SGCB – Beta-Sarcoglycanopathy (LGMD2E)

SGCB encodes the transmembrane protein beta-sarcoglycan, a critical component of the dystrophin-glycoprotein complex at the sarcolemma. Biallelic variants in SGCB cause autosomal recessive limb-girdle muscular dystrophy type 2E (LGMD2E) characterized by progressive proximal muscle weakness and highly elevated serum creatine kinase ([HP:0003236]). Initial studies in an Amish isolate identified a founder missense change, p.Thr151Arg, in 11 families and a second pathogenic allele, p.Arg91Cys, in a new sibship, both leading to complete loss of the sarcoglycan complex and secondary reduction of alpha-dystroglycan ([PMID:9565988]).

Subsequent reports expanded the variant spectrum to include homozygous p.Met100Lys in a consanguineous Spanish family with a Duchenne-like phenotype ([PMID:15938574]), a large homozygous genomic deletion in a Turkish toddler with a milder course ([PMID:27785400]), and a homozygous p.Ser114Phe in two siblings responsive to deflazacort therapy ([PMID:20071171]). An intronic pseudoexon variant, c.243+1548T>C, was functionally rescued in patient-derived iPSCs by antisense morpholino oligomers, restoring normal splicing and partial protein expression ([PMID:36077211]). Deep mutational scanning of all possible SGCB missense changes confirmed a loss-of-function mechanism and correlated variant functional scores with disease severity in LGMD2E ([PMID:37317968]).

Inheritance is strictly autosomal recessive, with compound heterozygotes and homozygotes reported across multiple ethnic groups. At least two additional affected siblings have segregated SGCB variants in pedigrees beyond the proband generation. The variant spectrum includes missense substitutions (e.g., c.271C>T (p.Arg91Cys)), large deletions, and deep intronic splice-altering alleles, underscoring the need for comprehensive genomic and transcript analyses.

Functional studies—ranging from immunohistochemical loss of sarcoglycan complex in muscle biopsy to in vitro splicing correction and high-throughput variant effect mapping—consistently demonstrate that SGCB loss leads to sarcolemma destabilization and impaired muscle integrity. Rescue of splicing defects by antisense morpholinos and correlates of residual protein function with milder phenotypes establish a strong experimental concordance with human disease.

No conflicting evidence disputing SGCB involvement in LGMD2E has been reported. The integrated genetic and functional data meet criteria for a definitive gene-disease relationship, supporting reliable genetic diagnosis, carrier screening, and potential antisense therapeutic development.

Key Take-home: Biallelic SGCB variants are definitively causal for LGMD2E; comprehensive variant detection and functional validation are essential for precise diagnosis and emerging personalized therapies.

References

• Neuromuscular Disorders • 1998 • Beta-sarcoglycan: genomic analysis and identification of a novel missense mutation in the LGMD2E Amish isolate. PMID:9565988
• Acta Myologica • 2004 • Beta-sarcoglycanopathy (LGMD 2E) in a Spanish family. PMID:15938574
• Balkan Journal of Medical Genetics • 2015 • Sarcolemmal deficiency of sarcoglycan complex in an 18-month-old Turkish boy with a large deletion in the beta sarcoglycan gene. PMID:27785400
• Neuromuscular Disorders • 2010 • Two siblings with limb-girdle muscular dystrophy type 2E responsive to deflazacort. PMID:20071171
• International Journal of Molecular Sciences • 2022 • Antisense Morpholino-Based In Vitro Correction of a Pseudoexon-Generating Variant in the SGCB Gene. PMID:36077211
• The Journal of Clinical Investigation • 2023 • Comprehensive functional characterization of SGCB coding variants predicts pathogenicity in limb-girdle muscular dystrophy type R4/2E. PMID:37317968

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