| *604149 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SARCOGLYCAN, EPSILON; SGCE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: SGCE | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 7q21.3 Genomic coordinates (GRCh37): 7:94,214,535 - 94,285,520 (from NCBI) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Description | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The SGCE gene encodes the epsilon member of the sarcoglycan family, single pass transmembrane proteins that are part of the dystrophin-glycoprotein complex (DGC), which links the actin cytoskeleton to the extracellular matrix in cardiac and skeletal muscle. There are 3 main subcomplexes of the DGC: the cytoplasmic subcomplex that contains dystrophin (DMD; 300377), dystrobrevins (DNTA1; 601239) and syntrophins (SNTA1; 601017), the alpha- and beta-dystroglycans (see 128239) subcomplex, and the sarcoglycan/sarcospan (SSPN; 601599) subcomplex (summary by Esapa et al., 2007). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cloning | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| By searching an EST database with the rabbit alpha-sarcoglycan (SGCA; 600119) sequence, Ettinger et al. (1997) identified a human EST encoding a partial sequence of a novel protein, which they named epsilon-sarcoglycan (SGCE). Using this EST, they isolated mouse cDNAs corresponding to the complete coding sequence of Sgce. Ettinger et al. (1997) showed that Sgce is a membrane-associated glycoprotein that is widely expressed in both muscle and nonmuscle cells, and in embryos as well as adults. They suggested that sarcoglycans may be important for embryonic development and/or for integrity of nonmuscle tissues. McNally et al. (1998) isolated a full-length human SGCE cDNA by screening a heart cDNA library with a human SGCE EST. The predicted 413-amino acid protein consists of a signal sequence; a large extracellular domain containing 4 conserved cysteine residues and a potential glycosylation site; a transmembrane domain; and a short cytoplasmic domain. The deduced SGCE protein is 43% identical to SGCA. Northern blot analysis detected a 1.7-kb SGCE transcript in all human tissues examined; this broad expression contrasts with the predominant or exclusive expression of the alpha-, beta (600900)-, gamma (608896)-, and delta (601411)-sarcoglycans in striated muscle. Nishiyama et al. (2004) identified 2 major alternatively spliced Sgce isoforms in the mouse brain. One was the conventional form including exon 8 (Sgce1), which immunoblot analysis showed was broadly expressed in various mouse tissues. The other form was a novel transcript excluding exon 8 but including a previously unknown exon 11b (Sgce2), which immunoblot analysis showed was exclusively expressed in brain. Both isoforms coexisted in neurons in various regions of the brain, but subcellular fractionation of brain homogenates indicated that Sgce1 and Sgce2 were enriched in postsynaptic and presynaptic membrane fractions, respectively. These results suggested that the 2 Sgce isoforms might play different roles in synaptic function of the central nervous system. Sgce is expressed in neurons in various regions of the murine central nervous system, including the cerebral cortex, basal ganglia, hippocampus, cerebellum, and the olfactory bulb. Esapa et al. (2007) found expression of Sgce at the plasma membrane of dendrites and soma in hippocampal neurons and muscle, as well as in intracellular inclusions and in association with the Golgi apparatus of cultured hippocampal cells. Ritz et al. (2011) analyzed alternative splicing events of the entire SGCE gene and found only 4 that occurred at frequencies above 1%: exon 1c, and the known alternatively spliced exons 2, 8, and 11b. Exon 1c transcript was found in brain (5.7%) and nonbrain tissue (2.0-2.3%). The exon 2 form was expressed at high levels in all tissues tested, whereas exon 8 form was highly represented in muscle and blood but low in brain. Ritz et al. (2011) found expression of the SGCE transcript containing exon 11b mainly in human brain tissue, with differential expression in various regions, including the somatosensory and motor cortex, putamen, thalamus, hippocampus, and cerebellum. The imprinting pattern of SGCE in muscle and blood was maintained in brain tissues. Ritz et al. (2011) suggested that the pathogenesis of myoclonic-dystonia (159900) may be related to dysfunction of the cerebellum due to the brain-specific exon 11b SGCE transcript. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Structure | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The SGCE gene contains 12 exons, and McNally et al. (1998) estimated that it spans between 50 and 100 kb. Exon 10, which encodes 25 amino acids in the cytoplasmic domain, is alternatively spliced and is absent from the majority of transcripts. The authors identified a polymorphic dinucleotide CA repeat 3-prime of exon 3. Nishiyama et al. (2004) identified a novel Sgce exon 11b that was present in a transcript exclusively expressed in the brain. Yokoi et al. (2005) identified another brain-specific transcript including exon 11c (an elongated exon 11b), in mouse brain. Transcripts containing either exon 11b or 11c encode proteins with a different C-terminal sequence containing a PDZ-binding motif. