更新于：2024-11-01

telethonin

更新于：2024-11-01

基本信息

别名

CMD1N、LGMD2G、T-cap

+ [5]

简介

Muscle assembly regulating factor. Mediates the antiparallel assembly of titin (TTN) molecules at the sarcomeric Z-disk.

关联

项与 telethonin 相关的药物

Limb Girdle Muscular Dystrophy 2g(CRD)

靶点

telethonin

作用机制

telethonin 刺激剂

在研机构

Cure Rare Disease, Inc.初创企业

原研机构

Cure Rare Disease, Inc.初创企业

在研适应症

肢带型肌营养不良2G型

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

rAAV.TCAP

靶点

telethonin

作用机制

telethonin modulators

在研机构

UMass Chan Medical School [+1]

原研机构

UMass Chan Medical School [+1]

在研适应症

肢带型肌营养不良2G型

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 telethonin 相关的临床结果

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100 项与 telethonin 相关的转化医学

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0 项与 telethonin 相关的专利（医药）

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309

项与 telethonin 相关的文献（医药）

2024-12-01·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Tcap deficiency impedes striated muscle function and heart regeneration with elevated ROS and autophagy

Article

作者: Gao, Peng ; Chang, Cheng ; Liu, Xuan ; Liang, Jieling ; Du, Fen ; Zhao, Yan ; Zhang, Ruilin ; Li, Huicong

Telethonin/titin-cap (TCAP) encodes a Z-disc protein that plays important roles in sarcomere/T-tubule interactions, stretch-sensing and signaling. Mutations in TCAP are associated with muscular dystrophy and cardiomyopathy; however, the complete etiology and its roles in myocardial infarction and regeneration are not fully understood. Here, we generated tcap gene knockout zebrafish with CRISPR/Cas9 technology and observed muscular dystrophy-like phenotypes and abnormal mitochondria in skeletal muscles. The stretch-sensing ability was inhibited in tcap^-^/^- mutants. Moreover, Tcap deficiency led to alterations in cardiac morphology and function as well as increases in reactive oxygen species (ROS) and mitophagy. In addition, the cardiac regeneration and cardiomyocyte proliferation ability of tcap^-^/^- mutants were impaired, but these impairments could be rescued by supplementation with ROS scavengers or autophagy inhibitors. Overall, our study demonstrates the essential roles of Tcap in striated muscle function and heart regeneration. Additionally, elevations in ROS and autophagy may account for the phenotypes resulting from Tcap deficiency and could serve as novel therapeutic targets for muscular dystrophy and cardiomyopathy.

2024-11-01·Clinical Genetics

Clinical and molecular characterization of limb‐girdle muscular dystrophy 2G/R7 in a large cohort of Brazilian patients

Article

作者: Zanoteli, Edmar ; Carvalho, Alzira A. S. ; Fustes, Otto J. H. ; Donis, Karina C. ; Costa e Silva, Cynthia ; Oliveira, Acary S. B. ; Ducci, Renata D. ; de Souza, Paulo V. S. ; Carvalho, Elmano H. T. ; Cavalcanti, Eduardo B. U. ; França, Marcondes C. ; Gaviraghi, Tobias ; de Moraes, Maria T. ; Saute, Jonas Alex Morales ; Pinto, Wladimir B. V. R. ; Cotta, Ana ; de Oliveira, André D. ; Sobreira, Cláudia F. R. ; Scola, Rosana H. ; Lorenzoni, Paulo José ; da Silva, André M. S. ; Kay, Cláudia S. K. ; Winckler, Pablo B. ; Rodrigues, Paula R. V. P. ; Marques, Marcos V. O.

AbstractLimb‐girdle muscular dystrophy type 2G/R7 (LGMD2G/R7) is an ultra‐rare condition initially identified within the Brazilian population. We aimed to expand clinical and genetic information about this disease, including its worldwide distribution. A multicenter historical cohort study was performed at 13 centers in Brazil in which data from index cases and their affected relatives from consecutive families with LGMD2G/R7 were reviewed from July 2017 to August 2023. Additionally, a systematic literature review was conducted to identify case reports and series of the disease worldwide. Forty‐one LGMD2G/R7 cases were described in the Brazilian cohort, being all subjects homozygous for the c.157C>T/(p.Gln53*) variant in TCAP. Survival curves showed that the median disease duration before individuals required walking aids was 21 years. Notably, women exhibited a slower disease progression, requiring walking aids 13 years later than men. LGMD2G/R7 was frequently reported not only in Brazil but also in China and Bulgaria, with 119 cases identified globally, with possible founder effects in the Brazilian, Eastern European, and Asian populations. These findings are pivotal in raising awareness of LGMD2G/R7, understanding its progression, and identifying potential modifiers. This can significantly contribute to the development of future natural history studies and clinical trials for this disease.

2024-09-13·Circulation Research

Restoring Atrial T-Tubules Augments Systolic Ca Upon Recovery From Heart Failure

Article

作者: Trafford, Andrew W. ; Eisner, David A. ; Radcliffe, Emma J. ; Madders, George W.P. ; Bode, Elizabeth F. ; Quinn, Callum J. ; Clarke, Jessica D. ; Dibb, Katharine M. ; Watkins, Amy ; Pinali, Christian ; Horn, Margaux A ; Adomaviciene, Aiste ; Smith, Charlotte E.R. ; Pearman, Charles M. ; Caldwell, Jessica L. ; Eisner, Mark

BACKGROUND: Transverse (t)-tubules drive the rapid and synchronous Ca 2+ rise in cardiac myocytes. The virtual complete atrial t-tubule loss in heart failure (HF) decreases Ca 2+ release. It is unknown if or how atrial t-tubules can be restored and how this affects systolic Ca 2+ . METHODS: HF was induced in sheep by rapid ventricular pacing and recovered following termination of rapid pacing. Serial block-face scanning electron microscopy and confocal imaging were used to study t-tubule ultrastructure. Function was assessed using patch clamp, Ca 2+ , and confocal imaging. Candidate proteins involved in atrial t-tubule recovery were identified by western blot and expressed in rat neonatal ventricular myocytes to determine if they altered t-tubule structure. RESULTS: Atrial t-tubules were lost in HF but reappeared following recovery from HF. Recovered t-tubules were disordered, adopting distinct morphologies with increased t-tubule length and branching. T-tubule disorder was associated with mitochondrial disorder. Recovered t-tubules were functional, triggering Ca 2+ release in the cell interior. Systolic Ca 2+ , ICa-L , sarcoplasmic reticulum Ca 2+ content, and sarcoendoplasmic reticulum Ca 2+ ATPase function were restored following recovery from HF. Confocal microscopy showed fragmentation of ryanodine receptor staining and movement away from the z-line in HF, which was reversed following recovery from HF. Acute detubulation, to remove recovered t-tubules, confirmed their key role in restoration of the systolic Ca 2+ transient, the rate of Ca 2+ removal, and the peak L-type Ca 2+ current. The abundance of telethonin and myotubularin decreased during HF and increased during recovery. Transfection with these proteins altered the density and structure of tubules in neonatal myocytes. Myotubularin had a greater effect, increasing tubule length and branching, replicating that seen in the recovery atria. CONCLUSIONS: We show that recovery from HF restores atrial t-tubules, and this promotes recovery of ICa-L , sarcoplasmic reticulum Ca 2+ content, and systolic Ca 2+ . We demonstrate an important role for myotubularin in t-tubule restoration. Our findings reveal a new and viable therapeutic strategy.