Disease relevance of SGCG

• Sarcoglycanopathies (SGPs) constitute a subgroup of limb-girdle muscular dystrophies (LGMD), where the primary defect in one sarcoglycan (SG) glycoprotein (alpha-SG, beta-SG, gamma-SG or delta-SG) results in a deficiency of the whole complex [1].
• Mutations in the dystrophin-associated protein gamma-sarcoglycan in chromosome 13 muscular dystrophy [2].
• The LGMD2C linked to chromosome 13q and related to a 35 KDa dystrophin-associated glycoprotein deficiency, is very similar to Duchenne muscular dystrophy with an autosomal recessive inheritance [3].
• The sequence of the Mycoplasma arthritidis superantigen, MAM: identification of functional domains and comparison with microbial superantigens and plant lectin mitogens [4].
• In addition, a V beta 17- MAM-reactive T cell population exists, assessed by MAM, induced T cell proliferation and cytotoxic T cell activity. mAb C1 will be useful in characterizing the functional properties of V beta 17+ T cells and their potential role in autoimmune disease [5].

Psychiatry related information on SGCG

• Recent heroin abuse (n = 5) could be demonstrated to some extent with Drugwipe on samples from the tongue but only the two subjects with the highest saliva concentrations of MAM (> 500 ng/ml) and morphine (> 500 ng/ml) were positive [6].
• Fixed-ratio (FR) discrimination learning in adult male spontaneously hypertensive rats (SHR), methylazoxymethanol-induced microencephalic Sprague-Dawley (MAM), and Sprague-Dawley control rats was examined [7].
• Recent National DMDA surveys have shown that people with mood disorders often have incorrect information about their illnesses, that misdiagnoses are frequent, that a significant physician/patient communication gap exists, and that noncompliance is widespread [8].
• The results of this preliminary study suggest that the MAM is a promising outcome measure that has adequate psychometric properties and can be used to complement other objective clinical measurements [9].

High impact information on SGCG

• Screening for sarcoglycan-gene mutations in 50 of the 54 patients revealed mutations in 29 patients (58 percent): 17 (34 percent) had mutations in the alpha-sarcoglycan gene, 8 (16 percent) in the beta-sarcoglycan gene, and 4 (8 percent) in the gamma-sarcoglycan gene [10].
• Patients whose biopsy specimens showed a deficiency of alpha-sarcoglycan on immunostaining were studied for mutations of the alpha-, beta-, and gamma-sarcoglycan genes with reverse transcription of muscle RNA, analysis involving single-strand conformation polymorphisms, and sequencing [10].
• Here, it is shown that a mutation in the gene encoding the 35-kilodalton dystrophin-associated glycoprotein, gamma-sarcoglycan, is likely to be the primary genetic defect in this disorder [2].
• The human gamma-sarcoglycan gene was mapped to chromosome 13q12, and deletions that alter its reading frame were identified in three families and one of four sporadic cases of SCARMD [2].
• Although MAM shares typical features with other superantigens, direct interaction with CDR3-beta is a feature of nominal peptide antigens situated in the antigen groove of major histocompatibility complex (MHC) molecules rather than superantigens [11].

Chemical compound and disease context of SGCG

• In other MAM-exposed pups and controls, status epilepticus was induced by intraperitoneal administration of kainic acid [12].
• In hair, we detect cocaine and MAM as major metabolites for cocaine and heroin abuse, respectively [13].

Biological context of SGCG

• The relatively high frequency of SGP among Brazilian people with LGMD may be due to the disproportionally high frequency of African Brazilian SGP patients with the same mutation (particularly among LGMD2C and 2F patients), suggesting a founder effect [1].
• Homozygous missense mutations in critical locations may result in the total absence of alpha-, beta- and gamma-sarcoglycan from the muscle membrane and a phenotype as severe as null mutations [14].
• Evidence for linkage disequilibrium in chromosome 13-linked Duchenne-like muscular dystrophy (LGMD2C) [15].
• To establish a mutation assay for genomic DNA, the intron-exon structure of the gamma-sarcoglycan gene was determined, and primers were designed to amplify each of the exons encoding gamma-sarcoglycan [16].
• Four patients with a severe muscular dystrophy phenotype were identified with homozygous, frameshifting mutations in gamma-sarcoglycan [17].

