{"id":55550,"date":"2022-04-27T09:25:03","date_gmt":"2022-04-27T07:25:03","guid":{"rendered":"https:\/\/cegat.com\/?p=55550"},"modified":"2025-02-12T11:15:40","modified_gmt":"2025-02-12T10:15:40","slug":"stx4-is-required-to-regulate-cardiomyocyte-ca2-handling-during-vertebrate-cardiac-development","status":"publish","type":"post","link":"https:\/\/cegat.com\/de\/stx4-is-required-to-regulate-cardiomyocyte-ca2-handling-during-vertebrate-cardiac-development\/","title":{"rendered":"Stx4 is required to regulate cardiomyocyte Ca2+ handling during vertebrate cardiac development"},"content":{"rendered":"

Eliyahu Perl\u00a0<\/span>1\u00a0<\/span>2\u00a0<\/span>3<\/sup>,\u00a0<\/span><\/span>Padmapriyadarshini Ravisankar\u00a0<\/span>3<\/sup>,\u00a0<\/span><\/span>Manu E Beerens\u00a0<\/span>4<\/sup>,\u00a0<\/span><\/span>Lejla Mulahasanovic\u00a0<\/span>5\u00a0<\/span>6<\/sup>,\u00a0<\/span><\/span>Kelly Smallwood\u00a0<\/span>7<\/sup>,\u00a0<\/span><\/span>Marion Berm\u00fadez Sasso\u00a0<\/span>8<\/sup>,\u00a0<\/span><\/span>Carina Wenzel\u00a0<\/span>9<\/sup>,\u00a0<\/span><\/span>Thomas D Ryan\u00a0<\/span>10\u00a0<\/span>11<\/sup>,\u00a0<\/span><\/span>Matej Kom\u00e1r\u00a0<\/span>12<\/sup>,\u00a0<\/span><\/span>Kevin E Bove\u00a0<\/span>10\u00a0<\/span>13\u00a0<\/span>14<\/sup>,\u00a0<\/span><\/span>Calum A MacRae\u00a0<\/span>4\u00a0<\/span>15\u00a0<\/span>16<\/sup>,\u00a0<\/span><\/span>K Nicole Weaver\u00a0<\/span>7\u00a0<\/span>10<\/sup>,\u00a0<\/span><\/span>Carlos E Prada\u00a0<\/span>7\u00a0<\/span>10<\/sup>,\u00a0<\/span><\/span>Joshua S Waxman\u00a0<\/span>3\u00a0<\/span>10\u00a0<\/span>17<\/sup><\/span><\/p>\n<\/div><\/div><\/div><\/div><\/div>

Abstract<\/h2><\/div><\/div><\/div>
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Requirements for vesicle fusion within the heart remain poorly understood, despite the multitude of processes that necessitate proper intracellular trafficking within cardiomyocytes. Here, we show that Syntaxin 4 (STX4), a target-Soluble\u00a0N<\/i>-ethylmaleimide sensitive factor attachment receptor (t-SNARE) protein, is required for normal vertebrate cardiac conduction and vesicular transport. Two patients were identified with damaging variants in\u00a0STX4<\/i>. A patient with a homozygous R240W missense variant displayed biventricular dilated cardiomyopathy, ectopy, and runs of non-sustained ventricular tachycardia, sensorineural hearing loss, global developmental delay, and hypotonia, while a second patient displayed severe pleiotropic abnormalities and perinatal lethality. CRISPR\/Cas9-generated\u00a0stx4<\/i>\u00a0mutant zebrafish exhibited defects reminiscent of these patients’ clinical presentations, including linearized hearts, bradycardia, otic vesicle dysgenesis, neuronal atrophy, and touch insensitivity by 3 days post fertilization. Imaging of Vamp2+ vesicles within\u00a0stx4<\/i>\u00a0mutant zebrafish hearts showed reduced docking to the cardiomyocyte sarcolemma. Optical mapping of the embryonic hearts coupled with pharmacological modulation of Ca2+<\/sup>\u00a0handling together support that zebrafish\u00a0stx4<\/i>\u00a0mutants have a reduction in L-type Ca2+<\/sup>\u00a0channel modulation. Transgenic overexpression of zebrafish Stx4R241W<\/sup>, analogous to the first patient’s STX4R240W<\/sup>\u00a0variant, indicated that the variant is hypomorphic. Thus, these data show an\u00a0in vivo<\/i>\u00a0requirement for SNAREs in regulating normal embryonic cardiac function and that variants in\u00a0STX4<\/i>\u00a0are associated with pleiotropic human disease, including cardiomyopathy.<\/p>\n<\/div>\n

Keywords:\u00a0<\/strong>SNARE; Syntaxin 4; calcium handling; conduction defects; congenital heart disease; dilated cardiomyopathy; vesicular transport; zebrafish.<\/p>\n<\/div><\/div><\/div><\/div><\/div>