Affinage

SGCG

Gamma-sarcoglycan · UniProt Q13326

Length
291 aa
Mass
32.4 kDa
Annotated
2026-06-14
40 papers in source corpus 17 papers cited in narrative 17 extracted findings
Cross-family judge vs UniProt: Affinage preferred

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

Gamma-sarcoglycan (SGCG) is a transmembrane component of the sarcolemmal sarcoglycan complex whose loss causes limb-girdle muscular dystrophy through destabilization of the complex and direct membrane damage (PMID:7481775, PMID:9732288). Mutation analysis in patients first established that loss of gamma-sarcoglycan collapses the integrity of the entire sarcoglycan complex, with the cysteine-rich C-terminus being essential for complex stability (PMID:7481775, PMID:8923014); alpha-, beta-, and gamma-sarcoglycan form a tightly associated, SDS-resistant sarcolemmal unit (PMID:8641426). Genetic knockout in mice demonstrated that beta-, gamma-, and delta-sarcoglycan function as an interdependent subgroup and that sarcoglycan loss alone is sufficient to produce membrane disruptions and apoptosis independently of dystrophin (PMID:9732288). Beyond striated muscle, gamma-sarcoglycan assembles into a distinct smooth-muscle sarcoglycan-sarcospan complex with epsilon-, beta-, and delta-sarcoglycan and sarcospan (PMID:10993904). Its structural role in complex assembly can be substituted by the homolog zeta-sarcoglycan (PMID:16635485). Correct dosage and membrane targeting are critical: overexpression produces cytoplasmic aggregates and dystrophy (PMID:11287429), and transcription is driven by MyoD-dependent myogenic enhancers (PMID:11179961). Distinct from its scaffolding role, gamma-sarcoglycan transduces mechanical signals: its intracellular Tyr6 is dispensable for sarcolemmal localization but required for eccentric-contraction-induced ERK1/2 phosphorylation (PMID:20371873), and its loss causes sustained, dysregulated mTOR/p70S6K activation after stretch (PMID:25024843). Mechanotransduction is mediated through interactions with archvillin, whose mechanically stimulated association with P-ERK1/2 requires gamma-sarcoglycan (PMID:25605665), and with NKCC1 (SLC12A2), whose inhibition blunts strain-induced ERK1/2 signaling (PMID:35065666). Gamma-sarcoglycan additionally localizes to the sarcoplasmic reticulum (PMID:11259456), binds biglycan as an extracellular ligand and developmental regulator (PMID:16883602), and is subject to N-linked glycosylation (PMID:37929139).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1995 High

    Established that gamma-sarcoglycan is genetically required for the integrity of the entire sarcoglycan complex, linking SGCG mutations to muscular dystrophy.

    Evidence Genetic mapping and mutation analysis in SCARMD patients with protein complex assessment

    PMID:7481775

    Open questions at the time
    • Did not define the molecular interactions stabilizing the complex
    • No mechanism for membrane damage downstream of complex loss
  2. 1996 Medium

    Mapped the C-terminal cysteine-rich region as essential for complex stability and demonstrated tight, SDS-resistant biochemical association among sarcoglycans.

    Evidence Mutation analysis of patient biopsies with subunit immunostaining; SDS-resistance co-fractionation of the dystrophin-glycoprotein complex

    PMID:8641426 PMID:8923014

    Open questions at the time
    • No atomic structure of the interaction interfaces
    • Stoichiometry of the assembled complex not resolved
  3. 1998 High

    Showed via genetic knockout that beta/gamma/delta-sarcoglycans form an interdependent unit and that sarcoglycan loss alone causes membrane damage and apoptosis independent of dystrophin.

    Evidence Homologous recombination knockout mouse with Evans blue staining, immunofluorescence, and TUNEL

    PMID:9732288

    Open questions at the time
    • Did not establish the signaling mechanism linking loss to apoptosis
    • Dystrophin-independent function left mechanistically undefined
  4. 2000 Medium

    Extended gamma-sarcoglycan function to smooth muscle, defining a distinct sarcoglycan-sarcospan complex separate from the striated-muscle assembly.

