更新于：2024-11-01

CMYA5

更新于：2024-11-01

基本信息

别名

C5orf10、cardiomyopathy associated 5、Cardiomyopathy-associated protein 5

+ [10]

简介

May serve as an anchoring protein that mediates the subcellular compartmentation of protein kinase A (PKA) via binding to PRKAR2A (By similarity). May function as a repressor of calcineurin-mediated transcriptional activity. May attenuate calcineurin ability to induce slow-fiber gene program in muscle and may negatively modulate skeletal muscle regeneration (By similarity). Plays a role in the assembly of ryanodine receptor (RYR2) clusters in striated muscle (By similarity).

关联

项与 CMYA5 相关的药物

miniCMYA5

靶点

CMYA5

作用机制

CMYA5 inhibitors

在研机构

Harvard Medical School [+2]

原研机构

复旦大学附属中山医院 [+2]

在研适应症

心脏衰竭

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 CMYA5 相关的临床结果

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100 项与 CMYA5 相关的转化医学

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0 项与 CMYA5 相关的专利（医药）

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项与 CMYA5 相关的文献（医药）

2024-06-01·Journal of Cachexia, Sarcopenia and Muscle

Integrated multi‐omics approach reveals the role of striated muscle preferentially expressed protein kinase in skeletal muscle including its relationship with myospryn complex

Article

作者: Moghadaszadeh, Behzad ; Li, Qifei ; Luo, Shiyu ; Agrawal, Rohan ; Liu, Xiaoli ; Meng, Melissa ; Beggs, Alan H ; Perrella, Mark A ; Schmitz-Abe, Klaus ; Lin, Jasmine ; Agrawal, Pankaj B

AbstractBackgroundAutosomal‐recessive mutations in SPEG (striated muscle preferentially expressed protein kinase) have been linked to centronuclear myopathy with or without dilated cardiomyopathy (CNM5). Loss of SPEG is associated with defective triad formation, abnormal excitation–contraction coupling, calcium mishandling and disruption of the focal adhesion complex in skeletal muscles. To elucidate the underlying molecular pathways, we have utilized multi‐omics tools and analysis to obtain a comprehensive view of the complex biological processes and molecular functions.MethodsSkeletal muscles from 2‐month‐old SPEG‐deficient (Speg‐CKO) and wild‐type (WT) mice were used for RNA sequencing (n = 4 per genotype) to profile transcriptomics and mass spectrometry (n = 4 for WT; n = 3 for Speg‐CKO mice) to profile proteomics and phosphoproteomics. In addition, interactomics was performed using the SPEG antibody on pooled muscle lysates (quadriceps, gastrocnemius and triceps) from WT and Speg‐CKO mice. Based on the multi‐omics results, we performed quantitative real‐time PCR, co‐immunoprecipitation and immunoblot to verify the findings.ResultsWe identified that SPEG interacts with myospryn complex proteins CMYA5, FSD2 and RyR1, which are critical for triad formation, and that SPEG deficiency results in myospryn complex abnormalities (protein levels decreased to 22 ± 3% for CMYA5 [P < 0.05] and 18 ± 3% for FSD2 [P < 0.01]). Furthermore, SPEG phosphorylates RyR1 at S2902 (phosphorylation level decreased to 55 ± 15% at S2902 in Speg‐CKO mice; P < 0.05), and its loss affects JPH2 phosphorylation at multiple sites (increased phosphorylation at T161 [1.90 ± 0.24‐fold], S162 [1.61 ± 0.37‐fold] and S165 [1.66 ± 0.13‐fold]; decreased phosphorylation at S228 and S231 [39 ± 6%], S234 [50 ± 12%], S593 [48 ± 3%] and S613 [66 ± 10%]; P < 0.05 for S162 and P < 0.01 for other sites). On analysing the transcriptome, the most dysregulated pathways affected by SPEG deficiency included extracellular matrix–receptor interaction (P < 1e−15) and peroxisome proliferator‐activated receptor signalling (P < 9e−14).ConclusionsWe have elucidated the critical role of SPEG in the triad as it works closely with myospryn complex proteins (CMYA5, FSD2 and RyR1), it regulates phosphorylation levels of various residues in JPH2 and S2902 in RyR1, and its deficiency is associated with dysregulation of several pathways. The study identifies unique SPEG‐interacting proteins and their phosphorylation functions and emphasizes the importance of using a multi‐omics approach to comprehensively evaluate the molecular function of proteins involved in various genetic disorders.

