SGCB – Autosomal Recessive Limb-Girdle Muscular Dystrophy

Beta-sarcoglycanopathy (LGMDR4) results from biallelic loss-of-function variants in the SGCB gene leading to autosomal recessive limb-girdle muscular dystrophy. Patients present with progressive proximal muscle weakness, elevated creatine kinase, and variable cardiomyopathy requiring multidisciplinary management.

In a European cohort of 69 probands with suspected sarcoglycanopathy, SGCB mutations accounted for 17% (8/47) of cases with abnormal muscle protein by Western blot (PMID:18285821). A Chinese series identified SGCB-related LGMD2E in 6 of 25 sarcoglycanopathy patients (PMID:30764848). Together these studies describe 14 unrelated probands with predominantly frameshift, nonsense, splice, and large exon-level deletions.

A targeted RT-PCR analysis of SGCB in two affected siblings (Family 1) and an unrelated patient (Family 2) revealed novel deep intronic splice-altering variants (c.243+1558C>T; c.243+1576C>G; c.243+6T>A) and a predicted nonsense change, all in compound heterozygosity (PMID:35813381). Segregation in Family 1 confirmed variant transmission to both affected siblings (one additional relative) (PMID:35813381).

The variant spectrum in SGCB includes at least 25 novel mutations: frameshifts (e.g., c.494del (p.Asp165fs)), splice-site variants (c.33+1G>C), deep intronic pseudoexon generators (c.243+1548T>C), and large exon deletions. Recurrent hypomorphic or founder alleles have yet to be defined, but LoF constitutes the predominant mechanism.

Functional assays demonstrate that antisense morpholino oligomers targeting the c.243+1548T>C pseudoexon restore correct SGCB splicing and protein expression in patient-derived iPSCs (PMID:36077211). A comprehensive deep mutational scan of 6,340 possible SGCB missense changes correlates functional scores with cell surface localization, perfectly distinguishing known pathogenic variants and validating loss of stability as the disease mechanism (PMID:37317968).

No studies have refuted the SGCB–LGMD association. Overall, biallelic SGCB variants produce a consistent phenotypic spectrum of proximal weakness and cardiomyopathy, with robust genetic and experimental support. Key Take-home: SGCB biallelic LoF variants cause a clinically recognizable autosomal recessive limb-girdle muscular dystrophy with validated in vitro assays for variant interpretation and emerging antisense therapies.

References

• European journal of human genetics | 2008 | Revised spectrum of mutations in sarcoglycanopathies. PMID:18285821
• Orphanet journal of rare diseases | 2019 | Clinical and genetic spectrum of sarcoglycanopathies in a large cohort of Chinese patients. PMID:30764848
• Frontiers in pediatrics | 2022 | First Identification of Rare Exonic and Deep Intronic Splice-Altering Variants in Patients With Beta-Sarcoglycanopathy. PMID:35813381
• 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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