Descrizione

The SGCE gene encodes the epsilon membro of the sarcoglycan family, transmembrane components of the dystrophin-glycoprotein complesso, which links the cytoskeleton to the extracellular matrix.

Cloning

The dystrophin-glycoprotein complesso (DGC) è a group of proteins che links the muscle cytoskeleton to the extracellular matrix e è critical to the stability of muscle fibre membranes. Components of the DGC include several cytoplasmic proteins, such come dystrophin (300377) e the syntrophins (e.g., 600027), e 2 subcomplexes of transmembrane glycoproteins, the dystroglycans (e.g., 128239) e the sarcoglycans. By searching an EST database con the rabbit alpha-sarcoglycan (SGCA; 600119) sequenza, Ettinger ed altri (1997) identificarono a human EST encoding a partial sequenza di una nuova protein, which esse named epsilon-sarcoglycan (SGCE). Using this EST, esse isolated mouse cDNAs corresponding to the complete coding sequenza of Sgce. Ettinger ed altri (1997) mostrava che Sgce è a membrane-associata glycoprotein che è widely expressed in both muscle e nonmuscle cellule, e in embryos come pure adults. They suggerivano che sarcoglycans may be important per embryonic development e/o per integrity of nonmuscle tessuti.

McNally ed altri (1998) isolated a full-length human SGCE cDNA by screening a heart cDNA library con a human SGCE EST. The predicted 413-amino acid protein consists of a signal sequenza; a large extracellular domain contenenti 4 conserved cysteine residues e a potential glycosylation site; a transmembrane domain; e a short cytoplasmic domain. The deduced SGCE protein è 43% identical to SGCA. Northern blot analisi detected a 1.7-kb SGCE transcript in all human tessuti examined; this broad espressione contrasts con the predominant o exclusive espressione of the alpha-, beta (600900)-, gamma (608896)-, e delta (601411)-sarcoglycans in striated muscle.

Gene Structure

The SGCE gene contains 12 exons, e McNally ed altri (1998) estimated che it spans fra 50 e 100 kb. Exon 10, which encodes 25 amino acids in the cytoplasmic domain, è alternatively spliced e è assente from the majority of transcripts. Gli autori identificarono a polymorphic dinucleotide CA repeat 3-prime of exon 3.

Mappatura

Using radiation hybrid mapping, McNally ed altri (1998) localized the human SGCE gene to 7q21-q22, fra markers D7S644 e D7S657. They mapped a processed SGCE pseudogene to 2q21 by FISH e radiation hybrid mapping. By analisi of backcross panels, McNally ed altri (1998) mapped the mouse Sgce gene near the telomere of chromosome 6, a region showing homology of synteny con human 7q21.

Genetica molecolare

The dystonias are a common clinicamente e genetically heterogeneous group of movement malattie. Zimprich ed altri (2001) stabilirono che più than 10 loci per ereditaria forms of dystonia avevano been mapped, although solo 3 mutated geni avevano been identificarono: DYT1 (605204) on 9q34; GCH1, formerly known come DYT5 (600225), on 14q; e TH (191290) on 11p15.5. Myoclonus-dystonia sindrome (159900) è an autosomica dominante disturbo caratterizzata by bilaterale, alcol-sensitive myoclonic jerks coinvolgenti mainly the braccia e assiale muscoli (Gasser, 1998). Dystonia, solitamente torticollis e/o writer's cramp, occurs in most ma not all affetti pazienti e may occasionally be la sola symptom of the malattia. In addition, pazienti often show prominent psychiatric anormalità, comprendenti panic attacks e obsessive-compulsive behavior. Linkage studies in most famiglie demonstrated che il disturbo è linked to a locus on 7q21. Using a positional cloning approach, Zimprich ed altri (2001) identificarono 5 differenti heterozygous loss-of-function mutazioni in the SGCE gene, which esse mapped to a refined critical region of 3.2 Mb per the myoclonus-dystonia sindrome. Pedigree analisi mostrava a marcato difference in penetranza depending on the parental origine of the malattia allele. This era indicative of a maternal imprinting mechanism, which avevano been demonstrated in the mouse epsilon-sarcoglycan gene (Piras ed altri, 2000).