2023-10-01·Journal of Feline Medicine and Surgery

Cardiomyopathy associated 5 (CMYA5) implicated as a genetic risk factor for radial hemimelia in Siamese cats

Article

作者: Kutlu, Furkan ; Çınar Kul, Bengi ; Buckley, Reuben M ; Lyons, Leslie A ; Akkurt, Mustafa Yenal ; Bilgen, Nüket ; Bakıcı, Caner ; Çıldır, Özge Şebnem ; Coghill, Lyndon M

Objectives The present study aimed to determine the inheritance pattern and genetic cause of congenital radial hemimelia (RH) in cats. Methods Clinical and genetic analyses were conducted on a Siamese cat family (n = 18), including two siblings with RH. Radiographs were obtained for the affected kittens and echocardiograms of an affected kitten and sire. Whole genome sequencing was completed on the two cases and the parents. Genomic data were compared with the 99 Lives Cat Genome data set of 420 additional domestic cats with whole genome and whole exome sequencing data. Variants were considered as homozygous in the two cases of the siblings with RH and heterozygous in the parents. Candidate variants were genotyped by Sanger sequencing in the extended pedigree. Results Radiographs of the female kitten revealed bilateral absence of the radii and bowing of the humeri, while the male kitten showed a dysplastic right radius. Echocardiography suggested the female kitten had restrictive cardiomyopathy with a positive left atrial-to-aortic root ratio (LA:Ao = 1.83 cm), whereas hypertrophic cardiomyopathy was more likely in the sire, showing diastolic dysfunction using tissue Doppler imaging (59.06 cm/s). Twenty-two DNA variants were unique and homozygous in the affected kittens and heterozygous in the parents. Seven variants clustered in one chromosomal region, including two frameshift variants in cardiomyopathy associated 5 ( CMYA5) and five variants in junction mediating and regulatory protein, P53 cofactor ( JMY ), including a missense and an in-frame deletion. Conclusions and relevance The present study suggested an autosomal recessive mode of inheritance with variable expression for RH in the Siamese cat family. Candidate variants for the phenotype were identified, implicating their roles in bone development. These genes should be considered as potentially causal for other cats with RH. Siamese cat breeders should consider genetically testing their cats for these variants to prevent further dissemination of the suspected variants within the breed.

2023-08-03·Molecular biology and evolution

Comparative Genomic Analysis Identifies Great-Ape-Specific Structural Variants and Their Evolutionary Relevance.

Article

作者: Su, Bing ; Chen, Yongjie ; He, Yaoxi ; Zhou, Bin

During the origin of great apes about 14 million years ago, a series of phenotypic innovations emerged, such as the increased body size, the enlarged brain volume, the improved cognitive skill, and the diversified diet. Yet, the genomic basis of these evolutionary changes remains unclear. Utilizing the high-quality genome assemblies of great apes (including human), gibbon, and macaque, we conducted comparative genome analyses and identified 15,885 great ape-specific structural variants (GSSVs), including eight coding GSSVs resulting in the creation of novel proteins (e.g., ACAN and CMYA5). Functional annotations of the GSSV-related genes revealed the enrichment of genes involved in development and morphogenesis, especially neurogenesis and neural network formation, suggesting the potential role of GSSVs in shaping the great ape-shared traits. Further dissection of the brain-related GSSVs shows great ape-specific changes of enhancer activities and gene expression in the brain, involving a group of GSSV-regulated genes (such as NOL3) that potentially contribute to the altered brain development and function in great apes. The presented data highlight the evolutionary role of structural variants in the phenotypic innovations during the origin of the great ape lineage.

