contains a 23 amino acid hydrophobic transmembrane region (aa317-339) and a 98 amino acid cytoplasmic domain (aa339-437). The cytoplasmic domain of murine Sgce contains three consensus sites for phosphorylation; Ser343, Thr377 (Leu377 in human) and Thr408 (one for casein kinase II, one for protein kinase C and one for both, Ettinger et al. ). Alternative splicing, including exon 9b, may introduce an additional cytoplasmic sequence (WSFAPVAQAGVQWRDLGSLQPPPPR, ).
The predicted molecular mass for SGCE, without post-translational modification and without exon 9b, is 47 kDa; the calculated pI is 5.78. The predicted size for the mature protein is 43.5 kDa. Endoglycosidase F treatment gave a ~1-2 kDa decrease in size of SGCE (Ettinger et al. ), which is consistent with the presence of one N-linked glycosylation site. Straub et al. (1999) characterized the DGC-complex in smooth muscle and show that epsilon-sarcoglycan is an integral part of the DGC, replacing alpha-sarcoglycan. A tight interaction of beta-, delta- and epsilon-sarcoglycan is also indicated by the loss of Sgcb- and Sgce-expression due to a Sgcd mutation in the BIO14.6 hamster (Straub et al. ).
Human and mouse epsilon-sarcoglycan are 96% identical.
SGCE is 43% identical (63% similar) to alpha-sarcoglycan (nucleotide level - 47% similarity within the coding region). Similarity for mouse Sgce and Sgca extends over the whole length of the protein. A 24 amino acid stretch in the extracellulair domain (aa168-191) and the transmembrane region (aa 283-325) are particulary conserved (Ettinger et al. ). The potential N-glycosylation site (Asn168) and the exact spacing of the four Cys-residues are also conserved. The cytoplasmic domain between the two proteins is rather divergent, suggesting that the proteins bind different partners.
Using a polyclonal antibody, Ettinger et al. (1997) detected a 45 kDa protein on Western blots (in heart, kidney, liver, lung and skeletal muscle). In brain tissue, two additional higher molecular mass bands were detected, 47 and 48 kDa resp. Immunohistochemistry showed a wide sarcolemmal expression of SGCE, in agreement with the Northern and Western blot data (Ettinger et al. ). Expression was also detected in E13.5 murine embryos, a time of development in which SGCA-expression is absent.
Straub et al. (1999) performed extensive studies on epsilon-sarcoglycan expression. Expression in mouse embryos was detectable as early as tested, i.e. from E8.5 onwards. A broad expression was detected by E12 (myoblasts, myotubes, cardiac myocytes, surrounding lung bronchi, vascular endothelium). Neither alpha- or beta-sarcoglycan expression were detectable at the E8.5 and E12 stages. At E15, Sgce expression was abundant in smooth muscle of lung and bronchus, in skeletal myotubes, cardiac myocytes and a variety of endodermal and ectodermal lineages. At E15, Sgca- and Sgcb-expression were detectable, but restricted to skeletal and cardiac muscle.
Links to other databases: OMIM: 159900
Using a positional cloning approach, Zimprich et al. (2001) detected mutations in the SGCE-gene in patients with Myoclonus–dystonia syndrome (MDS; DYT11). MDS is an autosomal dominant disorder characterized by bilateral, alcohol-sensitive myoclonic jerks involving mainly the arms and axial muscles. Dystonia, usually torticollis and/or writer's cramp, occurs in most affected patients and may occasionally be the only symptom of the disease. Often patients show prominent psychiatric abnormalities, including panic attacks and obsessive–compulsive behavior. In most MDS families, the disease is linked to a locus on chromosome 7q21. Zimprich et al. (2001) identified 5 different heterozygous loss of function mutations in the gene for epsilon-sarcoglycan (SGCE). Pedigree analysis showed a marked difference in penetrance depending on the parental origin of the disease allele. Of 62 clinically affected individuals (40 males and 22 females) in the combined families, 49 inherited the disease from their father and only 4 from their mother. This is indicative of a maternal imprinting mechanism, which has also been demonstrated in the mouse SGCE-gene.
Klein et al. (2002) describe SGCE-changes in two families with previously identified changes in the DRD2- and DYT1 genes respectively. All eight affected individuals in family 1 carry changes in two genes as well as both definitely affected members in family 2. The authors are unclear whether the change in the SGCE gene or the combination of mutations are pathogenic.
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