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Using radiation hybrid mapping, McNally et al. (1998) localized the human SGCE gene to chromosome 7q21-q22, between markers D7S644 and D7S657. They mapped a processed SGCE pseudogene to 2q21 by FISH and radiation hybrid mapping. By analysis of backcross panels, McNally et al. (1998) mapped the mouse Sgce gene near the telomere of chromosome 6, a region showing homology of synteny with human 7q21. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The dystonias are a common clinically and genetically heterogeneous group of movement disorders. Zimprich et al. (2001) stated that more than 10 loci for inherited forms of dystonia had been mapped, although only 3 mutated genes had been identified: DYT1 (TOR1A; 605204) on 9q34; GCH1, formerly known as DYT5 (600225), on 14q; and TH (191290) on 11p15.5. Myoclonus-dystonia syndrome (159900) is an autosomal dominant disorder characterized by bilateral, alcohol-sensitive myoclonic jerks involving mainly the arms and axial muscles (Gasser, 1998). Dystonia, usually torticollis and/or writer's cramp, occurs in most but not all affected patients and may occasionally be the only symptom of the disease. In addition, patients often show prominent psychiatric abnormalities, including panic attacks and obsessive-compulsive behavior. Linkage studies in most families demonstrated that the disorder is linked to a locus on 7q21. Using a positional cloning approach, Zimprich et al. (2001) identified 5 different heterozygous loss-of-function mutations in the SGCE gene, which they mapped to a refined critical region of 3.2 Mb for the myoclonus-dystonia syndrome. Pedigree analysis showed a marked difference in penetrance depending on the parental origin of the disease allele. This was indicative of a maternal imprinting mechanism, which had been demonstrated in the mouse epsilon-sarcoglycan gene (Piras et al., 2000). In 24 patients from 9 families with myoclonus-dystonia syndrome, Asmus et al. (2002) identified 1 previously known and 6 novel mutations in the SGCE gene. Pedigree analysis showed reduced penetrance of the phenotype upon maternal inheritance of the mutated allele, indicating genomic imprinting. Muller et al. (2002) presented an apparently sporadic myoclonus-dystonia case and 2 patients from a myoclonus-dystonia family with seemingly autosomal recessive inheritance. In both families, they detected an SGCE mutation that was inherited from the patients' clinically unaffected fathers in an autosomal dominant fashion. In the first family, RNA expression studies revealed expression of only the mutated allele in affected individuals and expression of the normal allele exclusively in unaffected mutation carriers, whereas the affected individual of the second family expressed both alleles. Muller et al. (2002) identified differentially methylated regions in the promoter region of the SGCE gene as a characteristic feature of imprinted genes. Using a rare polymorphism in the promoter region in a family unaffected with myoclonus-dystonia, they demonstrated methylation of the maternal allele, in keeping with maternal imprinting of the SGCE gene. Loss of imprinting in the patient with myoclonus-dystonia who had biallelic expression of the SGCE gene was associated with partial loss of methylation at several CpG dinucleotides. DeBerardinis et al. (2003) described a 32-month-old child with an interstitial deletion affecting 7q21 and a phenotype that included myoclonus, microcephaly, short stature, dysmorphic face, and language delay. They used FISH to estimate the size of the deletion (9.0 to 15 Mb) and to confirm absence of the SGCE gene on the affected chromosome. PCR analysis of polymorphic markers in the region revealed that the paternally inherited chromosome contained the deletion, consistent with a model of maternal SGCE imprinting. The patient appeared to represent a new contiguous gene disorder. Using bisulfite genomic sequencing, Grabowski et al. (2003) studied the methylation pattern of CpG dinucleotides within the CpG island containing the promoter region and the first exon of the SGCE gene. In peripheral blood leukocytes from MDS patients, the maternal allele was methylated and the paternal allele unmethylated; in brain tissue, the maternal allele appeared to be completely methylated. Grabowski et al. (2003) concluded that these results provided strong evidence for maternal imprinting of the SGCE gene. Asmus et al. (2005) identified 2 different large heterozygous deletions in the SGCE gene (604149.0010 and 604149.0011) in affected members from 2 unrelated families with myoclonic dystonia. The deletion was paternally inherited in all cases with motor symptoms. In 1 family, a man who inherited the mutation maternally did not have motor symptoms but did have alcohol dependence. Tezenas du Montcel et al. (2006) identified 13 different mutations in the SGCE gene in 16 of 76 unrelated French Caucasian patients with myoclonus-dystonia or essential myoclonus. In 12 families (75%), at least 1 other family member was affected. Penetrance was complete in paternal transmissions and null in maternal transmissions. None of the patients had severe psychiatric disorders. Esapa et al. (2007) performed in vitro functional expression studies with 3 different pathogenic mutations in the mouse Sgce gene, H36R, H36P, and L172R, which are homologous to the human disease-causing mutations H60R, H60P, and