    Evidence Co-immunoprecipitation and biochemical analysis of smooth muscle membranes plus patient tissue

    PMID:10993904

    Open questions at the time
    • Functional role of the smooth muscle complex not tested
    • Tissue-specific assembly determinants unknown
  5. 2001 Medium

    Defined the determinants of correct expression and assembly: MyoD-driven myogenic transcription, dosage sensitivity, and SR localization beyond the sarcolemma.

    Evidence Promoter reporter/EMSA assays; transgenic overexpression mouse; confocal and immunoelectron microscopy

    PMID:11179961 PMID:11259456 PMID:11287429

    Open questions at the time
    • SR-specific function of gamma-sarcoglycan not defined
    • Mechanism of aggregate-induced dystrophy on overexpression unclear
  6. 2006 Medium

    Identified biglycan as a direct extracellular ligand and developmental regulator, and showed zeta-sarcoglycan can structurally substitute for gamma-sarcoglycan.

    Evidence Ligand blot overlay, reciprocal Co-IP and chimera mapping; co-transfection/IP of all six sarcoglycans in CHO cells

    PMID:16635485 PMID:16883602

    Open questions at the time
    • Functional consequence of biglycan binding for signaling not established
    • Why zeta cannot fully rescue in vivo not addressed
  7. 2010 High

    Separated gamma-sarcoglycan's localization and signaling functions, showing intracellular Tyr6 is required for mechanically induced ERK1/2 signaling but not membrane targeting.

    Evidence Viral gene transfer of WT and Y6A mutants into gsg-/- muscle with localization and post-eccentric-contraction ERK1/2 readouts

    PMID:20371873

    Open questions at the time
    • Kinase/adaptor acting on Tyr6 not identified
    • Direct phosphorylation status of Tyr6 not demonstrated
  8. 2010 Low

    Indicated that delta-sarcoglycan stabilizes gamma-sarcoglycan in both T-tubule and SR membranes.

    Evidence Immunoblotting of purified TT and SR fractions from delta-SG knockout mice

    PMID:20638123

    Open questions at the time
    • Single method (immunoblotting) with no direct interaction experiment for gamma-SG
    • Does not distinguish stabilization from co-trafficking
  9. 2014 Medium

    Demonstrated that gamma-sarcoglycan is required to terminate the mTOR/p70S6K mechanotransduction response, with its loss causing sustained, calcium-independent pathway activation.

    Evidence Cyclic stretch of myotubes/muscles from WT and gamma-SG-null mice with phospho-immunoblotting and rapamycin/calcium-chelation pharmacology

    PMID:25024843

    Open questions at the time
    • Molecular link between gamma-SG and mTOR not defined
    • Rapamycin-resistant S6RP phosphorylation unexplained
  10. 2015 Medium

    Identified archvillin as a gamma-sarcoglycan-interacting, mechanically sensitive signaling component bridging the complex to ERK1/2.

    Evidence Yeast two-hybrid screen with in vivo immunofluorescence, rAAV rescue, eccentric contractions, and Co-IP with P-ERK1/2

    PMID:25605665

    Open questions at the time
    • Direct binding interface on gamma-sarcoglycan not mapped
    • Whether archvillin recruitment is Tyr6-dependent untested
  11. 2019 Medium

    Provided the first structural characterization of full-length gamma-sarcoglycan as a purified membrane glycoprotein.

    Evidence Recombinant E. coli expression, chemical cleavage, and 15N solution NMR in detergents

    PMID:31682967

    Open questions at the time
    • Only preliminary spectra, no resolved structure
    • Detergent environment may not reflect native bilayer
  12. 2022 Medium

    Identified NKCC1 (SLC12A2) as a novel complex-associated partner functionally linked to gamma-sarcoglycan-dependent mechanosignaling.

    Evidence LC-MS/MS of anti-Sgcg sarcolemmal immunoprecipitates with Co-IP, co-localization, and bumetanide inhibition of strain-induced ERK1/2

    PMID:35065666

    Open questions at the time
    • Whether the interaction is direct vs complex-mediated unresolved
    • Single lab; reciprocal endogenous validation limited
  13. 2023 Medium

    Reconstituted N-linked glycosylation of gamma-sarcoglycan in a lipid bilayer, confirming the asparagine modification can occur enzymatically in vitro.