项与 CMYA5 相关的新闻（医药）

2024-09-07

·生物谷

Nature子刊：路福建等开发心力衰竭治疗新手段和体外心肌细胞成熟新技术

miniCMYA5技术成为首个通过基因操纵促进hiPSC-CM结构和功能成熟的手段。复旦大学生物医学研究院、复旦大学附属中山医院心内科上海心研所路福建研究员和哈佛医学院波士顿儿童医院William Pu教授团队在 Nature Biomedical Engineering 期刊发表了题为：Virally delivered CMYA5 enhances the assembly of cardiac dyads 的研究论文。该研究揭示了心力衰竭的重要致病机制——CMYA5表达水平降低，并开发了一种可通过腺相关病毒（AAV）载体递送的微型化CMYA5蛋白（miniCMYA5）。心脏特异性表达miniCMYA5稳固了dyad的结构，显著改善心脏功能，并在hiPSC-CM中启动了dyad的组装，为心力衰竭的治疗和hiPSC-CM的体外成熟提供了新方法。在之前的研究中，研究团队使用生物素介导的邻近蛋白质组学标记技术（BioID），在活体、原位成功捕获了位于dyad空间的蛋白质组，发现了新型dyad蛋白CMYA5是调控jSR定位于Z线（dyad组装的早期和关键步骤）的重要分子。CMYA5缺失破坏了dyad结构、dyad在Z线上的定位以及jSR 的Ca2+释放，导致心力衰竭和对压力超载应激的不耐受。通过检测主动脉缩窄术（transverse aortic constriction，TAC）后小鼠和扩张型心肌病患者的心脏样本发现， CMYA5转录水平和定位正常，但与RYR2互作的CMYA5蛋白水平显著下调，成为心力衰竭中dyad结构破坏的重要因素。因此，增强CMYA5蛋白表达可能有助于保护dyad结构，抵抗和治疗心力衰竭。 AAV是主要的活体心脏基因递送载体，但其容量有限（~4.7 kb），无法用于表达全长的CMYA5（长达11.2 kb）。为此，研究团队设计了一种可以通过AAV递送的CMYA5衍生物，分析不同物种中CMYA5氨基酸的保守性发现，N端（78-319，NT）和C端（2731-3739，MD9）高度保守。免疫荧光和免疫共沉淀实验表明，NT负责CMYA5的Z线定位，而MD9负责与RYR2的互作。在CMYA5 缺失的心肌细胞中，NT和MD9单独均无法恢复RYR2的定位。相反地，研究团队将NT融合到 MD9后，产生了足够小、AAV可装载的微型化蛋白——miniCMYA5，能够定位于Z线并与RYR2互作，在缺失CMYA5的细胞中恢复了RYR2的定位。进一步功能评估表明，miniCMYA5能有效替代全长 CMYA5，修复由于CMYA5缺失引起的dyad组装、Z线定位和心脏功能方面的紊乱。在随后的实验中，研究团队采用两套方案测试AAV-miniCMYA5的治疗潜力：一是在新生小鼠注射全剂量AAV，成年后进行TAC手术，测试其抵抗心力衰竭的能力；二是对成年鼠进行TAC手术建立心力衰竭模型后进行AAV注射，验证治疗效果。通过超声心动图监测心脏功能、组织原位成像、免疫组化分析以及对单个心肌细胞进行收缩力和钙成像等操作，全面评估基因治疗效果。结果显示，通过 AAV-miniCMYA5增强CMYA5活性能稳定dyad结构，纠正异常的Ca2+释放，缓解心肌肥厚和功能障碍。与以往基于Junctophilin2 和Bin1的治疗策略相比，miniCMYA5展现出了更为优越的效果，是一种更具潜力的新型治疗心力衰竭的手段。最后，对体外分化的iPSC-CM和健康供体的成熟心肌进行对比分析发现， CMYA5及其互作蛋白在转录和蛋白水平的缺失，可能是hiPSC-CM结构不成熟的重要因素。结合细胞微图案（micropattern）和工程化人源心肌组织（engineered heart tissue，EHT）技术，在hiPSC-CM中表达miniCMYA5促进了RYR2/jSR与Z线的对齐，增加了钙释放的同步性和钙瞬变的幅度，同时提高了EHT的收缩力。miniCMYA5技术成为首个通过基因操纵促进hiPSC-CM结构和功能成熟的手段。复旦大学路福建研究员为该论文第一作者和共同通讯作者，波士顿儿童医院William Pu教授为论文共同通讯作者。此外，该研究还得到了中山大学吴泽璇博士，湖北大学张冬卉教授课题组，西安交通大学谢文俊教授，波士顿大学 Francisco Naya教授，宾夕法尼亚大学Kenneth Margulies教授课题组，哈佛大学Kit Parker教授课题组，加拿大卡尔加里大学Wayne Chen教授的帮助和支持。

