Functional Catalog of β-Sarcoglycan Alterations Aims to Help Interpret Uncertain Variants

By generating a catalog of the effects of different gene alterations on β-sarcoglycan, a protein involved in limb-girdle muscular dystrophy, researchers hope to better interpret variants of uncertain significance and inform gene therapy studies. A Washington University School of Medicine in St. Louis-led team conducted deep mutational scanning of SGCB, the gene encoding β-sarcoglycan. β-sarcoglycan, together with α-sarcoglycan, γ-sarcoglycan, and δ-sarcoglycan, form a transmembrane complex within myofibers and its disruption can lead to progressive muscle weakness, muscle wasting, and early death. The researchers assessed the functional effects of all 6,340 possible amino acids changes on the protein, and all variants already known to cause disease scored low on functionality, and the functionality scores further correlated with disease severity. As the researchers note in the Journal of Clinical Investigation, this catalog could help resolve variants of uncertain significance found among limb-girdle muscular dystrophy patients as well as improve disease diagnosis. "Twenty percent of the variants of unknown significance turned out to be pathogenic, which means they could be amenable to potential therapies," co-author Conrad Weihl, a neurology professor at WUSTL, adds in a statement. "My dream is that one day we'll be able to give people a genetic test report that says, 'You have this variant, and it's amenable to this type of therapy,' and we can start them on the best therapy right away. Or we tell them, 'Your variant is benign,' and we keep looking until we find the variant that is responsible for the patient's disease."