| *600900 | ||||||||||||||||||||||||||||||||||||
| SARCOGLYCAN, BETA; SGCB | ||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||
| DYSTROPHIN-ASSOCIATED GLYCOPROTEIN, 43-KD | ||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: SGCB | ||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 4q12 Genomic coordinates (GRCh37): 4:52,886,860 - 52,904,484 (from NCBI) | ||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | ||||||||||||||||||||||||||||||||||||
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| TEXT | ||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||
| The dystrophin-glycoprotein complex (DGC) is a multisubunit protein complex that spans the sarcolemma and provides structural linkage between the subsarcolemmal cytoskeleton and the extracellular matrix of muscle cells. There are 3 main subcomplexes of the DGC: the cytoplasmic proteins dystrophin (DMD; 300377) and syntrophin (SNTA1; 601017), the alpha- and beta-dystroglycans (see 128239), and the sarcoglycans (see, e.g., SGCA; 600119) (Crosbie et al., 2000). | ||||||||||||||||||||||||||||||||||||
| Cloning | ||||||||||||||||||||||||||||||||||||
| Lim et al. (1995) cloned and characterized human beta-sarcoglycan, a 43-kD component of the dystrophin-glycoprotein complex, and demonstrated its involvement in a form of muscular dystrophy, designated LGMD2E (604286). They showed that beta-sarcoglycan colocalizes with the DGC at the sarcolemma and is expressed ubiquitously, although predominantly in muscle. | ||||||||||||||||||||||||||||||||||||
| Gene Structure | ||||||||||||||||||||||||||||||||||||
| Bonnemann et al. (1996) reported that the SGCB gene contains 6 exons and spans 13.5 kb of genomic DNA. | ||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||
| By somatic cell hybridization and fluorescence in situ hybridization, Lim et al. (1995) assigned the SGCB gene to chromosome 4q12. Bonnemann et al. (1995) also mapped the SGCB gene, which they referred to as A3b, to 4q12. | ||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||
| In 2 Amish patients from southern Indiana with limb-girdle muscular dystrophy 2E (604286), Lim et al. (1995) identified a homozygous mutation in the SGCB gene (600900.0001). Bonnemann et al. (1995) described a young girl with autosomal recessive muscular dystrophy who was compound heterozygous for truncating SGCB mutations on both alleles (600900.0002; 600900.0003). Trabelsi et al. (2008) identified biallelic mutations in sarcoglycan genes in 46 (67%) of 69 patients with a clinical diagnosis of autosomal recessive LGMD. Twenty-six (56.5%) patients had SGCA mutations, 8 (17.3%) had SGCB mutations, and 12 (26%) had SGCG (608896) mutations. Seven of the 9 SGCB mutations were novel. | ||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||
| Durbeej et al. (2000) engineered Sgcb-null mice to analyze the biologic role of beta-sarcoglycan in the pathogenesis of LGMD2E. These mice developed severe muscular dystrophy and cardiomyopathy with focal areas of necrosis. The sarcoglycan-sarcospan and dystroglycan complexes were disrupted in skeletal, cardiac, and smooth muscle membranes. Epsilon-sarcoglycan (SGCE; 604149) was also reduced in membrane preparations of striated and smooth muscle. Loss of the sarcoglycan-sarcospan complex in vascular smooth muscle resulted in vascular irregularities in heart, diaphragm, and kidneys. Further biochemical characterization suggested the presence of a distinct epsilon-sarcoglycan complex in skeletal muscle that was disrupted in Sgcb-null mice. Thus, the authors concluded that perturbation of vascular function together with disruption of the epsilon-sarcoglycan-containing complex contribute to the pathogenesis of LGMD2E. Durbeej et al. (2003) injected recombinant beta- or delta-sarcoglycan (601411) adenoviruses into skeletal muscle of corresponding null mice. They found that the adenoviruses would not transduce vascular smooth muscle and would target only skeletal muscle. Gene transfer of the corresponding deleted sarcoglycan gene preserved sarcolemmal integrity, prevented pathologic dystrophy and hypertrophy, and protected against exercise-induced damage. They concluded that vascular dysfunction is not a primary cause of beta- and delta-sarcoglycan-deficient muscular dystrophy. In addition, they showed successful functional rescue of entire muscles after adenovirus-mediated gene delivery. Cohn et al. (2001) had demonstrated that cardiomyopathy in beta- and delta-sarcoglycan-deficient mice can be prevented by using vorapamil, a calcium-channel blocker. | ||||||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | ||||||||||||||||||||||||||||||||||||