Anatomical context of SGCG

• The hypothesis of bidirectional signalling between sarcoglycans and integrins could be supported by the identification of a skeletal and cardiac muscle filamin2 as a gamma-sarcoglycan, delta-sarcoglycan and, hypothetically, beta1 integrin interacting protein [18].
• We have partially sequenced rabbit skeletal muscle gamma-sarcoglycan, an integral component of the dystrophin-glycoprotein complex [19].
• In addition, we show that in normal muscle alpha-, beta-, and gamma-sarcoglycan constitute a tightly associated sarcolemma complex which cannot be disrupted by SDS treatment [19].
• These immunostimulatory effects of MAM on the humoral arm of the human immune system warranted a more precise characterization of MAM-reactive human T cells [5].
• Two functional domains on MAM are identified based on the ability of peptides encompassing these regions to inhibit lymphocyte proliferation by the intact MAM molecule [4].

Associations of SGCG with chemical compounds

• This region of gamma-sarcoglycan, like beta-sarcoglycan, has a number of cysteine residues similar to those in epidermal growth factor cysteine-rich regions [17].
• Using an uncloned MAM reactive human T cell line as immunogen, we have generated a monoclonal antibody (mAb) (termed C1) specific for the T cell receptor V beta gene expressed by the major fraction of MAM-reactive human T cells, V beta 17 [5].
• The crystal structure of a construct comprising its N-terminal MAM (meprin/A5/mu) and Ig domains was determined at 2.7 A resolution; this assigns the MAM fold to the jelly-roll family and reveals extensive interactions between the two domains, which form a rigid structural unit [20].
• Treatment with lactacystin, a specific inhibitor of the proteasome, significantly decreased the degradation, indicating that the mutants lacking the MAM domain are degraded by the proteasome as misfolded proteins [21].
• To explore the interactions of layer IV neurons and their thalamocortical input, we administered a mitotic inhibitor methylazoxymethanol acetate (MAM) intraperitoneally to time d pregnant hamsters on E14 when layer IV neurons are normally being generated in striate cortex [22].

Regulatory relationships of SGCG

• When beta-sarcoglycan was expressed appropriately at the sarcolemma of gamma-sarcoglycan-deficient patients, intracellular labeling of beta-sarcoglycan was also present [23].

Other interactions of SGCG

• The genes for LGMD2C, LGMD2D and LGMD2E code for proteins of the SG complex [24].
• All patients with LGMD2A and 2B had a mild clinical course while those with a primary sarcoglycan mutation (LGMD2C to 2F) had a range of clinical severity [25].
• We found a novel dystrophin-associated protein (DAP) exhibiting almost the same mobility as gamma-sarcoglycan on SDS-PAGE [26].
• Recently, zeta-sarcoglycan, a novel sarcoglycan highly related to gamma-sarcoglycan and delta-sarcoglycan, has been identified [27].
• RESULTS: gamma-Sarcoglycan, fibulin-2, and collagen XV were identified as the genes more highly expressed in SC than in TM cells [28].

Analytical, diagnostic and therapeutic context of SGCG

• We show by immunofluorescence and Western blotting that in skeletal muscle from these patients gamma-sarcoglycan is completely absent and alpha- and beta-sarcoglycan are greatly reduced in abundance, whereas other components of the DGC are preserved [19].
• The gamma-sarcoglycan cDNA was amplified by reverse transcriptase PCR from the muscle biopsy of the elder sister and sequenced [29].
• Clinical severity and progression was variable between and within families but early loss of ambulation, at or before the age of 12 years, was associated with a total absence of gamma-sarcoglycan [30].
• Here we show that the small leucine-rich repeat (LRR) proteoglycan biglycan binds to alpha- and gamma-sarcoglycan as judged by ligand blot overlay and co-immunoprecipitation assays [31].
• Structure-based site-directed mutagenesis, serial domain deletions and cell-adhesion assays allowed us to identify the four N-terminal domains (MAM, Ig, fibronectin type III (FNIII)-1 and FNIII-2) as a minimal functional unit [20].

References