SGCG – Autosomal recessive limb-girdle muscular dystrophy

SGCG is implicated in autosomal recessive limb-girdle muscular dystrophy (MONDO:0015152), with pathogenic loss-of-function variants leading to sarcolemmal instability and progressive muscle weakness. The inheritance is autosomal recessive. To date, only one unrelated proband with SGCG mutations has been reported in a Chinese cohort (PMID:30764848), and additional sarcoglycanopathy cases including SGCG were identified in a Dutch registry of 244 patients (PMID:30919934). No multigenerational segregation has been documented. The variant spectrum includes frameshift and splicing mutations; c.525del (p.Phe175fs) is a truncating allele found in LGMD2C patients (PMID:22367371). Clinical features across sarcoglycanopathies encompass early onset muscle weakness, loss of ambulation (HP:0002505), and cardiac abnormalities (HP:0001627) (PMID:30919934).

Functional studies demonstrate that phosphorodiamidate morpholino oligomer-mediated exon skipping restores the SGCG reading frame in patient-derived myogenic cells, producing a functional Mini-Gamma protein (PMID:29720576). A CRISPR/Cas9 knock-in mouse carrying the human founder 521ΔT mutation recapitulates LGMD2C pathology and responds to a multiexon-skipping antisense cocktail in vivo (PMID:31582396). Moreover, systemic AAV-mediated delivery of a codon-optimized human SGCG transgene in SGCG−/− mice reconstitutes the sarcoglycan complex, improves muscle histopathology, and enhances functional performance (PMID:36816759). These concordant findings support a haploinsufficiency mechanism.

Key Take-home: SGCG pathogenic variants cause AR LGMD with progressive weakness, loss of ambulation, and cardiac involvement, and proof-of-concept molecular therapies show clinical potential.

References

• Clinical genetics • 2019 • Autosomal recessive limb-girdle and Miyoshi muscular dystrophies in the Netherlands: The clinical and molecular spectrum of 244 patients. PMID:30919934
• Orphanet journal of rare diseases • 2019 • Clinical and genetic spectrum of sarcoglycanopathies in a large cohort of Chinese patients. PMID:30764848
• Molecular biology reports • 2012 • Impact of single-nucleotide polymorphisms at the TP53-binding and responsive promoter region of BCL2 gene in modulating the phenotypic variability of LGMD2C patients. PMID:22367371
• JCI insight • 2018 • Efficient exon skipping of SGCG mutations mediated by phosphorodiamidate morpholino oligomers. PMID:29720576
• Disease models & mechanisms • 2019 • A gene-edited mouse model of limb-girdle muscular dystrophy 2C for testing exon skipping. PMID:31582396
• Molecular therapy. Methods & clinical development • 2023 • Systemic γ-sarcoglycan AAV gene transfer results in dose-dependent correction of muscle deficits in the LGMD 2C/R5 mouse model. PMID:36816759

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