(last modified December 28, 2004)
delta-Sarcoglycan (Gene Symbol SGCD) was first described by Ervasti et al. as a 35 kD protein which was associated with dystrophin. Initially, it was not recognized that this 35 kD band consisted out of two individual proteins; gamma- and delta-sarcoglycan. This became only evident after Nigro et al. reported the cloning and characterisation of a new sarcoglycan with homology to gamma-sarcoglycan. Later, the same authors described variations in both alleles of this gene in patients with Limb-Girdle muscular dystrophy type 2F (LGMD2F, Nigro). They mapped the SGCD-gene to chromosome 5q33-q34, near D5S487 and D5S412, a region where an autosomal recessive form of LGMD was previously mapped (Passos-Bueno). The SGCD-gene spans some 433 kb of genomic DNA, contains 9 exons, is differentially spliced and produces a major 8.0 kb mRNA and a less abundant mRNA of 3.6 kb. The RNA is differentially spliced and codes two proteins which differ at their C-terminus, SGCD1 and SGCD2. SGCD1 is most similar to sarcoglycan-gamma and encodes a basic 35 kDa protein of 290 amino acids with a single transmembrane region. In patients, immuno-histochemical analysis of the muscle membrane shows a complete disintegration of the sarcoglycan complex, with complete absence of alpha-, gamma- and delta-sarcoglycan and a severe reduction of beta-sarcoglycan, while dystrophin is present but reduced (Nigro, Dincer). Tsubata et al. describe dominant mutations in the SGCD-gene in patient with dilatated cardiomyopathy (CMD-1L). Nigro et al. reported a deletion in the promoter region of the gene, causing a fatal cardiomyopathy in the BIO14.6 hamster. The murine gene was recently knocked-out by Coral-Vazquez et al. The mice showed both muscular dystrophy and cardiomyopathy.
Links to other databases:
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delta-Sarcoglycan (Gene Symbol SGCD, aliases SGD, DAGD) was discovered by Nigro et al. after the identification of an EST sequence which showed a weak homology with part of the gamma-sarcoglycan sequence. They focused on this region and isolated several cDNA-clones, clearly containing a sequence similar to gamma-sarcoglycan (58% identity at DNA-level).
The human SGCD gene was mapped to chromosome 5q33-q34 using somatic cell hybrids, radiation hybrids and FISH (Nigro). This localization was confirmed by the isolation of 4 YAC clones containing segments of the gene (e.g. CEPH 889c8 and 936d12) which are part of a chromosome 5 contig containing markers D5S487, D5S662, D5S1439 and D5S2112. Tsubata et al. report isolation of a BAC-contig covering the gene; BACs 523E7 and 417E23 (exons 2-3), 555B9 and 557H6 (exons 4-7)and 212M24 (exon 9). The SGCD-gene spans some 433 kb of genomic DNA and contains 9 exons (Tsubata), some of which are differentially spliced. In mouse the gene spans 400 kb and maps to chromosome 11B1.2, in hamster to chromosome 9qa2.1-b1 (Nigro).
| Exon | Exon size (bp) | Intron size (bp) | 5' cDNA position | Splice after | Remarks |
|---|---|---|---|---|---|
| 1 | (476) | 2,301 | (-342) | - | 5'UTR |
| 2 | 46 | 14,909 | -43 | 0 | 5'UTR / translation initiation codon |
| 3 | 189 | 163,876 | 4 | 0 | contains Trans Membrane Region (TMR) |
| 4 | 102 | 80,528 | 193 | 0 | |
| 5 | 88 | 5,613 | 295 | 1 | |
| 6 | 120 | 52,412 | 383 | 1 | |
| 7 | 73 | 110,045 | 503 | 2 | |
| 8 | 124 | 1,512 | 576 | 0 | |
| 8b | 439 | - | - | alternative 3' end (encodes unique C-terminus of SGCD2), unspliced into intron 7 | |
| 9 | (511) | - | 700 | - | 174 bp coding (unique C-terminus of SGCD1 end) / 3'UTR |
Legend:
Exon: numbering of exons and intron/exon boundaries are according to Tsubata
et al., with the first base of the Met-codon counted as
position 1 (see cDNA 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 the
cDNA 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 serine
phosphokinase C phosphorylation site, TMR = transmembrane region.
Links to other databases: RefSeq: NM_000337 UniGene: Hs.151899
The delta-sarcoglycan gene produces a major 8.0 kb mRNA and a less abundant mRNA of 3.6 kb (Nigro). Expression was only detected in skeletal, cardiac and smooth muscle and (on Western blot) not in brain, kidney, liver, lung, mammary gland, pancreas, placenta, small intestine, spleen and stomach. The currently available cDNA sequences adds up to not more than 1.55 kb, indicating that a large part of the transcript remains to be characterized.