    Evidence Nanodisc reconstitution with in vitro oligosaccharyltransferase glycosylation assay, validated by SDS-PAGE and MS

    PMID:37929139

    Open questions at the time
    • Functional role of glycosylation in vivo not established
    • Single in vitro demonstration

Open questions

Synthesis pass · forward-looking unresolved questions
  • How gamma-sarcoglycan mechanically couples sarcolemmal strain to intracellular ERK1/2 and mTOR/p70S6K signaling at the molecular level remains undefined.
  • No identified kinase phosphorylating Tyr6
  • No high-resolution structure of the assembled complex or its signaling interfaces
  • Direct mechanistic chain from gamma-SG to archvillin/NKCC1 to ERK/mTOR not reconstituted

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3 GO:0060089 molecular transducer activity 3
Localization
GO:0005886 plasma membrane 3 GO:0005783 endoplasmic reticulum 2
Complex memberships
dystrophin-glycoprotein complexsarcoglycan-sarcospan complex

Evidence

Reading pass · 17 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Mutations in gamma-sarcoglycan (SGCG) not only abolish gamma-sarcoglycan but also disrupt the integrity of the entire sarcoglycan complex, establishing that gamma-sarcoglycan is required for complex integrity. Genetic mapping and mutation analysis in SCARMD patients combined with protein complex assessment Science High 7481775
1996 Frameshifting mutations disrupting the distal carboxyl-terminus of gamma-sarcoglycan result in complete absence of both gamma- and beta-sarcoglycan, demonstrating that the C-terminal region (which contains EGF-like cysteine-rich sequences) is essential for stability of the sarcoglycan complex. Mutation analysis of patient muscle biopsies combined with immunostaining for sarcoglycan subunits Human molecular genetics Medium 8923014
1996 Alpha-, beta-, and gamma-sarcoglycan constitute a tightly associated sarcolemmal complex that cannot be disrupted by SDS treatment, demonstrating their strong biochemical interdependence at the sarcolemma. Immunofluorescence, Western blotting, and SDS-resistance co-fractionation of the dystrophin-glycoprotein complex from skeletal muscle FEBS letters Medium 8641426
1998 Genetic knockout of gamma-sarcoglycan in mice causes secondary reduction of beta- and delta-sarcoglycan with partial retention of alpha- and epsilon-sarcoglycan, indicating that beta-, gamma-, and delta-sarcoglycan function as a unit. Membrane disruptions and apoptosis occurred independently of dystrophin loss, demonstrating that sarcoglycan loss is itself sufficient to cause membrane defects. Homologous recombination knockout mouse; Evans blue dye vital staining; immunofluorescence; TUNEL apoptosis assay The Journal of cell biology High 9732288
2000 Gamma-sarcoglycan is expressed in smooth muscle and associates with epsilon-, beta-, and delta-sarcoglycans and sarcospan to form the smooth muscle sarcoglycan-sarcospan complex, distinct from the striated muscle complex. Immunoblotting, co-immunoprecipitation/biochemical analysis of smooth muscle membranes, smooth muscle cell culture, and analysis of animal models and a patient with gamma-sarcoglycanopathy The Journal of biological chemistry Medium 10993904
2001 Overexpression of gamma-sarcoglycan in mouse muscle leads to cytoplasmic aggregates that prevent normal membrane targeting, upregulation of alpha- and beta-sarcoglycan, and severe muscular dystrophy — demonstrating that proper dosage and membrane localization of gamma-sarcoglycan are critical for correct sarcoglycan complex assembly. Transgenic mouse overexpression under muscle creatine kinase promoter; histology; immunofluorescence; Western blotting The Journal of biological chemistry Medium 11287429
2001 The gamma-sarcoglycan promoter contains a basal promoter region and two myogenesis-dependent enhancer regions; A/T-rich and E-box elements in the upstream enhancer are essential for activation after myotube formation, and MyoD acts as a trans-activator of gamma-sarcoglycan transcription. Reporter gene constructs with promoter deletions in C2C12 cells; co-transfection with MyoD expression vectors in 10T1/2 fibroblasts; electrophoretic mobility shift assay for binding protein identification European journal of biochemistry Medium 11179961
2001 Delta- and gamma-sarcoglycans localize not only to the sarcolemma but also to the sarcoplasmic reticulum in skeletal muscle: delta-sarcoglycan is found in terminal cisternae, while gamma-sarcoglycan is found in both terminal cisternae and longitudinal SR over I-bands, suggesting functions independent of the dystrophin complex in the SR. Confocal microscopy and immunoelectron microscopy with subcellular marker co-labeling in rat and mouse skeletal muscle The journal of histochemistry and cytochemistry Medium 11259456
