SGCG – Limb-girdle Muscular Dystrophy

SGCG encodes the dystrophin-associated protein γ-sarcoglycan, and biallelic pathogenic variants cause autosomal recessive limb-girdle muscular dystrophy type 2C (LGMD2C), a subtype of LGMD (MONDO:0016971). Clinical presentations range from childhood-onset, slowly progressive proximal weakness to rhabdomyolysis with episodic myoglobinuria. Immunohistochemistry consistently shows absent γ-sarcoglycan staining in muscle biopsies, confirming the molecular defect.

Autosomal recessive inheritance is established by segregation of homozygous or compound heterozygous SGCG variants in multiple consanguineous and non-consanguineous families. To date, at least 23 affected individuals from 9 unrelated families have been reported, with segregation in sibships and multi-generation branches ([PMID:9673983]; [PMID:10714584]; [PMID:20356742]; [PMID:24534832]; [PMID:15954112]; [PMID:10619713]; [PMID:10807695]).

The variant spectrum includes nonsense (e.g., c.581T>G (p.Leu194Ter)), missense (c.206G>C (p.Gly69Ala)), frameshift (c.525del (p.Phe175fs)), small insertions, deep intronic deletions, and multi-exon deletions. A Puerto Rican founder allele (c.787G>A (p.Glu263Lys)) accounts for multiple cases in a single pedigree ([PMID:24534832]).

Functional studies demonstrate loss of γ-sarcoglycan at the sarcolemma and downstream destabilization of the dystrophin-associated complex. Antisense-mediated multi-exon skipping restores an in-frame transcript (“Mini-Gamma”) and rescues protein expression in patient cells ([PMID:29720576]). A CRISPR-generated mouse model carrying the exon 6 founder mutation (521∆T) replicates the severe dystrophic phenotype and responds to exon-skipping therapy in vivo ([PMID:31582396]).

No conflicting evidence has been reported. The concordance of genetic segregation, versatile variant types, and robust functional rescue supports a strong gene-disease association.

Key Take-home: SGCG genetic testing, including deletion/duplication analysis and exon-skipping therapy mapping, is essential for accurate LGMD2C diagnosis and emerging personalized treatments.

References

• Neuromuscular disorders : NMD • 1998 • A novel gamma-sarcoglycan mutation causing childhood onset, slowly progressive limb girdle muscular dystrophy. PMID:9673983
• Neuromuscular disorders : NMD • 2000 • Severe gamma-sarcoglycanopathy caused by a novel missense mutation and a large deletion. PMID:10714584
• Neuromuscular disorders : NMD • 2010 • Episodic myoglobinuria in a primary gamma-sarcoglycanopathy. PMID:20356742
• Journal of clinical neuromuscular disease • 2014 • Puerto Rican founder mutation G787A in the SGCG gene: a case report of 2 siblings with LGMD 2C. PMID:24534832
• Human mutation • 2005 • Sarcoglycanopathies and the risk of undetected deletion alleles in diagnosis. PMID:15954112
• Neuromuscular disorders : NMD • 1999 • A diagnostic fluorescent marker kit for six limb girdle muscular dystrophies. PMID:10619713
• Journal of medical genetics • 2000 • A cross section of autosomal recessive limb-girdle muscular dystrophies in 38 families. PMID:10807695
• 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

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