The sequence databases contain two major transcripts containing different 3'-terminal exons and different polyA-addition sites (we use the descriptions SGCD1 and SGCD2 to describe these transcripts and the encoded protein isoforms). The transcript most similar to gamma-sarcoglycan contains 9 exons, terminates at different sites in this exon and encodes delta-sarcoglycan 1 (SGCD1). The alternative transcript does not contain exon 9 but terminates in intron 8 and encodes a protein designated SGCD2. dbEST contains only few SGCD transcripts but the SGCD1/SGCD2 transcripts are present at about equal levels. Similar transcripts seem to be present in mouse, hamster sand pig..
In hamster, a second far upstream promoter seems active in heart, producing very low transcript levels, i.e <3-5% of normal (Nigro). Both hamster promoters are directly followed by a unique exon 1 which contains 5'-untranslated sequences only.
Links to other databases: RefSeq: NP_000328
delta-Sarcoglycan 1 (SGCD1) is a basic 35 kDa protein of 290 amino acids (Nigro) with a calculated molecular weght of 32,174 kDa (theoretical pI 9.15). SGCD2 transcripts encode a different C-terminal sequence, exchanging the last 57 amino acids of SGCD1 for 23 other amino acids.
delta-Sarcoglycan is a 290 amino acid protein, encoding a typical sarcolgycan protein. At its N-terminus it contains a 36 amino acid hydrophobic cytoplasmic domain, followed by a 21 amino acid transmembrane region (Phe37-Leu57). The 233 amino acid extra-cellular C-terminal domain contains three potential sites for asparagine-linked N-glycosolation (Asn61, Asn109 and Asn285 - first two conserved) and four conserved cysteine residues (Cys264, Cys266, Cys282 and Cys289).
Links to other databases: OMIM: 601287 (LGMD2F) / 606685 (CMD1L)
Sequence variations in both alleles of this gene were found in patients with a severe DMD-like course of muscular dystrophy, designated limb-girdle muscular dystrophy type 2F (LGMD-2F, Nigro). Most LGMD2F patients reported show a severe muscular dystrophy which presents early in life and which has a rapid progression. Immuno-histochemical analysis of the muscle membrane shows a complete disintegration of the sarcoglycan complex, with complete absence of alpha-, gamma- and delta-sarcoglycan and a severe reduction of beta-sarcoglycan, while dystrophin is present but reduced (Nigro, Dincer).
Based on the hypothesis that dilated cardiomyopathy is a disease of the cytoskeleton and sarcolemma, and the observed phenotype of animal models with SGCD rearrangements (mouse, hamster), Tsubata et al. (2000) considered the SGCD gene as a candidate for CMD. Upon direct screening of the SGCD-gene in one family and 50 sporadic patients with dilated cardiomyopathy (CMD-1L), they identified dominant mutations in a Japanese family (451T>G / Ser151Ala) and two sporadic cases with a de novo mutation (699+13_699+15del / Lys233+5del). Interestingly, the latter change affects the SGCD2 isoform only. Immuno-histochemical staining of the heart of one of the psoradic patients showed a signbificantly reduced staining with an N-terminal SGCD-antibody, but normal staining for dystrophin, SGCA, SGCB and SGCG (Tsubata).
The SGCD:c.656delC mutation is found most frequently, found nearly exclusively on one haplotype, originating from African ancestries (Moreira [1998]).
The BIO14.6 hamster is an extensively used animal model of autosomal recessive cardiomyopathy and muscular dystrophy. Nigro et al. showed that the primary genetic defect in this hamster lies in the delta-sarcolgycan gene, being a large deletion in the 5' end/promoter region of the gene. In these animals, delta-sarcoglycan protein is undetectable in heart and muscle. Very low mRNA-levels can be detected in heart (<3-5% of normal), but not in muscle. The heart mRNA seems derived from an alternative, upstream promoter.
Straub et al. studied the effects of this mutation on transcription, expression and function of the dystrophin-glycoprotein complex in skeletal and cardiac muscle. They demonstrated that the genetic defect leads in striated muscle to a complete deficiency of delta-sarcoglycan and a concomitant loss of alpha-, beta- and gamma-sarcoglycan. In addition, absence of the sarcoglycan complex reduced the expression of alpha-dystroglycan in striated muscle fibers. These findings indicated that the primary defect in the BIO14.6 hamster leads to a dissociation of the dystroglycan complex from the sarcoglycan complex and disrupted anchorage of alpha-dystroglycan to the cell surface.
The murine gene was recently knocked-out by Coral-Vazquez et al. The mice showed both muscular dystrophy and cardiomyopathy.
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