(last modified March 7, 2004)
beta-Sarcoglycan was first described by Ervasti et al. as a 43 kDa protein which was associated with dystrophin. Both Lim and Bönnemann concurrently reported the cloning of the beta-sarcoglycan gene and its involverment in limb-girdle muscular dystrophy type 2E (LGMD2E). beta-sarcoglycan is a 318 amino acid protein containing a 63 amino acid intra-cellulair N-terminal region, a transmembrane region and a 228 amino acid extra-cellular C-terminus. The gene maps to chromosome 4q12, spans ~13.5 kb of genomic DNA and contains 6 exons (Bönnemann). Mutations in both alleles of the beta-sarcoglycan gene were first reported by Lim and Bönnemann in patients with LGMD2E. Disease severity may vary from either a severe (Bonnemann) to a mild (Lim) phenotype, depending on the mutation; i.e. truncating mutations (in both alleles) give more severe phenotypes than missense mutations. Even homozygous missense mutations result in the total absence of alpha-, beta- and gamma-sarcoglycan from the muscle membrane (Bonnemann).
Links to other databases:
Gene
Symbol nomenclature LocusLink db
OMIM Gene Map
GDB
The genomic structure of the beta-sarcoglycan gene (Gene Symbol SGCB, A3b, SGC) was deduced by Bönnemann et al. The gene spans 15 kb and contains 6 exons (GenBank files U63796-U63801). Exons 1 and 6 include the 5' and 3' untranslated regions respectively. Homology searches with the beta-sarcoglycan gene sequences revealed identity with CpG-island clone 48d12 (GenBank files Z65591 and Z65592), now predicted to contain the gene's promoter, exon 1 and part of intron 1.
The results of Lim et al. suggest that the gene may be transcribed by alternative promoters (e.g. in fetal liver and adult pancreas). Lim also detected an alternate poly-A addition site in brain, about 300 bp downstream of the translational stop codon.
The beta-sarcoglycan gene was mapped to human chromosome 4q12 using somatic cell hybrids, radiation hybrids and FISH. This localization was confirmed by the isolation of a YAC clone containing the gene (CEPH 976a3) which overlapped other YAC clones (CEPH 790e6 and 767d12) which contained the chromosome 4 markers D4S1577, D4S2443 and D4S1628. A highly polymorphic CA-repeat (CA12T) in intron 4 was detected by Lim et al. (observed heterozygosity of 0.70). Lim observed a perfect cosegregation of allele-9 of the CA12T marker with the disease in all affected families of the southern Indiana US-Amish population analysed. The order of CA-repeat markers in the region is D4S396 - D4S518 - D4S1577 - CA12T - D4S1630.
| Exon | Exon size (bp) | Intron size (kb) | 5' cDNA position | Splice after | Amino acids | Remarks |
|---|---|---|---|---|---|---|
| 1 | >75 | 4.569 | -42 | 0 | 1-11 | 5' UTR / 33 bp coding |
| 2 | 210 | 3.546 | 34 | 0 | 12-81 | Ser21 Phos |
| 3 | 186 | 0.756 | 244 | 0 | 82-143 | Leu64-Ile90 TMR |
| 4 | 192 | 0.629 | 430 | 0 | 144-207 | Asn158 N-Glyco |
| 5 | 132 | 3.800 | 622 | 0 | 208-251 | Asn211 N-Glyco |
| 6 | >1000 | - | 754 | - | 252-318 | 204 bp coding / 3'UTR; Asn258 N-Glyco |
Legend:
Exon: numbering of exons and intron/exon boundaries are according to Bönnemann and Duclos, with the first base of the Met-codon
counted as position 1 (see Reference sequence). Exon
size: size of exon indicated in basepairs. Intron size: size of intron
indicated in kilobasepairs. 5' cDNA position: first base of the exon (according to
cDNA sequence U31116, Bönnemann et al.). 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
serine phosphokinase C phosphorylation site, TMR = transmembrane region.
Links to other databases: RefSeq: NM_000232 UniGene: Hs.77501
The major beta-sarcoglycan transcript measures 4.3 kb. Weaker transripts can be detected at 3 and 1.35 kb. The latter transript most probably derives form the use of an alternate polyadenylation site about 300 basepairs downstream of the translational stop codon (Lim). Results of Lim et al. suggest that alternative promoters may be used in fetal liver and adult pancreas.
beta-sarcoglycan mRNA expression is most abundant in cardiac and skeletal muscle (Lim, Bönnemann). On Northern blots, expression can also be detected in placenta, adult pancreas and fetal and adult brain, kidney, liver and lung.
Links to other databases: RefSeq: NP_000223
beta-sarcoglycan is a 318 amino acid / 43 kDa protein with a 63 amino acid intracellular domain (N-terminal), a single transmembrane region (amino acids Leu64-Ile90) and a 228 amino acid carboxy-terminal extracellular domain containing five conserved Cys-residues (Cys97, 288, 290, 307 and 314). The hydrophobic N-terminal stretch of 8 Alanine residues is not followed by a consensus site for cleavage with a signal peptidase. beta-sarcoglycan contains a potential serine phosphokinase C phosphorylation site (Ser21) and three potential N-linked glycosylation sites (Asn158, Asn211 and Asn258). The predicted native molecular mass is 34,777 Daltons and the predicted isoelectric point is 9.2. If native rabbit beta-sarcoglycan is treated with endoglycosidase F, its molecular mass increases to 43 kD (Bönnemann).
Human and rabbit beta-sarcoglycan are strongly conserved with a 97% identity at the amino acid level. Furthermore, human beta-sarcoglycan shows homology with gamma- and delta-sarcoglycan and a weak homology with the N-terminus of C.elegans clone F07H5.2.
Links to other databases: OMIM: 600900
Lim and Bönnemann concurrently identified the first mutations in the beta-sarcoglycan which caused limb-girdle muscular dystrophy type 2E (LGMD2E). Skeletal muscle biopsy samples of patients showed that beta-sarcoglycan is greatly reduced or absent, with a concomittant reduction in alpha- and gamma-sarcoglycan. Dystrophin, beta-dystroglycan, syntrophin, merosin and laminin-alpha2 were present at levels comparable to control muscle.
Disease severity may vary from either a severe (Bonnemann) to a mild (Lim) phenotype. A severe phenotype seems to correlate with the presence of truncating mutations (in both alleles), while milder phenotype correlate with missense mutations.
Araishi et al. developed an animal model for beta-sarcoglycanopathy by generating beta-sarcoglycan deficient mice using a gene targeting technique. Homozygous beta-sarcoglycan deficient mice exhibited a progressive muscular dystrophy with extensive muscle degeneration and regeneration. The mice also exhibited muscular hypertrophy characteristic of beta-sarcoglycanopathy. Immunohistochemical and immunoblot analyses demonstrated that deficiency of beta-sarcoglycan caused loss of all other sarcoglycans as well as of sarcospan in the sarcolemma. Laminin-alpha2, alpha- and beta-dystroglycan and dystrophin were still present in the sarcolemma, but the dystrophin-dystroglycan complex in was unstable compared with that in the wild-type mice.
The CA-repeat in intron 4 of the beta-sarcoglycan gene can be amplified with the primers 5'-TATCTTCTAATGTCTTCTGTCTAT-3' and 5'-GAAACAAGAATAACATGCCATTT-3' (Lim).
| Top of page | LMDp homepage
|
| Sarcoglycan homepage | SGC-homlogies
| SGC-alpha, SGC-gamma,
SGC-delta, SGC-epsilon,
SGC-zeta |
| Remarks / information | Copyright©,
liability |