{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSTAC3 is a crucial adaptor protein that underpins skeletal muscle excitation–contraction coupling by facilitating communication between key ion channels. Through its tandem SH3 domains, STAC3 directly interacts with the cytosolic II–III loop of the voltage‐gated calcium channel CaV1.1, thereby supporting the effective coupling of membrane depolarization to calcium release from the sarcoplasmic reticulum. This interaction is essential for the regulation of calcium‐induced muscle contraction, and mutations in STAC3 disrupt this process resulting in impaired Ca²⁺ release and muscle weakness. In humans, such mutations have been identified as the genetic basis of congenital disorders such as Native American myopathy and have also been linked to episodes of malignant hyperthermia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its established role in muscle physiology, STAC3 appears to have functions in non‐muscle tissues. Notably, its expression in Leydig cells of the testicular interstitium indicates a role in testicular steroidogenesis. Experimental evidence demonstrates that suppression of STAC3 in these cells disrupts mitochondrial homeostasis and the processing of steroidogenic proteins, leading to reduced testosterone production and consequent impairments in spermatogenesis and male fertility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic analyses further underscore the clinical importance of STAC3 variants in neuromuscular disorders. Whole exome sequencing studies have identified both known and novel STAC3 mutations in patients presenting with clinical features ranging from congenital myopathy to malignant hyperthermia–like reactions. Bayesian approaches to variant pathogenicity prediction have been applied to these findings, underscoring the contribution of STAC3 alterations to disease phenotypes and emphasizing the need to include STAC3 gene analysis in diagnostic screenings for individuals with a history of such symptoms."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Eric J Horstick, Jeremy W Linsley, James J Dowling, et al. 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"}, {"type": "b", "children": [{"type": "t", "text": "STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Hum Mutat (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/humu.23635"}], "href": "https://doi.org/10.1002/humu.23635"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30168660"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30168660"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Bernhard E Flucher, Marta Campiglio "}, {"type": "b", "children": [{"type": "t", "text": "STAC proteins: The missing link in skeletal muscle EC coupling and new regulators of calcium channel function."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochim Biophys Acta Mol Cell Res (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbamcr.2018.12.004"}], "href": "https://doi.org/10.1016/j.bbamcr.2018.12.004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30543836"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30543836"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Britany Rufenach, Darren Christy, Bernhard E Flucher, et al. 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