Correlation of Phenotype–Genotype and Protein Structure in RYR1-Related Myopathy
IntroductionNext generation sequencing results in an explosive identification of rare variants of RYR1, making the correlation between phenotype and genotype complicated. We analyzed the data of 33 patients with RYR1-related myopathy, attempting to elucidate correlations between phenotype, genotype,...
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| Format: | Article |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Neurology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fneur.2022.870285/full |
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| author | Xingzhi Chang Risheng Wei Cuijie Wei Jieyu Liu Lun Qin Hui Yan Yinan Ma Zhaoxia Wang Hui Xiong |
| author_facet | Xingzhi Chang Risheng Wei Cuijie Wei Jieyu Liu Lun Qin Hui Yan Yinan Ma Zhaoxia Wang Hui Xiong |
| author_sort | Xingzhi Chang |
| collection | DOAJ |
| description | IntroductionNext generation sequencing results in an explosive identification of rare variants of RYR1, making the correlation between phenotype and genotype complicated. We analyzed the data of 33 patients with RYR1-related myopathy, attempting to elucidate correlations between phenotype, genotype, and protein structure of RyR1.MethodsClinical, histopathologic, and genetic data were evaluated, and variants were mapped to the cryo-EM RyR1 structure. The three-dimensional structure of the variant on RyR1 was analyzed.ResultsThe clinical spectrum was highly variable regardless of the mode of inheritance. Recessive variations were associated with more severe feeding problems and respiratory insufficiency in infancy (p < 0.05). Forty pathogenic and likely pathogenic variations were identified, and 14 of them were novel. Missense was the most common variation type regardless of inheritance mode. Arginine (15/45) was the most frequently involved residue. All but one dominant variation clustered in Pore forming and pVSD domains, while recessive variations enriched in Bsol (7/25) and SPRYs (6/25) domains. Analysis of the spatial structure of variants showed that dominant variants may impact RyR1 mainly by breaking down hydrogen or electrovalent bonds (10/21); recessive variants located in different domains may impact the function of RyR1 through different pathways. Variants located in RyR1 coupling sites (PY1&2 and the outermost of Bsol) may cause the most severe clinical manifestation.ConclusionClinical diversity of RYR1-related myopathy was impacted by the inheritance mode, variation type, and variant location. Dominant and recessive variants have different sensitive domains impacting the function of RyR1 through different pathways. |
| first_indexed | 2024-04-12T17:41:46Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1664-2295 |
| language | English |
| last_indexed | 2024-04-12T17:41:46Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Neurology |
| spelling | doaj.art-b0b285f960474f67b96bf89d631f87612022-12-22T03:22:47ZengFrontiers Media S.A.Frontiers in Neurology1664-22952022-05-011310.3389/fneur.2022.870285870285Correlation of Phenotype–Genotype and Protein Structure in RYR1-Related MyopathyXingzhi Chang0Risheng Wei1Cuijie Wei2Jieyu Liu3Lun Qin4Hui Yan5Yinan Ma6Zhaoxia Wang7Hui Xiong8Department of Pediatrics, Peking University First Hospital, Beijing, ChinaDepartment of Biochemistry and Biophysics, Peking University Health Science Center, Peking University, Beijing, ChinaDepartment of Pediatrics, Peking University First Hospital, Beijing, ChinaDepartment of Pediatrics, Peking University First Hospital, Beijing, ChinaDepartment of Rehabilitation Medicine, Peking University First Hospital, Beijing, ChinaDepartment of Pediatrics, Peking University First Hospital, Beijing, ChinaDepartment of Central Laboratory, Peking University First Hospital, Beijing, ChinaDepartment of Neurology, Peking University First Hospital, Beijing, ChinaDepartment of Pediatrics, Peking University First Hospital, Beijing, ChinaIntroductionNext generation sequencing results in an explosive identification of rare variants of RYR1, making the correlation between phenotype and genotype complicated. We analyzed the data of 33 patients with RYR1-related myopathy, attempting to elucidate correlations between phenotype, genotype, and protein structure of RyR1.MethodsClinical, histopathologic, and genetic data were evaluated, and variants were mapped to the cryo-EM RyR1 structure. The three-dimensional structure of the variant on RyR1 was analyzed.ResultsThe clinical spectrum was highly variable regardless of the mode of inheritance. Recessive variations were associated with more severe feeding problems and respiratory insufficiency in infancy (p < 0.05). Forty pathogenic and likely pathogenic variations were identified, and 14 of them were novel. Missense was the most common variation type regardless of inheritance mode. Arginine (15/45) was the most frequently involved residue. All but one dominant variation clustered in Pore forming and pVSD domains, while recessive variations enriched in Bsol (7/25) and SPRYs (6/25) domains. Analysis of the spatial structure of variants showed that dominant variants may impact RyR1 mainly by breaking down hydrogen or electrovalent bonds (10/21); recessive variants located in different domains may impact the function of RyR1 through different pathways. Variants located in RyR1 coupling sites (PY1&2 and the outermost of Bsol) may cause the most severe clinical manifestation.ConclusionClinical diversity of RYR1-related myopathy was impacted by the inheritance mode, variation type, and variant location. Dominant and recessive variants have different sensitive domains impacting the function of RyR1 through different pathways.https://www.frontiersin.org/articles/10.3389/fneur.2022.870285/fullphenotypegenotypeprotein structureRYR1-related myopathycohort study |
| spellingShingle | Xingzhi Chang Risheng Wei Cuijie Wei Jieyu Liu Lun Qin Hui Yan Yinan Ma Zhaoxia Wang Hui Xiong Correlation of Phenotype–Genotype and Protein Structure in RYR1-Related Myopathy Frontiers in Neurology phenotype genotype protein structure RYR1-related myopathy cohort study |
| title | Correlation of Phenotype–Genotype and Protein Structure in RYR1-Related Myopathy |
| title_full | Correlation of Phenotype–Genotype and Protein Structure in RYR1-Related Myopathy |
| title_fullStr | Correlation of Phenotype–Genotype and Protein Structure in RYR1-Related Myopathy |
| title_full_unstemmed | Correlation of Phenotype–Genotype and Protein Structure in RYR1-Related Myopathy |
| title_short | Correlation of Phenotype–Genotype and Protein Structure in RYR1-Related Myopathy |
| title_sort | correlation of phenotype genotype and protein structure in ryr1 related myopathy |
| topic | phenotype genotype protein structure RYR1-related myopathy cohort study |
| url | https://www.frontiersin.org/articles/10.3389/fneur.2022.870285/full |
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