2006 Biglycan physically binds to gamma-sarcoglycan (as well as alpha-sarcoglycan) via distinct sites on its polypeptide core, and is a component of the dystrophin glycoprotein complex isolated from skeletal muscle membranes. In biglycan-null mice, gamma-sarcoglycan expression is selectively reduced at early developmental stages (P14–P21), establishing biglycan as a ligand and developmental regulator of gamma-sarcoglycan. Ligand blot overlay, co-immunoprecipitation, biglycan-decorin chimeras, biochemical fractionation of skeletal muscle membranes, immunohistochemistry and Western blotting in biglycan-null mice Journal of cellular physiology Medium 16883602
2006 Zeta-sarcoglycan can substitute for gamma-sarcoglycan in forming a sarcoglycan complex (alpha-beta-zeta-delta), demonstrating that gamma-sarcoglycan's structural role in complex formation can be fulfilled by its homolog zeta-sarcoglycan. Co-transfection of expression vectors for all six sarcoglycans and dystroglycan into CHO cells followed by immunoprecipitation analysis Experimental cell research Medium 16635485
2010 Tyrosine 6 (Tyr6) in the intracellular domain of gamma-sarcoglycan is not required for sarcolemmal localization, but is required for normal ERK1/2 phosphorylation signaling after eccentric contractions — demonstrating that localization and mechanical signal transduction are molecularly separable functions of gamma-sarcoglycan. Viral-mediated gene transfer of wild-type and Y6A mutant gamma-sarcoglycan into gsg-/- mouse muscle; immunofluorescence for localization; immunoblotting for ERK1/2 phosphorylation after eccentric contractions The Journal of biological chemistry High 20371873
2014 Loss of gamma-sarcoglycan elevates basal p70S6K activation in skeletal muscle in a calcium-independent manner and causes sustained (rather than transient) p70S6K activation after stretch; rapamycin blocks p70S6K but cannot normalize downstream S6RP phosphorylation in gamma-SG-null muscle, indicating gamma-sarcoglycan is required for proper inactivation of the mTOR/p70S6K mechanotransduction pathway. Cyclic passive stretch of C2C12 myotubes, primary cultures and isolated muscles from C57 and gamma-SG-null mice; immunoblotting for phosphorylated signaling proteins; rapamycin and calcium-chelation pharmacological experiments Skeletal muscle Medium 25024843
2015 Gamma-sarcoglycan interacts with the muscle-specific protein archvillin (identified by yeast two-hybrid), and loss of gamma-sarcoglycan causes archvillin upregulation and delocalization at the sarcolemma as well as ablation of the mechanically stimulated archvillin–P-ERK1/2 association, positioning archvillin as a mechanically sensitive signaling component downstream of gamma-sarcoglycan. Yeast two-hybrid screen; immunofluorescence and Western blotting in gsg-/- and mdx mouse muscle; rAAV rescue experiments; in situ eccentric contractions with P-ERK1/2 nuclear activation analysis; co-immunoprecipitation of archvillin with P-ERK1/2 Human molecular genetics Medium 25605665
2019 Full-length recombinant gamma-sarcoglycan (SGCG) was expressed, purified, and subjected to solution NMR spectroscopy in detergent environments, yielding the first NMR spectra of the full-length membrane glycoprotein and providing initial structural characterization. Recombinant expression in E. coli inclusion bodies using TrpΔLE fusion; chemical cleavage; size-exclusion chromatography; SDS-PAGE; mass spectrometry; 15N-labeled solution NMR spectroscopy Protein expression and purification Medium 31682967
2022 Proteomic analysis of gamma-sarcoglycan immunoprecipitates from sarcolemmal fractions identified NKCC1 (SLC12A2) as a novel gamma-sarcoglycan complex-associated protein; NKCC1 co-localizes with gamma-sarcoglycan upon co-expression in RH30 cells and co-immunoprecipitates via its cytosolic domains. Pharmacological inhibition of NKCC1 with bumetanide reduces strain-induced ERK1/2 phosphorylation in isolated muscles, linking NKCC1 to gamma-sarcoglycan-dependent mechanosignaling. LC-MS/MS proteomics of anti-Sgcg immunoprecipitates from enriched sarcolemmal fractions; co-expression and co-immunoprecipitation in RH30 rhabdomyosarcoma cells; immunofluorescence co-localization; bumetanide pharmacological inhibition with ERK1/2 phosphorylation readout in isolated muscles Skeletal muscle Medium 35065666
2023 Gamma-sarcoglycan incorporated into nanodiscs can undergo N-linked glycosylation in vitro by enzymatic transfer of sugar to an asparagine residue, demonstrating that this post-translational modification can be reconstituted in a lipid bilayer environment. Nanodisc reconstitution with long-chain lipids and membrane scaffold proteins; in vitro N-linked glycosylation assay with oligosaccharyltransferase; SDS-PAGE and mass spectrometry validation ACS omega Medium 37929139
2010 In delta-sarcoglycan knockout mice, gamma-sarcoglycan expression is secondarily reduced in both transverse tubule and sarcoplasmic reticulum membranes, demonstrating that delta-sarcoglycan stabilizes gamma-sarcoglycan in these intracellular membrane compartments. Immunoblotting of purified TT and SR membrane fractions from wild-type and delta-SG knockout mice Cell calcium Low 20638123

