SGCG explained

Gamma-sarcoglycan is a protein that in humans is encoded by the SGCG gene.^{[1] [2]} The α to δ-sarcoglycans are expressed predominantly (β) or exclusively (α, γ and δ) in striated muscle.^[3] A mutation in any of the sarcoglycan genes may lead to a secondary deficiency of the other sarcoglycan proteins, presumably due to destabilisation of the sarcoglycan complex.^[4] The disease-causing mutations in the α to δ genes cause disruptions within the dystrophin-associated protein (DAP) complex in the muscle cell membrane.^[5] The transmembrane components of the DAP complex link the cytoskeleton to the extracellular matrix in adult muscle fibres,^[6] and are essential for the preservation of the integrity of the muscle cell membrane.^[7]

Function

Gamma-sarcoglycan is one of several sarcolemmal transmembrane glycoproteins that interact with dystrophin, probably to provide a link between the membrane associated cytoskeleton and the extracellular matrix. Defects in the protein can lead to early onset autosomal recessive muscular dystrophy, in particular limb-girdle muscular dystrophy, type 2C (LGMD2C).

Structure

Gene

Human SGCG gene maps to chromosome 13 at q12, spans over 100 kb of DNA and includes 8 exons.^[8]

Protein

Gamma-sarcoglycan is a type II transmembrane protein and consists of 291 amino acids. It has a 35 amino acid intracellular N-terminal region, a 25 amino acid single transmembrane domain, and a 231 amino acid extra-cellular C-terminus.^[4]

Clinical significance

Sarcoglycanopathies are autosomal recessive limb girdle muscular dystrophies (LGMDs) caused by mutations in any of the four sarcoglycan genes: α (LGMD2D), β (LGMD2E), γ (LGMD2C) and δ (LGMD2F).^[3] Severe childhood autosomal recessive muscular dystrophy (SCARMD) is a progressive muscle-wasting disorder that segregates with microsatellite markers at γ-sarcoglycan gene. Mutations in the γ-sarcoglycan gene were first described in the Maghreb countries of North Africa,^[9] where γ-sarcoglycanopathy has a higher than usual incidence. One common mutation, Δ-521T, which causes a severe phenotype, occurs both in the Maghreb population and in other countries.^[8] A Cys283Tyr mutation has been identified in the Gypsy population causing a severe phenotype and a Leu193Ser mutation which causes a mild phenotype.^{[1] [10]}