L195R (604149.0006), respectively. Studies in COS-7 cells, cortical neurons, and neuroblastoma cells showed mislocalization of the mutant proteins, with the mutant proteins either being retained in the endoplasmic reticulum or diffusely distributed in soma and dendrites rather than in discrete punctae like wildtype. Studies in HEK293 cells showed decreased levels of the mutant proteins resulting from ubiquitination and degradation by the proteosome. The L172R mutant appeared to be misfolded with a propensity to form aggregates, which was not demonstrated with either of the H60 mutants. Coexpression of the mutants with wildtype TOR1A resulted in a reduction in levels of the mutant proteins, suggesting that TOR1A can help clear mutant SGCE from the cell. The overall findings indicated that myoclonus-dystonia is caused by loss of function of SGCE at the plasma membrane. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Imamura et al. (2005) established several transgenic mouse lines that overexpressed Sgce in skeletal muscle. Overexpression in normal mice resulted in substitution of Sgce for Sgca in the sarcoglycan complex of skeletal muscle without any obvious abnormalities. Mice overexpressing Sgce were crossed with Sgca-deficient mice, and Sgca-deficient mice overexpressing Sgce exhibited no skeletal muscle cell membrane damage or abnormal contraction. Imamura et al. (2005) suggested that overexpression of SGCE may represent a therapeutic strategy for treatment of LGMD2D (608099). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Table View | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0001 MYOCLONUS-DYSTONIA SYNDROME | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SGCE, ARG97TER [dbSNP:rs121908489] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In affected members of a family with myoclonus-dystonia syndrome (159900), Zimprich et al. (2001) found an arg97-to-ter (R97X) nonsense mutation in exon 3 of the SGCE gene. Valente et al. (2005) identified the R97X mutation in 2 of 58 unrelated patients with a range of myoclonic/dystonic syndromes. Both patients had a phenotype consistent with myoclonus-dystonia syndrome. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0002 MYOCLONUS-DYSTONIA SYNDROME | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SGCE, ARG102TER [dbSNP:rs121908490] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 2 families with myoclonus-dystonia syndrome (159900), Zimprich et al. (2001) found that affected members had the same nonsense mutation of the SGCE gene: a 304C-T transition causing an arg102-to-ter (R102X) amino acid change. In 1 of these families there was a demonstration of reduced penetrance in the offspring of an affected female, who had 2 unaffected sons, 1 of whom transmitted the disorder to a daughter. Han et al. (2003) reported 2 families with myoclonus-dystonia syndrome caused by the R102X mutation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0003 MYOCLONUS-DYSTONIA SYNDROME | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SGCE, 1-BP DEL, 565A | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a family with myoclonus-dystonia syndrome (159900) in an irregular autosomal dominant pedigree pattern, Zimprich et al. (2001) found that affected individuals had a 1-bp deletion, 565delA, leading to a frameshift of the coding region of the SGCE gene, with a premature stop at codon 169. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0004 MYOCLONUS-DYSTONIA SYNDROME | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SGCE, 97-BP DEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a family with myoclonus-dystonia syndrome (159900), Zimprich et al. (2001) demonstrated a 97-bp deletion in the SGCE gene affecting intron 3 and 15 bp of exon 4. There were 2 affected members of the family, a grandmother who did not transmit the disorder to her son, who, however, had an affected daughter. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0005 MYOCLONUS-DYSTONIA SYNDROME | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SGCE, 5-BP DEL, NT835 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a family with myoclonus-dystonia syndrome (159900) first reported by Klein et al. (1999) and found to have a heterozygous mutation in the DRD2 gene (126450.0001), Klein et al. (2002) identified a 5-bp deletion in the SGCE gene in all 8 affected members. The mutation resulted in a frameshift and premature stop. There were 2 unaffected carriers of both mutations. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0006 MYOCLONUS-DYSTONIA SYNDROME | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SGCE, LEU196ARG [dbSNP:rs121908491] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 2 sibs with myoclonus-dystonia syndrome (159900) first reported by Leung et al. (2001) and found to have a heterozygous 18-bp deletion in the DYT1 gene (TOR1A; 605204.0002), Klein et al. (2002) identified a 587T-G missense mutation in exon 5 of the SGCE gene, resulting in a leu196-to-arg substitution. The sibs had inherited the DYT1 deletion from their mother, who showed dystonic features, and the SGCE mutation from their father, who showed myoclonic features. The SGCE missense change was not detected in 500 control chromosomes. Doheny et al. (2002) described the clinical features of this family in greater detail. The proband had onset at age 5 