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The sarcoglycans

(last modified on October 09, 2004)


Contents



Introduction


The sarcoglycans are all N-glycosylated transmembrane proteins with a short intra-cellular domain, a single transmembrane region and a large extra-cellular domain containing a carboxyl-terminal cluster of several conserved cysteine residues Both alpha/epsilon-sarcoglycan (SGCA/SGCE) and gamma/delta-sarcoglycan (SGCG/SGCD) are closely related proteins which are similar in size and sequence. gamma- and delta-sarcoglycan also show significant similarity to zeta-sarcoglycan and to a lesser extent with beta-sarcoglycan.

The sarcoglycans form a complex of glycoproteins, integrated in the membrane, which is fixed to the dystrophin axis by a lateral association with the dystroglycan complex. While dystroglycan is found in nearly all cell types, the sarcoglycan complex is exclusively found in muscle. The sarcoglycan complex is thought to stabilize the interaction between alpha- and beta-sarcoglycan (Straub et al. 1998).  On the cytoplasmic surface, SGCG and SGCD bind a muscle-specific form of filamin (FLN2, Thompson et al. 2000).

The sarcoglycan constituents of the DGC differ between different tissues. The smooth muscle DGC contains dystrophin, alpha- and beta-dystroglycan, beta-, delta-, epsilon- and zeta-sarcoglycan and sarcospan. Furthermore, in smooth muscle, the molecular weight of delta-sarcoglycan appears to be slightly lower (Straub). Shi et al. (ASHG2002 abstract 940, Am.J.Hum.Genet. 71: S333) reported that the complex is generated by assembly of the sarcoglycans in a specific order. Assembly is initiated by SGCB to which SGCD binds. Next, SGCG binds to the complex at SGCD and finally SGCA attaches to SGCG.

SGCE-expression is both earlier and more widely than SGCA (Ettinger). The distribution of expression of SGCA and SGCE is also markedly different, with SGCA largely restricted to striated (cardiac and skeletal) muscle and very low levels in lung and none in brain (Ettinger). Althuogh alpha/epsilon-sarcoglycan and beta/gamma/delta-sarcoglycan have a related structure, their sequences differs greatly.

Since alpha- and gamma-sarcoglycan are not expressed in smooth muscle cells and epsilon-sarcoglycan is not an integral component of the skeletal muscle DGC, the association between the sarcoglycan-complex and alhpa-dystroglycan is either mediated by beta- and delta-sarcoglycan or by sarcospan (Straub). Similarly, since homozygous beta-sarcoglycan missense mutations result in the total absence of alpha-, beta- and gamma-sarcoglycan from the skeletal muscle membrane, it has also been suggested that beta-sarcoglycan plays a critical role in the assembly and/or maintenance of the sarcoglycan complex (B÷nnemann).


Individual sarcoglycans



Tabular overview

Protein Gene
symbol
Length
(aa)
Calculated weigth On gel PI Protein sequence mRNA
(kb)
cDNA sequence Gene size (kb) Exons Genomic sequence
alpha-sarcoglycan SGCA 387 43,255 50 (5.7) NP_000014 1.5 NM_000023 17 10  
beta-sarcoglycan SGCB 318 34,777 43 9.2 NP_000223 4.3 NM_000232 15 6  
gamma-sarcoglycan SGCG 291 32,350 35 5.0 NP_000222   NM_000231 144 8  
delta-sarcoglycan SGCD 290 32,174 35   NP_000328 8.0 NM_000337 433 9  
epsilon-sarcoglycan SGCE 405 43.5 45 5.8 NM_011360 1.7 NM_003919  71 12 AC069292
zeta-sarcoglycan SGCZ 299       NP_631906    NM_139167 >465 8  

Legend:
Protein: name of the protein. Gene symbol: official gene symbol for the gene. Length: length of the protein in amino acids (aa). Calculated weigth: calculated molecular mass of the protein in Daltons. On gel: observed molecular mass on polyacrylamide gel (in kilo Dalton). PI: calculated isoelectric point. mRNA: length of the mRNA on Northern blot (in kilobases). cDNA-sequence: referende cDNA-sequence. Exons: number of exons. Genomic sequence: genomic sequence containing the gene sequence.


