(last modified December 28, 2004)
alpha-Sarcoglycan was first described by Ervasti et al. (1990) as a 50 kD protein which was associated with dystrophin. Roberds et al. (1993) first reported the cloning of alpha-sarcoglycan from rabbit. The gene for alpha-sarcoglycan maps to chromosome 17q21, spans 17 kb of genomic DNA and contains 10 exons. alpha-sarcoglycan is a 387 amino acid glycoprotein with an extracellular N-terminus, one transmembrane domain and an intra-cellular C-terminus. Initially, missense variations were found in both alleles of the gene in a family with late-onset severe chilhood autosomal recessive muscular dystrophy (SCARMD, Roberds et al. [1994]). Later, variations were described in other SCARMD families and in families with limb-girdle muscular dystrophy type 2D (LGMD-2D). In a larger patient study, Piccolo et al. (1995) reported that disease severity can vary from very mild to severe and correlates with alpha-sarcoglycan staining and the underlying variation, i.e. residual staining is found in a mild phenotype with missense variations while alpha-sarcoglycan staining is totally absent in severe cases with homozygous null variations.
Links to other databases:
Gene
Symbol nomenclature LocusLink OMIM Gene Map
GDB
alpha-Sarcoglycan (Gene Symbol SGCA, aliases ADL [adhalin], 50DAG, DAG2, LGMD2D, A2, SCARMD1) was first described by Ervasti et al. (1990) as a 50 kilodalton protein which was associated with dystrophin. Roberds et al. (1993) first reported the cloning of the alpha-sarcoglycan from a rabbit skeletal muscle cDNA expression library using an alpha-sarcoglycan antibody. The gene maps to chromosome 17q21.33. The alpha-sarcoglycan gene spans 17 kb of genomic DNA and contains 10 exons. The SGCA gene is flanked 5' by the protein phosphatase 1, regulatory subunit 9B (PPP1R9B) gene and 3' by the collagen type I alpha 1 (COL1A1) gene (both transcribed from the opposite DNA strand).
| Exon | Exon size (bp) | Intron size (in bp) |
5' cDNA position | Splice after | Remarks |
|---|---|---|---|---|---|
| 1a | (103) | ~3.0 kb | starts in exon 4 | alternative 5' end | |
| 1 | (84) | 1,291 | -84 | 1 | 5'UTR / 37 bp coding |
| 2 | 120 | 94 | 38 | 1 | |
| 3 | 155 | 210 | 158 | 0 | |
| 4 | 73 | 352 | 313 | 1 | |
| 5 | 199 | 519 | 386 | 2 | Asn174 N-Glyco |
| 6 | 163 | 888 | 585 | 0 | TMR; D5S... lies in intron 6a |
| 7 | 209 | 288 | 748 | 2 | TMR; Asn246 N-Glyco |
| 8 | 27 | 4,590 | 957 | 2 | |
| 9 | 193 | 262 | 984 | 3'UTR | 181 bp coding / 3'UTR; Thr-336, Ser-377 Phos |
| 10 | 217 | - | 1177 | - | 3'UTR |
Legend:
Exon: numbering of exons and intron/exon boundaries are according to Roberds et
al. (1993), with the first base of the Met-codon counted as
position 1 (see coding
DNA Reference Sequence). Exon size:
size of exon indicated in base pairs (bp). Intron size: size of intron indicated in
base pairs (bp). 5' cDNA position: first base of the exon in relation to
the coding DNA Reference Sequence. Splice after: splicing occurs in between of two coding
triplets (0), after the first (1) or the second (2) base of a triplet. Remarks:
5'UTR = 5' untranslated region, 3'UTR = 3' untranslated region, N-Glyco = potential
N-linked glycosylation site, Phos = putative phosphorylation site, TMR = transmembrane
region. aamplification with primers 5'-tatctccgtctctctgattgctcc-3' and
5'-ttgcggactctgttgccctcttgt-3' (Roberds et
al. [1993]).
Links to other databases: RefSeq: NM_000023 UniGene: Hs.463412
On Northern blots, alpha-sarcoglycan transcripts were highest in skeletal muscle, diaphragm and cardiac muscle while low amounts could be detected in bladder and small intestine (Roberds et al. [1993]), suggesting that it is expressed in smooth muscle cells. The major alpha-sarcoglycan transcript measures 1.5 kb, although larger transcripts of 3.5 and 7 kb could also be detected (in rabbit, Roberds et al. [1993]).
Several SGCA transcripts have been identified, deriving both from alternative splicing and the use of different polyA-addition sites (see SGCA coding DNA Reference Sequence). Analysing human skeletal and cardiac muscle RNA McNally et al. (1994) reported the existence of a differentially spliced transcript, missing exons 6 and 7. Both mRNA's were present at equimolar levels although overall expression in skeletal muscle was about 6-fold higher than in heart. The transcript would remove the transmembrane domain from the SGCA-protein. The transcript lacking exons 6 and 7 is also present in dbEST, as well as transcripts lacking exon 3 (with and without the exon 6+7 skip) and rare transcripts using an alternative splice donor site in exon 9 (halfway, see e.g. AA460823). dbEST also contains one transcript using an alternative 5'-first exon, upstream of the normal exon 1 (BM452810). SGCA-transcripts in dbEST use two different polyA-addition sites, separated by 26 nucleotides (compare BC025702.1 and L34355.1).
