Comprehensive functional characterization of SGCB coding variants predicts pathogenicity in limb-girdle muscular dystrophy type R4/2E
Genetic testing is essential for patients with a suspected hereditary myopathy. More than 50% of patients clinically diagnosed with a myopathy carry a variant of unknown significance in a myopathy gene, often leaving them without a genetic diagnosis. Limb-girdle muscular dystrophy (LGMD) type R4/2E...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical Investigation
2023-06-01
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| Series: | The Journal of Clinical Investigation |
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| Online Access: | https://doi.org/10.1172/JCI168156 |
| _version_ | 1827768144718987264 |
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| author | Chengcheng Li Jackson Wilborn Sara Pittman Jil Daw Jorge Alonso-Pérez Jordi Díaz-Manera Conrad C. Weihl Gabe Haller |
| author_facet | Chengcheng Li Jackson Wilborn Sara Pittman Jil Daw Jorge Alonso-Pérez Jordi Díaz-Manera Conrad C. Weihl Gabe Haller |
| author_sort | Chengcheng Li |
| collection | DOAJ |
| description | Genetic testing is essential for patients with a suspected hereditary myopathy. More than 50% of patients clinically diagnosed with a myopathy carry a variant of unknown significance in a myopathy gene, often leaving them without a genetic diagnosis. Limb-girdle muscular dystrophy (LGMD) type R4/2E is caused by mutations in β-sarcoglycan (SGCB). Together, β-, α-, γ-, and δ-sarcoglycan form a 4-protein transmembrane complex (SGC) that localizes to the sarcolemma. Biallelic loss-of-function mutations in any subunit can lead to LGMD. To provide functional evidence for the pathogenicity of missense variants, we performed deep mutational scanning of SGCB and assessed SGC cell surface localization for all 6,340 possible amino acid changes. Variant functional scores were bimodally distributed and perfectly predicted pathogenicity of known variants. Variants with less severe functional scores more often appeared in patients with slower disease progression, implying a relationship between variant function and disease severity. Amino acid positions intolerant to variation mapped to points of predicted SGC interactions, validated in silico structural models, and enabled accurate prediction of pathogenic variants in other SGC genes. These results will be useful for clinical interpretation of SGCB variants and improving diagnosis of LGMD; we hope they enable wider use of potentially life-saving gene therapy. |
| first_indexed | 2024-03-11T12:09:12Z |
| format | Article |
| id | doaj.art-d80b71611c5f4cd7b0e9659e8d6e5684 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:09:12Z |
| publishDate | 2023-06-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-d80b71611c5f4cd7b0e9659e8d6e56842023-11-07T16:20:29ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-06-0113312Comprehensive functional characterization of SGCB coding variants predicts pathogenicity in limb-girdle muscular dystrophy type R4/2EChengcheng LiJackson WilbornSara PittmanJil DawJorge Alonso-PérezJordi Díaz-ManeraConrad C. WeihlGabe HallerGenetic testing is essential for patients with a suspected hereditary myopathy. More than 50% of patients clinically diagnosed with a myopathy carry a variant of unknown significance in a myopathy gene, often leaving them without a genetic diagnosis. Limb-girdle muscular dystrophy (LGMD) type R4/2E is caused by mutations in β-sarcoglycan (SGCB). Together, β-, α-, γ-, and δ-sarcoglycan form a 4-protein transmembrane complex (SGC) that localizes to the sarcolemma. Biallelic loss-of-function mutations in any subunit can lead to LGMD. To provide functional evidence for the pathogenicity of missense variants, we performed deep mutational scanning of SGCB and assessed SGC cell surface localization for all 6,340 possible amino acid changes. Variant functional scores were bimodally distributed and perfectly predicted pathogenicity of known variants. Variants with less severe functional scores more often appeared in patients with slower disease progression, implying a relationship between variant function and disease severity. Amino acid positions intolerant to variation mapped to points of predicted SGC interactions, validated in silico structural models, and enabled accurate prediction of pathogenic variants in other SGC genes. These results will be useful for clinical interpretation of SGCB variants and improving diagnosis of LGMD; we hope they enable wider use of potentially life-saving gene therapy.https://doi.org/10.1172/JCI168156GeneticsMuscle biology |
| spellingShingle | Chengcheng Li Jackson Wilborn Sara Pittman Jil Daw Jorge Alonso-Pérez Jordi Díaz-Manera Conrad C. Weihl Gabe Haller Comprehensive functional characterization of SGCB coding variants predicts pathogenicity in limb-girdle muscular dystrophy type R4/2E The Journal of Clinical Investigation Genetics Muscle biology |
| title | Comprehensive functional characterization of SGCB coding variants predicts pathogenicity in limb-girdle muscular dystrophy type R4/2E |
| title_full | Comprehensive functional characterization of SGCB coding variants predicts pathogenicity in limb-girdle muscular dystrophy type R4/2E |
| title_fullStr | Comprehensive functional characterization of SGCB coding variants predicts pathogenicity in limb-girdle muscular dystrophy type R4/2E |
| title_full_unstemmed | Comprehensive functional characterization of SGCB coding variants predicts pathogenicity in limb-girdle muscular dystrophy type R4/2E |
| title_short | Comprehensive functional characterization of SGCB coding variants predicts pathogenicity in limb-girdle muscular dystrophy type R4/2E |
| title_sort | comprehensive functional characterization of sgcb coding variants predicts pathogenicity in limb girdle muscular dystrophy type r4 2e |
| topic | Genetics Muscle biology |
| url | https://doi.org/10.1172/JCI168156 |
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