2024-09-06

·生物探索

Nat Biomed Eng丨路福建/William Pu团队合作发明心力衰竭治疗新手段和体外心肌细胞成熟新技术

引言在成熟的心肌细胞中，高效的兴奋-收缩偶联（excitation-contraction coupling，ECC）依赖于结构和功能完整的二联体 (dyad) 单元：由横管（T-tubule）和连接型肌浆网（junctional sarcoplasmic reticulum，jSR）偶联在Z线形成规则排列的纳米级结构。T-tubule 为心肌细胞质膜的管状凹陷，膜上分布着电压敏感型钙通道；jSR 是富含 Ca2+释放通道RYR2 (Ryanodine Receptor 2) 的肌浆网特殊区域。dyad紧密地将电活动与Ca2+释放和心肌收缩联系在一起，其结构异常和功能紊乱直接导致ECC缺陷，是源于不同病因心力衰竭患者的共同特征。人源诱导型多能干细胞分化的心肌细胞（human induced pluripotent stem cell-derived cardiomyocytes，hiPSC-CMs）未能形成dyad，这限制了其在疾病建模和组织修复中的应用。因此，促进dyad的组装和稳定的方法有望保护心脏免受重塑和心力衰竭的影响，并提高hiPSC-CMs的研究和治疗潜力。 2024年9月5日，复旦大学生物医学研究院、附属中山医院心内科上海心研所的路福建研究员和哈佛医学院波士顿儿童医院William Pu教授在Nature Biomedical Engineering上发表题为Virally delivered CMYA5 enhances the assembly of cardiac dyads的研究论文。该研究揭示了心力衰竭的重要致病机制—CMYA5表达水平降低，并发明了一种可通过腺相关病毒（AAV）载体递送的微型化CMYA5蛋白（miniCMYA5）。心脏特异性表达miniCMYA5稳固了dyad的结构，显著改善心脏功能，并在hiPSC-CMs中启动了dyad的组装，为心力衰竭的治疗和hiPSC-CMs的体外成熟提供了新方法。在先前的研究中，研究人员使用生物素介导的邻近蛋白质组学标记技术（BioID），在活体、原位成功捕获了位于dyad空间的蛋白质组（Lu, F., Ma, Q., Xie, W. et al. CMYA5 establishes cardiac dyad architecture and positioning. Nat Commun 13, 2185 (2022). https://doi.org/10.1038/s41467-022-29902-4），发现了新型dyad蛋白CMYA5是调控jSR定位于Z线（dyad组装的早期和关键步骤）的重要分子。CMYA5缺失破坏了dyad结构、dyad在Z线上的定位以及jSR 的Ca2+释放，导致心力衰竭和对压力超载应激的不耐受。通过检测主动脉缩窄术（transverse aortic constriction, TAC）后小鼠和扩张型心肌病患者的心脏样本发现， CMYA5转录水平和定位正常，但与RYR2互作的CMYA5蛋白水平显著下调，成为心力衰竭中dyad结构破坏的重要因素。因此，增强CMYA5蛋白表达可能有助于保护dyad结构，抵抗和治疗心力衰竭。 AAV是主要的活体心脏基因递送载体，但其容量有限（~4.7 kb），无法用于表达全长的CMYA5（11.2 kb）。为此，研究人员设计了一种可以通过AAV递送的CMYA5衍生物，分析不同物种中CMYA5氨基酸的保守性发现，N端（78-319，NT）和C端（2731-3739，MD9）高度保守。免疫荧光和免疫共沉淀实验表明，NT负责CMYA5的Z线定位，而MD9负责与RYR2的互作。在CMYA5 缺失的心肌细胞中，NT和MD9单独均无法恢复RYR2的定位。相反地，研究人员将 NT 融合到 MD9后，产生了足够小、AAV可装载的微型化蛋白 miniCMYA5，能够定位于Z线并与RYR2互作，在缺失CMYA5的细胞中恢复了RYR2的定位。进一步功能评估表明，miniCMYA5能有效替代全长 CMYA5，修复由于CMYA5缺失引起的dyad组装、Z线定位和心脏功能方面的紊乱。在随后的实验中，研究人员采用两套方案测试AAV-miniCMYA5的治疗潜力：一是在新生小鼠注射全剂量AAV，成年后进行TAC手术，测试其抵抗心力衰竭的能力；二是对成年鼠进行TAC手术建立心力衰竭模型后进行AAV注射，验证治疗效果。通过超声心动图监测心脏功能、组织原位成像、免疫组化分析以及对单个心肌细胞进行收缩力和钙成像等操作，全面评估基因治疗效果。结果显示，通过 AAV-miniCMYA5增强CMYA5活性能稳定dyad结构，纠正异常的Ca2+释放，缓解心肌肥厚和功能障碍。与以往基于Junctophilin2 和Bin1的治疗策略相比，miniCMYA5展现出了更为优越的效果，是一种更具潜力的新型治疗心力衰竭的手段。最后，对体外分化的iPSC-CMs和健康供体的成熟心肌进行对比分析发现， CMYA5及其互作蛋白在转录和蛋白水平的缺失，可能是hiPSC-CMs结构不成熟的重要因素。结合细胞微图案（micropattern）和工程化人源心肌组织（engineered heart tissue，EHT）技术，在hiPSC-CMs中表达miniCMYA5促进了RYR2/jSR与Z线的对齐，增加了钙释放的同步性和钙瞬变的幅度，同时提高了EHT的收缩力。miniCMYA5技术成为首个通过基因操纵促进hiPSC-CMs结构和功能成熟的手段。参考文献 https://www.nature.com/articles/s41551-024-01253-z 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

细胞疗法临床研究