Sarcoglycans and disease


Mutations in the proteins of the sarcoglycan complex appear to be a significant cause of recessive autosomally inherited muscular dystrophy. The phenotypes range from closely resembling Duchenne (DLMD = Duchenne-like muscular dystrophy / SCARMD = severe childhood autosomal recessive muscular dystrophy) to the late-onset forms of Limb-Girdle muscular dystrophy (LGMD). Together, these diseases are indicated as the "sarcoglycanopathies". The differences in the expression of the sarcoglycans, especially those between SGCA/SGCE versus SGCB/SGCG/SGCD (where smooth muscle seems unaffected), have been suggested to cause clinical differences. Straub et al. suggest that, based on the differences in sarcoglycan expression, analysis of skin biopsies might be helpful in the diagnosis of LGMD.

Frequency of sarcoglycanopathies

The relative frequency of the different sarcoglycanopathies differs world-wide. Moreira et al. (2003) report that in 48 families and sporadic cases where a suspect of a sarcoglycanopathy was present,  mutations could be identified in both alleles in 35; SGCA 14 (40%), SGCB 8 (23%), SGCG 8 (23%) and SGCD 5 (14%). Mutations were not found in 8 unrelated patients showing a severe course, including one in whom muscle analysis showed deficiency of all sarcoglycans. In Europe and North America the great majority of patients deficient for the sarcoglycan proteins carry changes in SGCA (Fanin [1997], Angelini [1999], Duggan [1997]). Changes in SGCG are found in almost 100% of the sarcoglycanopathies in Northern Africa (Othmane [1995]). Changes in SGCD seem to be rare all over the world (Fanin [1997], Duggan [1997], Zatz [2000], Duggan [1997]). Several alterations were probably introduced into Brazil by African ancestries, including SGCG:c.521delT and SGCD:c.656delC; all patients in these two subgroups share a common haplotype (McNally [1996], Moreira [1998]). The recurring SGCA:c.229C>T change is associated with at least three distinct haplotypes in Brazil (Passo Bueno [1995]).

Duggan et al. (1997) reported that in a set of 263 patients with a dystrophinopathy-like disorder (DLMD or LGMD) and normal dystrophin, 25 (10%) showed a complete and 29 (11%) a partial alpha-sarcoglycan deficiency in muscle biopsy samples. RNA-derived mutation analysis in 50 of these 54 patients revealed sarcoglycan mutations in 32 (59%, Duggan et al. [1997]):

Affected
protein
alpha-sarcoglycan
absent (N=25)
alpha-sarcoglycan
reduced (N=29)
Total (N=54) Brazil
(Moreira)
alpha-sarcoglycan 15 (60%) 3 (10%) 18 (33%) 14 (40%)
beta-sarcoglycan 5 (20%) 3 (10%) 8 (15%) 8 (23%)
gamma-sarcoglycan 0 (0%) 4 (14%) 4 (7%) 8 (23%)
delta-sarcoglycan 2 (8%) 0 (0%) 2 (4%) 5 (14%)
epsilon-sarcoglycan ? ? ?  
zeta-sarcoglycan ? ? ?  
TOTAL 22 (88%) 10 (34%) 32 (59%)  


The observation that in sarcoglycanaopathies the alpha-sarcoglycan gene is mutated most frequently was confirmed by CarriÚ et al. (1997) who found alpha-sarcoglycan mutations in 20 out of 51 (39%) unrelated families scanned.

Sarcoglycan sequence variations


Sarcoglycan homologies



Alignment of sarcoglycan protein sequences


Not available yet


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