Comprehensive Mapping of SGCA Variant Effects Reveals Domain-Specific Constraints Relevant to Sarcoglycanopathies
Huang, S.; Ng, K.; Lu, Y.; Xie, Z.; Hu, C.; Zhu, B.; Zhu, W.; Lek, A.; Ma, K.; Lek, M.
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Pathogenic variants in SGCA, encoding -sarcoglycan, cause an autosomal recessive limb-girdle muscular dystrophy, LGMDR3/2D, yet clinical interpretation of SGCA variants remains challenging due to the high prevalence of rare missense variants. -sarcoglycan is an essential component of the sarcoglycan complex at the muscle cell membrane, and pathogenic variants frequently impair its membrane localization. Here, we systematically assess the effects of all possible single-nucleotide variants across the SGCA coding sequence using a saturation mutagenesis-based experimental assay that quantifies -sarcoglycan surface expression. We generate a comprehensive functional atlas that distinguishes tolerated and damaging variants, aligning with independent genetic and clinical evidence, and reveals domain-specific properties of the cytoplasmic region, in which C-terminal truncating variants retain membrane localization, suggesting possible pathogenic mechanisms beyond impaired trafficking. This work provides a scalable functional framework to support genetic diagnosis and variant interpretation in sarcoglycanopathies. Graphical AbstractSchematic overview of saturation mutagenesis-based functional mapping of SGCA. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=187 SRC="FIGDIR/small/740214v1_ufig1.gif" ALT="Figure 1"> View larger version (41K): org.highwire.dtl.DTLVardef@1dc3d7corg.highwire.dtl.DTLVardef@48a213org.highwire.dtl.DTLVardef@88bec7org.highwire.dtl.DTLVardef@1a51bea_HPS_FORMAT_FIGEXP M_FIG C_FIG
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