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Stx4 is required to regulate cardiomyocyte Ca2+ handling during vertebrate cardiac development

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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, Vol. 3, No. 3, 100115, 14.07.2022.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Perl, E, Ravisankar, P, Beerens, ME, Mulahasanovic, L, Smallwood, K, Sasso, MB, Wenzel, C, Ryan, TD, Komár, M, Bove, KE, MacRae, CA, Weaver, KN, Prada, CE & Waxman, JS 2022, 'Stx4 is required to regulate cardiomyocyte Ca2+ handling during vertebrate cardiac development', HUM GENET GENOM ADV, vol. 3, no. 3, 100115. https://doi.org/10.1016/j.xhgg.2022.100115

APA

Perl, E., Ravisankar, P., Beerens, M. E., Mulahasanovic, L., Smallwood, K., Sasso, M. B., Wenzel, C., Ryan, T. D., Komár, M., Bove, K. E., MacRae, C. A., Weaver, K. N., Prada, C. E., & Waxman, J. S. (2022). Stx4 is required to regulate cardiomyocyte Ca2+ handling during vertebrate cardiac development. HUM GENET GENOM ADV, 3(3), [100115]. https://doi.org/10.1016/j.xhgg.2022.100115

Vancouver

Perl E, Ravisankar P, Beerens ME, Mulahasanovic L, Smallwood K, Sasso MB et al. Stx4 is required to regulate cardiomyocyte Ca2+ handling during vertebrate cardiac development. HUM GENET GENOM ADV. 2022 Jul 14;3(3). 100115. https://doi.org/10.1016/j.xhgg.2022.100115

Bibtex

@article{c2dfb1eac7454f7d88924d486ebfa2cd,
title = "Stx4 is required to regulate cardiomyocyte Ca2+ handling during vertebrate cardiac development",
abstract = "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.",
author = "Eliyahu Perl and Padmapriyadarshini Ravisankar and Beerens, {Manu E} and Lejla Mulahasanovic and Kelly Smallwood and Sasso, {Marion Berm{\'u}dez} and Carina Wenzel and Ryan, {Thomas D} and Matej Kom{\'a}r and Bove, {Kevin E} and MacRae, {Calum A} and Weaver, {K Nicole} and Prada, {Carlos E} and Waxman, {Joshua S}",
note = "{\textcopyright} 2022 The Author(s).",
year = "2022",
month = jul,
day = "14",
doi = "10.1016/j.xhgg.2022.100115",
language = "English",
volume = "3",
journal = "HUM GENET GENOM ADV",
issn = "2666-2477",
publisher = "Cell Press",
number = "3",

}

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 -