| Table View | ||||||||||||||||||||||||||||||||||||
| .0001 MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2E | ||||||||||||||||||||||||||||||||||||
| SGCB, THR151ARG [dbSNP:rs28936383] | ||||||||||||||||||||||||||||||||||||
| In 2 affected Amish patients from southern Indiana with limb-girdle muscular dystrophy (LGMD2E; 604286), Lim et al. (1995) identified a homozygous 461C-G transversion in the SGCB gene, resulting in a thr151-to-arg (T151R) substitution. The major muscle beta-sarcoglycan mRNA transcript (4.4 kb) was present at normal levels and size in affected individuals. The mutation led to a dramatically reduced expression of the beta-sarcoglycan protein in the sarcolemma and a concomitant loss of adhalin (600119) and 35-DAG (SGCG; 608896), which was interpreted as representing a disruption of a functional subcomplex within the dystrophin-glycoprotein complex. Lim et al. (1995) identified a unique carrier haplotype suggestive of a founder effect different from the one found in northern Indiana and Pennsylvania Amish LGMD2A (253600) families. | ||||||||||||||||||||||||||||||||||||
| .0002 MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2E | ||||||||||||||||||||||||||||||||||||
| SGCB, TYR184TER [dbSNP:rs104893868] | ||||||||||||||||||||||||||||||||||||
| In a child with an autosomal recessive muscular dystrophy (LGMD2E; 604286), the only child of clinically unaffected and unrelated parents of Italian background, Bonnemann et al. (1995) found compound heterozygosity for 2 mutations in the SGCB gene: a T-to-G transversion, resulting in a tyr184-to-ter (Y184X) nonsense mutation, inherited from the mother, and an 8-bp duplication after codon 125 (600900.0003), resulting in frameshift and a premature termination at codon 129, inherited from the father. Both mutations were predicted to severely truncate the protein, ablating most of its extracellular domain. At age 1 year, the patient had an increased serum creatine phosphokinase (CPK) without symptoms. Persistent elevation of CPK values prompted muscle biopsy at 13 months of age, which showed fiber size variation, scattered degenerating and regenerating muscle fibers, and mild increase in perimysial tissue. Reassessment at 40 months of age revealed signs of muscle weakness: she used a modified Gowers maneuver to get up from the floor and rolled onto her side to go from a lying into a sitting position. She had mild scapular winging and firmness of her calf muscles. | ||||||||||||||||||||||||||||||||||||
| .0003 MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2E | ||||||||||||||||||||||||||||||||||||
| SGCB, 8-BP DUP, NT383 | ||||||||||||||||||||||||||||||||||||
| See 600900.0002 and Bonnemann et al. (1995). In 6 unrelated families from northern Italy with mutations in the beta- or gamma-sarcoglycan gene, Fanin et al. (2000) found the 8-bp duplication in the SGCB gene and a 1-bp insertion in the SGCG gene (608896.0006). Neither mutation had been found in other populations. Many patients were homozygotes, although they derived from nonconsanguineous marriages, and in each case linkage disequilibrium with neighboring polymorphisms was demonstrated. Fanin et al. (2000) presented this as an example of founder effect. Barresi et al. (2000) identified the 8-bp duplication (which they referred to as 383^384ins376-383) in 2 cousins with LGMD2E (604286). A girl, who was proven homozygous for the mutation, had severe myopathy from early infancy and was confined to a wheelchair since age 15. She had no cardiomyopathy. Muscle biopsy showed severe dystrophic features. In her male cousin, only a heterozygous 8-bp dup was identified; a second mutation in the SGCB gene was not detected, but presumed to be in a noncoding region. He developed proximal muscle weakness at age 15 years, and later developed fatal dilated cardiomyopathy. His heart muscle showed a major reduction of beta-sarcoglycan. Barresi et al. (2000) reported a second unrelated male who was compound heterozygous for the 8-bp duplication and a 4-bp deletion at the donor splice site in intron 2 (243+3delGAGT; 600900.0009), resulting in aberrant splicing and a 6-bp insertion (243insGTATTT) between exons 2 and 3. He showed onset of muscle weakness at age 4, and later developed fatal cardiomyopathy with death at age 18. The duplication mutation was predicted to produce a truncated protein lacking most of the extracellular region. | ||||||||||||||||||||||||||||||||||||