Links to other databases: RefSeq: NP_000014
alpha-Sarcoglycan is an integral membrane glycoprotein localized to the sarcolemma of skeletal muscle (Ervasti et al. [1990]). alpha-sarcoglycan is also known as 50-DAG, A2, SL50 and adhalin. The latter name derives from the Arabic word for muscle, i.e. adhal, and refers to the fact that the 50DAG protein was first implicated in the pathogenesis of SCARMD, which is prevalent in Arabic countries Roberds et al. (1993).
alpha-Sarcoglycan consists of 387 amino acids with a predicted molecular weigth of 43,225 daltons. It contains a single membrane-spanning domain (Leu-291 to Val-311) and a highly hydrophobic region which suggest an N-terminal signal sequence. Consequently, the N-terminal 280 amino acids are predicted to be extra-cellular. alpha-sarcoglycan contains two consensus sites for N-linked glycosylation, Asn-174 and Asn-246, and two consensus sites for phosphorylation, one for casein II kinase at Thr-336 and one for Ca2+/calmodulin kinase at Ser-377. Like other sarcoglycans, alpha-sarcoglycan contains five extra-cellular Cysteine residues.
The isoform reported by McNally et al. (1994), missing amino acids 196-319, would miss the transmembrane domain and, in its glycosylated form, have an estimated MW of 35 kD.
Links to other databases: OMIM: 600119
Roberds et al. [1994] first reported the identification of missense variations in both alleles of the gene in a family with late-onset severe chilhood autosomal recessive muscular dystrophy (SCARMD). Later, variations were described in other SCARMD families and in families with limb-girdle muscular dystrophy type (LGMD-2D).
Carrié et al. (1997) reported alpha-sarcoglycan variation screening in a set of 51 unrelated families of widespread geographical origin selected for (1) proximal muscular dystrophy, (2) normal dystrophin, and (3) alpha-sarcoglycan deficiency (i.e. absence or reduced staining ascertained by immunofluorescence and/or Westernblotting). In 20 of these families (39%), variations were found in the alpha-sarcoglycan gene, confirming the observation of Duggan that among sarcoglycanopathies, alpha-sarcolgycan variations are most frequent.
Carrié et al. (1997) reports 25 different variations. In patients, 46% of the chromosomes had variations in exon 3. 229C>T (Arg77Cys) was found on 32% of the chromosomes. mRNA-level and size were normal in all cases except for two where splice site variations resulted in the production of aberrant transcripts. This observation confirms that of Roberds et al. [1994], who suggested that the upto 80-90% reduction of alpha-sarcoglycan in DMD-patients and mdx-mice is likely a post-translational event. All missense variations, except 229C>T (Arg77Cys), resulted in a drastic decrease of alpha-sarcolgycan protein. The phenotype of 15 patients, described by Eymard et al.(1997), shows a large variability, including differences between affected sibs. Without exception, homozygous null variations are responsible for a severe clinical course.
The SGCA:c.229C>T change is the most frequent identified thus far, corresponding to 14-32% of the LGMD2D alleles found in different populations. In Brazil c.229C>T is found associated with at least three distinct haplotypes (Passos-Bueno [1995]). 229C lies in a CpG island and is considered a mutational hot spot causing recurrent mutations at this site.
Mutations associated with LGMD-2D are almost exclusively missense, spread across five exons resulting in amino acid substitutions localised in the extracellular domain of the protein.
Duclos et al. (1998) attempted to generate a murine LGMD-2D model by disrupting the alpha-sarcoglycan gene. Sgca-null mice developed progressive muscular dystrophy and ongoing muscle necrosis with age, a hallmark of the human disease. Sgca-null mice also revealed loss of sarcolemmal integrity, elevated serum levels of muscle enzymes, increased muscle masses and changes in the generation of absolute force. Molecular analysis of Sgca-null mice demonstrated that the absence of alpha-sarcoglycan resulted in the complete loss of the sarcoglycan complex, sarcospan, and a disruption of alpha-dystroglycan association with membranes. No change in the expression of epsilon-sarcoglycan (alpha-sarcoglycan homologue) was observed.
Using injection of recombinant alpha-sarcoglycan adenovirus into Sgca-deficient muscles, Duclos et al. (1998) were able to restore the sarcoglycan complex and sarcospan to the membrane. From these experiments, they concluded that the sarcoglycan-sarcospan complex is requisite for stable association of alpha-dystroglycan with the sarcolemma. Sgca-deficient mice may provide a valuable model for elucidating the pathogenesis of sarcoglycan deficient limb-girdle muscular dystrophies and for the development of therapeutic strategies for this disease.
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