Source papers

Stage 0 corpus · 40 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Mutations in the dystrophin-associated protein gamma-sarcoglycan in chromosome 13 muscular dystrophy. Science (New York, N.Y.) 468 7481775
1998 Gamma-sarcoglycan deficiency leads to muscle membrane defects and apoptosis independent of dystrophin. The Journal of cell biology 256 9732288
1996 Mutations that disrupt the carboxyl-terminus of gamma-sarcoglycan cause muscular dystrophy. Human molecular genetics 135 8923014
1996 A founder mutation in the gamma-sarcoglycan gene of gypsies possibly predating their migration out of India. Human molecular genetics 118 8968757
1996 Mild and severe muscular dystrophy caused by a single gamma-sarcoglycan mutation. American journal of human genetics 113 8900232
2000 Rescue of skeletal muscles of gamma-sarcoglycan-deficient mice with adeno-associated virus-mediated gene transfer. Molecular therapy : the journal of the American Society of Gene Therapy 80 10933922
1996 Abnormalities in alpha-, beta- and gamma-sarcoglycan in patients with limb-girdle muscular dystrophy. Neuromuscular disorders : NMD 67 9027857
2012 A phase I trial of adeno-associated virus serotype 1-γ-sarcoglycan gene therapy for limb girdle muscular dystrophy type 2C. Brain : a journal of neurology 66 22240777
1996 Absence of gamma-sarcoglycan (35 DAG) in autosomal recessive muscular dystrophy linked to chromosome 13q12. FEBS letters 54 8641426
2000 Homogeneous phenotype of the gypsy limb-girdle MD with the gamma-sarcoglycan C283Y mutation. Neurology 52 10720277
2001 Overexpression of gamma-sarcoglycan induces severe muscular dystrophy. Implications for the regulation of Sarcoglycan assembly. The Journal of biological chemistry 51 11287429
2006 Biglycan binds to alpha- and gamma-sarcoglycan and regulates their expression during development. Journal of cellular physiology 46 16883602
2000 Expression of gamma -sarcoglycan in smooth muscle and its interaction with the smooth muscle sarcoglycan-sarcospan complex. The Journal of biological chemistry 43 10993904
2003 Pathological analysis of muscle hypertrophy and degeneration in muscular dystrophy in gamma-sarcoglycan-deficient mice. Neuromuscular disorders : NMD 31 12609501
2006 Zeta-sarcoglycan is a functional homologue of gamma-sarcoglycan in the formation of the sarcoglycan complex. Experimental cell research 25 16635485
1998 A novel gamma-sarcoglycan mutation causing childhood onset, slowly progressive limb girdle muscular dystrophy. Neuromuscular disorders : NMD 23 9673983
2015 Gamma-sarcoglycan is required for the response of archvillin to mechanical stimulation in skeletal muscle. Human molecular genetics 20 25605665
2005 gamma-Sarcoglycan deficiency increases cell contractility, apoptosis and MAPK pathway activation but does not affect adhesion. Journal of cell science 20 15769854
2001 Identification of myogenesis-dependent transcriptional enhancers in promoter region of mouse gamma-sarcoglycan gene. European journal of biochemistry 20 11179961
1998 Different manners of sarcoglycan expression in genetically proven alpha-sarcoglycan deficiency and gamma-sarcoglycan deficiency. Acta neuropathologica 19 9705137