In 24 pazienti from 9 famiglie con myoclonus-dystonia sindrome, Asmus ed altri (2002) identificarono 1 previously known e 6 novel mutazioni in the SGCE gene. Pedigree analisi mostrava penetranza ridotta of il fenotipo upon maternal ereditarietà of the mutated allele, indicando genomic imprinting.

Muller ed altri (2002) presentarono an apparently sporadiche myoclonus-dystonia case e 2 pazienti from a myoclonus-dystonia family con seemingly autosomica recessive ereditarietà. In both famiglie, esse detected an SGCE mutazione che era ereditaria from i pazienti' clinicamente non affetti fathers in an autosomica dominante fashion. In the first family, RNA espressione studies revealed espressione of solo the mutated allele in individui affetti e espressione of the normale allele exclusively in non affetti mutazione carriers, mentre the affetti individuo of the seconda family expressed both alleles. Muller ed altri (2002) identificarono differentially methylated regions in the promoter region of the SGCE gene come a caratteristiche caratteristica of imprinted geni. Using una rara polymorphism in the promoter region in a family non affetti con myoclonus-dystonia, esse demonstrated methylation of the maternal allele, in keeping con maternal imprinting of the SGCE gene. Loss of imprinting in the paziente con myoclonus-dystonia who avevano biallelic espressione of the SGCE gene era associata con partial loss of methylation a several CpG dinucleotides.

DeBerardinis ed altri (2003) descrivono a 32-month-old child con an interstiziale delezione colpendo 7q21 e a fenotipo che included myoclonus, microcephaly, bassa statura, dysmorphic faccia, e language delay. They used FISH to estimate the dimensioni of la delezione (9.0 to 15 Mb) e to confirm absence of the SGCE gene on the affetti chromosome. PCR analisi of polymorphic markers in the region revealed che the paternally ereditaria chromosome contained la delezione, coerente con a model of maternal SGCE imprinting. The paziente appeared to represent una nuova contiguous gene disturbo.

Using bisulfite genomic sequencing, Grabowski ed altri (2003) studiarono the methylation pattern of CpG dinucleotides within the CpG island contenenti the promoter region e the first exon of the SGCE gene. In periferica sangue leukocytes from MDS pazienti, the maternal allele era methylated e the paternal allele unmethylated; in cervello tissue, the maternal allele appeared to be completely methylated. Grabowski ed altri (2003) conclusero che these results fornirono strong prove per maternal imprinting of the SGCE gene.

Asmus ed altri (2005) identificarono 2 differenti large heterozygous delezioni in the SGCE gene (604149.0010 e 604149.0011) in affetti membri from 2 non imparentati famiglie con myoclonic dystonia. The delezione era paternally ereditaria in all casi con motor sintomi. In 1 family, a man who ereditaria la mutazione maternally did not have motor sintomi ma did have alcol dependence.

Tezenas du Montcel ed altri (2006) identificarono 13 differenti mutazioni in the SGCE gene in 16 of 76 non imparentati French Caucasian pazienti con myoclonus-dystonia o essential myoclonus. In 12 famiglie (75%), almeno 1 altra family membro era affetti. Penetrance era complete in paternal transmissions e null in maternal transmissions. None of i pazienti avevano grave psychiatric malattie.

Modello animale

Imamura ed altri (2005) established several transgenic mouse linee che overexpressed Sgce in muscoli scheletrici. Overexpression in normale mice resulted in substitution of Sgce per Sgca in the sarcoglycan complesso of muscoli scheletrici senza any obvious anormalità. Mice overexpressing Sgce erano crossed con Sgca-deficient mice, e Sgca-deficient mice overexpressing Sgce esibivano no muscoli scheletrici cell membrane damage o anormali contraction. Imamura ed altri (2005) suggerivano che overexpression of SGCE may represent a therapeutic strategy per treatment of LGMD2D (608099).

Varianti alleliche

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Riferimenti

Collaboratori

Data di inizio

Revisioni

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