Stx4 is required to regulate cardiomyocyte Ca2+ handling during vertebrate cardiac development
Standard
Stx4 is required to regulate cardiomyocyte Ca2+ handling during vertebrate cardiac development. / Perl, Eliyahu; Ravisankar, Padmapriyadarshini; Beerens, Manu E; Mulahasanovic, Lejla; Smallwood, Kelly; Sasso, Marion Bermúdez; Wenzel, Carina; Ryan, Thomas D; Komár, Matej; Bove, Kevin E; MacRae, Calum A; Weaver, K Nicole; Prada, Carlos E; Waxman, Joshua S.
in: HUM GENET GENOM ADV, Jahrgang 3, Nr. 3, 100115, 14.07.2022.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
Harvard
APA
Vancouver
Bibtex
}
RIS
TY - JOUR
T1 - Stx4 is required to regulate cardiomyocyte Ca2+ handling during vertebrate cardiac development
AU - Perl, Eliyahu
AU - Ravisankar, Padmapriyadarshini
AU - Beerens, Manu E
AU - Mulahasanovic, Lejla
AU - Smallwood, Kelly
AU - Sasso, Marion Bermúdez
AU - Wenzel, Carina
AU - Ryan, Thomas D
AU - Komár, Matej
AU - Bove, Kevin E
AU - MacRae, Calum A
AU - Weaver, K Nicole
AU - Prada, Carlos E
AU - Waxman, Joshua S
N1 - © 2022 The Author(s).
PY - 2022/7/14
Y1 - 2022/7/14
N2 - 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 N-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 STX4. 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 stx4 mutant 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 stx4 mutant zebrafish hearts showed reduced docking to the cardiomyocyte sarcolemma. Optical mapping of the embryonic hearts coupled with pharmacological modulation of Ca2+ handling together support that zebrafish stx4 mutants have a reduction in L-type Ca2+ channel modulation. Transgenic overexpression of zebrafish Stx4R241W, analogous to the first patient's STX4R240W variant, indicated that the variant is hypomorphic. Thus, these data show an in vivo requirement for SNAREs in regulating normal embryonic cardiac function and that variants in STX4 are associated with pleiotropic human disease, including cardiomyopathy.
AB - 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 N-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 STX4. 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 stx4 mutant 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 stx4 mutant zebrafish hearts showed reduced docking to the cardiomyocyte sarcolemma. Optical mapping of the embryonic hearts coupled with pharmacological modulation of Ca2+ handling together support that zebrafish stx4 mutants have a reduction in L-type Ca2+ channel modulation. Transgenic overexpression of zebrafish Stx4R241W, analogous to the first patient's STX4R240W variant, indicated that the variant is hypomorphic. Thus, these data show an in vivo requirement for SNAREs in regulating normal embryonic cardiac function and that variants in STX4 are associated with pleiotropic human disease, including cardiomyopathy.
U2 - 10.1016/j.xhgg.2022.100115
DO - 10.1016/j.xhgg.2022.100115
M3 - SCORING: Journal article
C2 - 35599850
VL - 3
JO - HUM GENET GENOM ADV
JF - HUM GENET GENOM ADV
SN - 2666-2477
IS - 3
M1 - 100115
ER -