Interactions

SGCG has been shown to interact with FLNC.^{[11] [12]}

Further reading

• Noguchi S, McNally EM, Ben Othmane K, Hagiwara Y, Mizuno Y, Yoshida M, Yamamoto H, Bönnemann CG, Gussoni E, Denton PH, Kyriakides T, Middleton L, Hentati F, Ben Hamida M, Nonaka I, Vance JM, Kunkel LM, Ozawa E . Mutations in the dystrophin-associated protein gamma-sarcoglycan in chromosome 13 muscular dystrophy. . Science . 270 . 5237 . 819–22 . 1995 . 7481775 . 10.1126/science.270.5237.819 . 1995Sci...270..819N . 84713401 .
• Ben Othmane K, Speer MC, Stauffer J, Blel S, Middleton L, Ben Hamida C, Etribi A, Loeb D, Hentati F, Roses AD . Evidence for linkage disequilibrium in chromosome 13-linked Duchenne-like muscular dystrophy (LGMD2C) . Am. J. Hum. Genet. . 57 . 3 . 732–4 . 1995 . 7668303 . 1801260 .
• Jorde LB, Watkins WS, Viskochil D, O'Connell P, Ward K . Linkage disequilibrium in the neurofibromatosis 1 (NF1) region: implications for gene mapping. . Am. J. Hum. Genet. . 53 . 5 . 1038–50 . 1993 . 8105688 . 1682302 .
• Jung D, Leturcq F, Sunada Y, Duclos F, Tomé FM, Moomaw C, Merlini L, Azibi K, Chaouch M, Slaughter C, Fardeau M, Kaplan JC, Campbell KP . Absence of gamma-sarcoglycan (35 DAG) in autosomal recessive muscular dystrophy linked to chromosome 13q12. . FEBS Lett. . 381 . 1–2 . 15–20 . 1996 . 8641426 . 10.1016/0014-5793(96)00056-7 . free .
• McNally EM, Passos-Bueno MR, Bönnemann CG, Vainzof M, de Sá Moreira E, Lidov HG, Othmane KB, Denton PH, Vance JM, Zatz M, Kunkel LM . Mild and severe muscular dystrophy caused by a single gamma-sarcoglycan mutation. . Am. J. Hum. Genet. . 59 . 5 . 1040–7 . 1996 . 8900232 . 1914841 .
• McNally EM, Duggan D, Gorospe JR, Bönnemann CG, Fanin M, Pegoraro E, Lidov HG, Noguchi S, Ozawa E, Finkel RS, Cruse RP, Angelini C, Kunkel LM, Hoffman EP . Mutations that disrupt the carboxyl-terminus of gamma-sarcoglycan cause muscular dystrophy. . Hum. Mol. Genet. . 5 . 11 . 1841–7 . 1997 . 8923014 . 10.1093/hmg/5.11.1841 . free .
• Chan YM, Bönnemann CG, Lidov HG, Kunkel LM . Molecular organization of sarcoglycan complex in mouse myotubes in culture. . J. Cell Biol. . 143 . 7 . 2033–44 . 1999 . 9864373 . 2175228 . 10.1083/jcb.143.7.2033 .
• Thompson TG, Chan YM, Hack AA, Brosius M, Rajala M, Lidov HG, McNally EM, Watkins S, Kunkel LM . Filamin 2 (FLN2): A muscle-specific sarcoglycan interacting protein. . J. Cell Biol. . 148 . 1 . 115–26 . 2000 . 10629222 . 3207142 . 10.1083/jcb.148.1.115 .
• Nowak KJ, Walsh P, Jacob RL, Johnsen RD, Peverall J, McNally EM, Wilton SD, Kakulas BA, Laing NG . Severe gamma-sarcoglycanopathy caused by a novel missense mutation and a large deletion. . Neuromuscul. Disord. . 10 . 2 . 100–7 . 2000 . 10714584 . 10.1016/S0960-8966(99)00063-2 . 54410727 .
• Yoshida M, Hama H, Ishikawa-Sakurai M, Imamura M, Mizuno Y, Araishi K, Wakabayashi-Takai E, Noguchi S, Sasaoka T, Ozawa E . Biochemical evidence for association of dystrobrevin with the sarcoglycan-sarcospan complex as a basis for understanding sarcoglycanopathy. . Hum. Mol. Genet. . 9 . 7 . 1033–40 . 2000 . 10767327 . 10.1093/hmg/9.7.1033 . free .
• Crosbie RH, Lim LE, Moore SA, Hirano M, Hays AP, Maybaum SW, Collin H, Dovico SA, Stolle CA, Fardeau M, Tomé FM, Campbell KP . Molecular and genetic characterization of sarcospan: insights into sarcoglycan-sarcospan interactions. . Hum. Mol. Genet. . 9 . 13 . 2019–27 . 2000 . 10942431 . 10.1093/hmg/9.13.2019 . free .
• Barresi R, Moore SA, Stolle CA, Mendell JR, Campbell KP . Expression of gamma -sarcoglycan in smooth muscle and its interaction with the smooth muscle sarcoglycan-sarcospan complex. . J. Biol. Chem. . 275 . 49 . 38554–60 . 2001 . 10993904 . 10.1074/jbc.M007799200 . free .
• Wheeler MT, Zarnegar S, McNally EM . Zeta-sarcoglycan, a novel component of the sarcoglycan complex, is reduced in muscular dystrophy. . Hum. Mol. Genet. . 11 . 18 . 2147–54 . 2003 . 12189167 . 10.1093/hmg/11.18.2147 . free .
• Vermeer S, Verrips A, Willemsen MA, ter Laak HJ, Ginjaar IB, Hamel BC . Novel mutations in three patients with LGMD2C with phenotypic differences. . Pediatr. Neurol. . 30 . 4 . 291–4 . 2004 . 15087111 . 10.1016/j.pediatrneurol.2003.11.006 .
• White SJ, Uitte de Willige S, Verbove D, Politano L, Ginjaar I, Breuning MH, den Dunnen JT . Sarcoglycanopathies and the risk of undetected deletion alleles in diagnosis. . Hum. Mutat. . 26 . 1 . 59 . 2006 . 15954112 . 10.1002/humu.9347 . free .
• Duncan DR, Kang PB, Rabbat JC, Briggs CE, Lidov HG, Darras BT, Kunkel LM . A novel mutation in two families with limb-girdle muscular dystrophy type 2C. . Neurology . 67 . 1 . 167–9 . 2006 . 16832103 . 10.1212/01.wnl.0000223600.78363.dd . 35310350 .
• Rafii MS, Hagiwara H, Mercado ML, Seo NS, Xu T, Dugan T, Owens RT, Hook M, McQuillan DJ, Young MF, Fallon JR . Biglycan binds to alpha- and gamma-sarcoglycan and regulates their expression during development. . J. Cell. Physiol. . 209 . 2 . 439–47 . 2006 . 16883602 . 2929672 . 10.1002/jcp.20740 .