| .0004 MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2E | ||||||||||||||||||||||||||||||||||||
| SGCB, 2-BP DEL, NT465 | ||||||||||||||||||||||||||||||||||||
| In a female patient with severe LGMD2E (604286), Bonnemann et al. (1996) identified a homozygous 2-bp deletion at nucleotide 465 in the SGCB gene, resulting in a truncated protein. Age of onset was 5 to 6 years and loss of ambulation occurred at 11 years. | ||||||||||||||||||||||||||||||||||||
| .0005 MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2E | ||||||||||||||||||||||||||||||||||||
| SGCB, ARG91PRO [dbSNP:rs104893869] | ||||||||||||||||||||||||||||||||||||
| In 3 affected children from a family with LGMD2E (604286), Bonnemann et al. (1996) identified a homozygous 272G-C transversion in the SGCB gene, resulting in an arg91-to-pro (R91P) substitution. One, a male patient who had onset of symptoms between age 5 and 6 years, lost ambulation at age 10 and died at age 22. | ||||||||||||||||||||||||||||||||||||
| .0006 MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2E | ||||||||||||||||||||||||||||||||||||
| SGCB, LEU108ARG [dbSNP:rs104893870] | ||||||||||||||||||||||||||||||||||||
| In a female patient with LGMD2E (604286), Bonnemann et al. (1996) identified a 323T-G transversion in the SGCB gene, resulting in a leu108-to-arg (L108R) substitution. Onset of symptoms was at age 7 years, and she lost ambulation at 12 years of age. An affected male sib of the proband had died of muscular dystrophy at age 16 years. Only 1 allele was identified in this family. | ||||||||||||||||||||||||||||||||||||
| .0007 MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2E | ||||||||||||||||||||||||||||||||||||
| SGCB, MET100LYS [dbSNP:rs104893871] | ||||||||||||||||||||||||||||||||||||
| In a female patient with LGMD2E, Bonnemann et al. (1996) identified a 299T-A transversion in the SGCB gene, resulting in a met100-to-lys (M100K) substitution. Onset of symptoms was at age 5 years; the patient had marked elevation of CPK and calf hypertrophy. | ||||||||||||||||||||||||||||||||||||
| .0008 MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2E | ||||||||||||||||||||||||||||||||||||
| SGCB, ARG91LEU [dbSNP:rs104893869] | ||||||||||||||||||||||||||||||||||||
| Bonnemann et al. (1998) demonstrated that affected members of a Tunisian family with beta-sarcoglycanopathy (LGMD2E; 604286) had a 272G-T mutation in exon 3 of the SGCB gene, resulting in an arg91-to-leu (R91L) substitution. The change affected the same arginine residue in the immediate extracellular domain of the protein that was mutated in a Brazilian family with a severe form of the disease: 272G-C, arg91 to pro (600900.0005). In both the R91L and the R91P families, immunohistochemical analysis for the sarcoglycan complex demonstrated absence of the known components of the complex. Bonnemann et al. (1998) postulated that the immediate extracellular domain of beta-sarcoglycan may be important for the assembly and/or maintenance of this complex, potentially mediated by disulfide-bond formation to another sarcoglycan via the single cysteine residue in that domain. The identification of a Tunisian family with LGMD2E demonstrated further the heterogeneity of autosomal recessive LGMD in that geographic region. LGMD2C (253700), caused by mutations in gamma-sarcoglycan (SGCG; 608896), is prevalent in northern Africa, especially in Tunisia where this type of muscular dystrophy was first described. Although the disease initially was assumed to be genetically homogeneous in that region, linkage to the alpha-sarcoglycan locus (LGMD2D; 608099) had also been found. | ||||||||||||||||||||||||||||||||||||
| .0009 MUSCULAR DYSTROPHY, LIMB-GIRDLE, TYPE 2E | ||||||||||||||||||||||||||||||||||||
| SGCB, 4-BP DEL, 243+3GAGT | ||||||||||||||||||||||||||||||||||||
| See 600900.0003 and Barresi et al. (2000). | ||||||||||||||||||||||||||||||||||||
| See Also: | ||||||||||||||||||||||||||||||||||||
| Coral-Vazquez et al. (1999) | ||||||||||||||||||||||||||||||||||||
| REFERENCES | ||||||||||||||||||||||||||||||||||||
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