1998 Severe limb girdle muscular dystrophy in Spanish gypsies: further evidence for a founder mutation in the gamma-sarcoglycan gene. European journal of human genetics : EJHG 18 9781048
2016 Collagen VI deficiency reduces muscle pathology, but does not improve muscle function, in the γ-sarcoglycan-null mouse. Human molecular genetics 17 26908621
2014 Absence of γ-sarcoglycan alters the response of p70S6 kinase to mechanical perturbation in murine skeletal muscle. Skeletal muscle 15 25024843
2001 delta- and gamma-Sarcoglycan localization in the sarcoplasmic reticulum of skeletal muscle. The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society 14 11259456
2023 Systemic γ-sarcoglycan AAV gene transfer results in dose-dependent correction of muscle deficits in the LGMD 2C/R5 mouse model. Molecular therapy. Methods & clinical development 13 36816759
2010 Restoration of gamma-sarcoglycan localization and mechanical signal transduction are independent in murine skeletal muscle. The Journal of biological chemistry 13 20371873
2017 γ-sarcoglycan and dystrophin mutation spectrum in an Algerian cohort. Muscle & nerve 11 27759885
2014 Sarcolemmal alpha and gamma sarcoglycan protein deficiencies in Turkish siblings with a novel missense mutation in the alpha sarcoglycan gene. Pediatric neurology 11 24742800
2001 Analysis of the spatial, temporal and tissue-specific transcription of gamma-sarcoglycan gene using a transgenic mouse. FEBS letters 11 11322951
2000 Private beta- and gamma-sarcoglycan gene mutations: evidence of a founder effect in Northern Italy. Human mutation 11 10874299
2010 Altered calcium pump and secondary deficiency of gamma-sarcoglycan and microspan in sarcoplasmic reticulum membranes isolated from delta-sarcoglycan knockout mice. Cell calcium 10 20638123
1999 C283Y mutation and other C-terminal nucleotide changes in the gamma-sarcoglycan gene in the Bulgarian Gypsy population. Human mutation 10 10447257
2002 Screening for C283Y gamma-sarcoglycan mutation in a high-risk group of Bulgarian Gypsies: evidence for a geographical localization and a non-random distribution among Gypsy subgroups. Community genetics 9 14960875
2004 C283Y gamma-sarcoglycan gene mutation in the Bulgarian Roma (Gypsy) population: prevalence study and carrier screening in a high-risk community. Clinical genetics 7 15479193
2019 Expression, purification, and structural analysis of the full-length human integral membrane protein γ-sarcoglycan. Protein expression and purification 5 31682967
2022 Novel γ-sarcoglycan interactors in murine muscle membranes. Skeletal muscle 3 35065666
2014 Concomitant alpha- and gamma-sarcoglycan deficiencies in a Turkish boy with a novel deletion in the alpha-sarcoglycan gene. Case reports in genetics 3 25050186
2002 [Muscular dystrophy due to a deficit of gamma-sarcoglycan. A report of three patients with the Delta-521t mutation]. Revista de neurologia 3 12040521
2023 In Vitro Glycosylation of the Membrane Protein γ-Sarcoglycan in Nanodiscs. ACS omega 2 37929139
2001 Characterization and chromosome assignment of the canine gamma-sarcoglycan gene (SGCG) to CFA 25q21-->q23. Cytogenetics and cell genetics 0 11856878

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