SGCG – Autosomal Recessive Limb-Girdle Muscular Dystrophy Type 2C

Limb-girdle muscular dystrophy type 2C (LGMD2C) is an autosomal recessive myopathy characterized by childhood-onset proximal muscle weakness, calf hypertrophy, scapular winging, and exercise intolerance. Pathogenic biallelic variants in SGCG (encoding γ-sarcoglycan), a component of the dystrophin-associated glycoprotein complex, lead to sarcolemmal fragility and progressive muscle degeneration. Clinical presentation overlaps with dystrophinopathies and Charcot-Marie-Tooth phenotypes, prompting genetic testing for SGCG in atypical cases (PMID:19208398, PMID:19167890).

A founder c.525delT (p.Phe175fs) variant is prevalent in North African populations, identified in 132 homozygous patients with variable severity PMID:14678800. Additional cohorts include 20 unrelated Turkish and Moroccan individuals with novel splice (IVS5+2T>C) and nonsense (c.93G>A (p.Trp31Ter)) variants PMID:15087111, and 2 Japanese DMD-like cases with exon deletions PMID:20350330. Segregation of SGCG alleles in 4 affected siblings further corroborates autosomal recessive inheritance PMID:24638197.

Variant spectrum encompasses frameshift, nonsense, splice-site, and missense mutations distributed across SGCG, with recurrent founder alleles (E263K) in Puerto Rican Hispanics PMID:25802879. A representative loss-of-function variant c.93G>A (p.Trp31Ter) illustrates the truncating impact on γ-sarcoglycan expression PMID:15087111.

Functional studies reveal that antisense-mediated exon skipping restores internally truncated “Mini-Gamma” protein expression in patient-derived myotubes PMID:29720576, while systemic AAV-mediated SGCG gene transfer in knockout mice reconstitutes sarcoglycan complex and ameliorates muscle pathology and function PMID:36816759. These concordant in vitro and in vivo assays support haploinsufficiency as the primary pathogenic mechanism.

No conflicting reports have been described to date, although intrafamilial phenotypic variability suggests modifier gene effects. Together, robust genetic, segregation, and functional data justify a Strong ClinGen classification for SGCG in LGMD2C, underpin comprehensive diagnostic genotyping, carrier screening in high-prevalence populations, and advancement of gene-based therapies.

Key Take-home: Bi-allelic SGCG loss-of-function variants cause autosomal recessive LGMD2C, with clear implications for diagnosis, prognostication, and therapeutic development.

References

• Muscle & nerve • 2009 • Homozygous contiguous gene deletion of 13q12 causing LGMD2C and ARSACS in the same patient. PMID:19208398
• Neuromuscular disorders : NMD • 2009 • Eosinophilic myositis as presenting symptom in gamma-sarcoglycanopathy. PMID:19167890
• Neuromuscular disorders : NMD • 2003 • Phenotype and sarcoglycan expression in Tunisian LGMD 2C patients sharing the same del521-T mutation. PMID:14678800
• Pediatric neurology • 2004 • Novel mutations in three patients with LGMD2C with phenotypic differences. PMID:15087111
• BMC medical genetics • 2010 • Low incidence of limb-girdle muscular dystrophy type 2C revealed by a mutation study in Japanese patients clinically diagnosed with DMD. PMID:20350330
• Turk patoloji dergisi • 2014 • Histopathological and genetic features of patients with limb girdle muscular dystrophy type 2C. PMID:24638197
• JCI insight • 2018 • Efficient exon skipping of SGCG mutations mediated by phosphorodiamidate morpholino oligomers. PMID:29720576
• 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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