Ryanodine receptors are part of the myospryn complex in cardiac muscle

Abstract

The Cardiomyopathy–associated gene 5 (Cmya5) encodes myospryn, a large tripartite motif (TRIM)-related protein found predominantly in cardiac and skeletal muscle. Cmya5 is an expression biomarker for a number of diseases affecting striated muscle and may also be a schizophrenia risk gene. To further understand the function of myospryn in striated muscle, we searched for additional myospryn paralogs. Here we identify a novel muscle-expressed TRIM-related protein minispryn, encoded by Fsd2, that has extensive sequence similarity with the C-terminus of myospryn. Cmya5 and Fsd2 appear to have originated by a chromosomal duplication and are found within evolutionarily-conserved gene clusters on different chromosomes. Using immunoaffinity purification and mass spectrometry we show that minispryn co-purifies with myospryn and the major cardiac ryanodine receptor (RyR2) from heart. Accordingly, myospryn, minispryn and RyR2 co-localise at the junctional sarcoplasmic reticulum of isolated cardiomyocytes. Myospryn redistributes RyR2 into clusters when co-expressed in heterologous cells whereas minispryn lacks this activity. Together these data suggest a novel role for the myospryn complex in the assembly of ryanodine receptor clusters in striated muscle.

Single-Cell Transcriptomic Analyses of Cell Fate Transitions during Human Cardiac Reprogramming

“…To identify the potential selection markers for reprogramming or refractory populations, we focused on those genes repeatedly ranked at the top of the DEG list (p < 0.05 at each time point; Figure 7D, highlight in red dots; Table S4). Among the genes highly expressed in reprogramming cells (Figure 7E), we found several makers already known in heart, like cardiomyopathy-associated 5 (CMYA5) encoding MYOSPRYN (Benson et al, 2017;Durham et al, 2006), crystallin alpha B (CRYAB or HSPB5) and heat shock protein family B (small) member 2 (HSPB2) (Sugiyama et al, 2000). Transforming growth factor beta 3 (TGFB3), another potential marker for reprogramming cells, exhibited increasing See also Figure S7 and Tables S4 and S5.…”

Intermediate filaments in cardiomyopathy

“…Moreover, a recently shown association of RyR2a with the desmin-associated protein myospryn (CMYA5, cardiomyopathy-associated 5), a novel tripartite motif family (TRIM)-like protein, demonstrated in addition to VDAC an indirect way of desmin association to the SR of cardiomyocytes (Benson et al 2017). The desmin-myospryn interaction is important for perinuclear and lysosomal localization of myospryn (see below) (Kouloumenta et al 2007).…”

In vivoidentification and validation of novel potential predictors for human cardiovascular diseases

“…Across the hGWAS set of 40 genes, comparative heart rate analysis showed statistically significant heart rate phenotypes in a total of 16 genes ( Fig 3B). The five positive controls, known to play key roles in heart functions such as cardiac contraction (TTN and NACA) and heart rate regulation (CASQ2, Beyond known cardiac genes, we revealed new genes linked to various biological functions (CCDC141, GIGYF1, HOMEZ, MYRF, SMG6, CMYA5, CNOT1, SLC17A3, TRAPPC12, SSPO and PADI4) which up to now, had little to no experimental evidence in cardiac function (Rathjens et al 2020;Benson et al 2017;Yamaguchi et al 2018;Elmen et al 2020).…”

“…clearly responded in the assay. Beyond known cardiac genes, we revealed new genes linked to various biological functions (CCDC141, GIGYF1, HOMEZ, MYRF, SMG6, CMYA5, CNOT1, SLC17A3, TRAPPC12, SSPO and PADI4) which up to now, had little to no experimental evidence in cardiac function (Rathjens et al 2020;Benson et al 2017;Yamaguchi et al 2018;Elmen et al 2020).…”