years of myoclonic jerky movements of the legs and arms, which later progressed to the head, and dystonic features. Psychiatric evaluation revealed depression and anxiety. Her brother had onset of motor jerks at age 6 years, which later developed into multifocal myoclonus at rest, and dystonic posturing. Psychiatric evaluation revealed depression, anxiety and panic disorders, attention deficit disorder, and alcoholism. The mother, who carried the DYT1 mutation, had intermittent lip puckering, neck stiffness, tremulous voice, clumsiness, involuntary toe movements, and post-traumatic stress disorder after the death of her mother. No myoclonus was noted. The father, who carried the SGCE mutation, had occasional jerking of the upper limbs and action tremor. Psychiatric history was negative. The maternal grandfather, who carried the DYT1 mutation, reportedly had lip puckering and tremulous voice, as well as depression, anxiety and panic disorders, and posttraumatic stress disorder (PTSD). Doheny et al. (2002) noted that the clinical picture in this family is unique and that the contributions of each mutation to the clinical phenotype could not definitively be determined. (See also Furukawa and Rajput, 2002). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0007 MYOCLONUS-DYSTONIA SYNDROME | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SGCE, 1-BP INS, 885T | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a 5-generation Dutch family with myoclonus-dystonia syndrome (159900) in which 3 of 5 affected members also had seizures, Foncke et al. (2003) identified a 1-bp insertion in the SGCE gene, 885insT, resulting in frameshift and subsequent protein truncation at amino acid 297. One asymptomatic 21-year-old individual in the fifth generation also carried the mutation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0008 MYOCLONUS-DYSTONIA SYNDROME | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SGCE, 1-BP DEL, 974C | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a large family in which 9 individuals were affected with myoclonus-dystonia syndrome (159900), Hjermind et al. (2003) identified a 1-bp deletion (974delC) in exon 7 of the SGCE gene, resulting in a premature stop at codon 325. Affected individuals had prominent symptoms in their legs, and children in the fourth generation were particularly severely affected. In addition, affected individuals had laryngeal involvement causing vocal myoclonus. Three of 12 gene carriers (25%) were unaffected, showing incomplete penetrance of the disorder. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0009 MYOCLONUS-DYSTONIA SYNDROME | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SGCE, ARG372TER [dbSNP:rs121908492] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 2 of 58 unrelated patients with a range of myoclonic/dystonic syndromes, Valente et al. (2005) identified a heterozygous mutation in the SGCE gene, resulting in an arg372-to-ter (R372X) substitution. Both patients had a phenotype consistent with myoclonus-dystonia syndrome (159900). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0010 MYOCLONUS-DYSTONIA SYNDROME | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SGCE, EX5 DEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 5 affected members of a German pedigree with myoclonus-dystonia syndrome (159900), Asmus et al. (2005) identified a heterozygous 15-kb deletion in the SGCE gene, resulting in the deletion of exon 5 and truncation of the protein before the transmembrane domain. The deletion was paternally inherited in all cases. Asmus et al. (2005) suggested nonhomologous end joining as the molecular mechanism for the deletion. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0011 MYOCLONUS-DYSTONIA SYNDROME | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SGCE, EX6 DEL | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 2 sibs from a Danish family with myoclonus-dystonia syndrome (159900), Asmus et al. (2005) identified a heterozygous 6,872-bp deletion in the SGCE gene, resulting in the deletion of exon 6 and truncation of the protein before the transmembrane domain. The deletion was paternally inherited in both cases. Their father, who inherited the mutation maternally, did not have motor symptoms, but did have alcohol dependence. Asmus et al. (2005) suggested nonhomologous end joining as the molecular mechanism for the deletion. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0012 MYOCLONUS-DYSTONIA SYNDROME | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| SGCE, 2-BP DEL, 619AG | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In affected members of a large Dutch family with myoclonus-dystonia syndrome (159900) reported by Korten et al. (1974), Foncke et al. (2006) identified a heterozygous 2-bp deletion (619delAG) in exon 5 of the SGCE gene, resulting in a frameshift and premature truncation. The mutation was identified in all 19 symptomatic relatives, all 5 'possibly affected' relatives, and in 9 clinically unaffected relatives. All symptomatic individuals inherited the mutation from their father, and all asymptomatic individuals inherited it from their mother. Foncke et al. (2006) noted that subtle distal myoclonus of the fingers was a prominent feature in this family. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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