External links

• LOVD mutation database: SGCG

Notes and References

1. Piccolo F, Jeanpierre M, Leturcq F, Dodé C, Azibi K, Toutain A, Merlini L, Jarre L, Navarro C, Krishnamoorthy R, Tomé FM, Urtizberea JA, Beckmann JS, Campbell KP, Kaplan JC . A founder mutation in the gamma-sarcoglycan gene of gypsies possibly predating their migration out of India . Human Molecular Genetics . 5 . 12 . 2019–22 . Dec 1996 . 8968757 . 10.1093/hmg/5.12.2019 . free .
2. Web site: Entrez Gene: SGCG sarcoglycan, gamma (35kDa dystrophin-associated glycoprotein).
3. Noguchi S, McNally EM, Ben Othmane K, Hagiwara Y, Mizuno Y, Yoshida M, Yamamoto H, Bönnemann CG, Gussoni E, Denton PH, Kyriakides T, Middleton L, Hentati F, Ben Hamida M, Nonaka I, Vance JM, Kunkel LM, Ozawa E . Mutations in the dystrophin-associated protein gamma-sarcoglycan in chromosome 13 muscular dystrophy . Science . 270 . 5237 . 819–22 . Nov 1995 . 7481775 . 10.1126/science.270.5237.819. 1995Sci...270..819N . 84713401 .
4. Nowak KJ, Walsh P, Jacob RL, Johnsen RD, Peverall J, McNally EM, Wilton SD, Kakulas BA, Laing NG . Severe gamma-sarcoglycanopathy caused by a novel missense mutation and a large deletion . Neuromuscular Disorders . 10 . 2 . 100–7 . Feb 2000 . 10714584 . 10.1016/s0960-8966(99)00063-2. 54410727 .
5. Vainzof M, Passos-Bueno MR, Canovas M, Moreira ES, Pavanello RC, Marie SK, Anderson LV, Bonnemann CG, McNally EM, Nigro V, Kunkel LM, Zatz M . The sarcoglycan complex in the six autosomal recessive limb-girdle muscular dystrophies . Human Molecular Genetics . 5 . 12 . 1963–9 . Dec 1996 . 8968750 . 10.1093/hmg/5.12.1963. free .
6. Ettinger AJ, Feng G, Sanes JR . epsilon-Sarcoglycan, a broadly expressed homologue of the gene mutated in limb-girdle muscular dystrophy 2D . The Journal of Biological Chemistry . 272 . 51 . 32534–8 . Dec 1997 . 9405466 . 10.1074/jbc.272.51.32534. free .
7. Holt KH, Campbell KP . Assembly of the sarcoglycan complex. Insights for muscular dystrophy . The Journal of Biological Chemistry . 273 . 52 . 34667–70 . Dec 1998 . 9856984 . 10.1074/jbc.273.52.34667. free .
8. McNally EM, Duggan D, Gorospe JR, Bönnemann CG, Fanin M, Pegoraro E, Lidov HG, Noguchi S, Ozawa E, Finkel RS, Cruse RP, Angelini C, Kunkel LM, Hoffman EP . Mutations that disrupt the carboxyl-terminus of gamma-sarcoglycan cause muscular dystrophy . Human Molecular Genetics . 5 . 11 . 1841–7 . Nov 1996 . 8923014 . 10.1093/hmg/5.11.1841. free .
9. el Kerch F, Sefiani A, Azibi K, Boutaleb N, Yahyaoui M, Bentahila A, Vinet MC, Leturcq F, Bachner L, Beckmann J . Linkage analysis of families with severe childhood autosomal recessive muscular dystrophy in Morocco indicates genetic homogeneity of the disease in north Africa . Journal of Medical Genetics . 31 . 4 . 342–3 . Apr 1994 . 8071965 . 10.1136/jmg.31.4.342 . 1049813.
10. van der Kooi AJ, de Visser M, van Meegen M, Ginjaar HB, van Essen AJ, Jennekens FG, Jongen PJ, Leschot NJ, Bolhuis PA . A novel gamma-sarcoglycan mutation causing childhood onset, slowly progressive limb girdle muscular dystrophy . Neuromuscular Disorders . 8 . 5 . 305–8 . Jun 1998 . 9673983 . 10.1016/s0960-8966(98)00040-6. 33437157 .
11. Guyon JR, Kudryashova E, Potts A, Dalkilic I, Brosius MA, Thompson TG, Beckmann JS, Kunkel LM, Spencer MJ . Calpain 3 cleaves filamin C and regulates its ability to interact with gamma- and delta-sarcoglycans . Muscle Nerve . 28 . 4 . 472–83 . October 2003 . 14506720 . 10.1002/mus.10465 . 86353802 .
12. Thompson TG, Chan YM, Hack AA, Brosius M, Rajala M, Lidov HG, McNally EM, Watkins S, Kunkel LM . Filamin 2 (FLN2): A muscle-specific sarcoglycan interacting protein . J. Cell Biol. . 148 . 1 . 115–26 . January 2000 . 10629222 . 3207142 . 10.1083/jcb.148.1.115 .