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Functional Characterization of Rare Variants in the SHOX2 Gene Identified in Sinus Node Dysfunction and Atrial Fibrillation

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Functional Characterization of Rare Variants in the SHOX2 Gene Identified in Sinus Node Dysfunction and Atrial Fibrillation. / Hoffmann, Sandra; Paone, Christoph; Sumer, Simon A; Diebold, Sabrina; Weiss, Birgit; Roeth, Ralph; Clauss, Sebastian; Klier, Ina; Kääb, Stefan; Schulz, Andreas; Wild, Philipp S; Ghrib, Adil; Zeller, Tanja; Schnabel, Renate B; Just, Steffen; Rappold, Gudrun A.

in: FRONT GENET, Jahrgang 10, 2019, S. 648.

Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung

Harvard

Hoffmann, S, Paone, C, Sumer, SA, Diebold, S, Weiss, B, Roeth, R, Clauss, S, Klier, I, Kääb, S, Schulz, A, Wild, PS, Ghrib, A, Zeller, T, Schnabel, RB, Just, S & Rappold, GA 2019, 'Functional Characterization of Rare Variants in the SHOX2 Gene Identified in Sinus Node Dysfunction and Atrial Fibrillation', FRONT GENET, Jg. 10, S. 648. https://doi.org/10.3389/fgene.2019.00648

APA

Hoffmann, S., Paone, C., Sumer, S. A., Diebold, S., Weiss, B., Roeth, R., Clauss, S., Klier, I., Kääb, S., Schulz, A., Wild, P. S., Ghrib, A., Zeller, T., Schnabel, R. B., Just, S., & Rappold, G. A. (2019). Functional Characterization of Rare Variants in the SHOX2 Gene Identified in Sinus Node Dysfunction and Atrial Fibrillation. FRONT GENET, 10, 648. https://doi.org/10.3389/fgene.2019.00648

Vancouver

Hoffmann S, Paone C, Sumer SA, Diebold S, Weiss B, Roeth R et al. Functional Characterization of Rare Variants in the SHOX2 Gene Identified in Sinus Node Dysfunction and Atrial Fibrillation. FRONT GENET. 2019;10:648. https://doi.org/10.3389/fgene.2019.00648

Bibtex

@article{4b31597ec18c41949008e177fcfb470e,
title = "Functional Characterization of Rare Variants in the SHOX2 Gene Identified in Sinus Node Dysfunction and Atrial Fibrillation",
abstract = "Sinus node dysfunction (SND) and atrial fibrillation (AF) often coexist; however, the molecular mechanisms linking both conditions remain elusive. Mutations in the homeobox-containing SHOX2 gene have been recently associated with early-onset and familial AF. Shox2 is a key regulator of sinus node development, and its deficiency leads to bradycardia, as demonstrated in animal models. To provide an extended SHOX2 gene analysis in patients with distinct arrhythmias, we investigated SHOX2 as a susceptibility gene for SND and AF by screening 98 SND patients and 450 individuals with AF. The functional relevance of the novel mutations was investigated in vivo and in vitro, together with the previously reported p.H283Q variant. A heterozygous missense mutation (p.P33R) was identified in the SND cohort and four heterozygous variants (p.G77D, p.L129=, p.L130F, p.A293=) in the AF cohort. Overexpression of the pathogenic predicted mutations in zebrafish revealed pericardial edema for p.G77D and the positive control p.H283Q, whereas the p.P33R and p.A293= variants showed no effect. In addition, a dominant-negative effect with reduced heart rates was detected for p.G77D and p.H283Q. In vitro reporter assays demonstrated for both missense variants p.P33R and p.G77D significantly impaired transactivation activity, similar to the described p.H283Q variant. Also, a reduced Bmp4 target gene expression was revealed in zebrafish hearts upon overexpression of the p.P33R mutant. This study associates additional rare variants in the SHOX2 gene implicated in the susceptibility to distinct arrhythmias and allows frequency estimations in the AF cohort (3/990). We also demonstrate for the first time a genetic link between SND and AF involving SHOX2. Moreover, our data highlight the importance of functional investigations of rare variants.",
author = "Sandra Hoffmann and Christoph Paone and Sumer, {Simon A} and Sabrina Diebold and Birgit Weiss and Ralph Roeth and Sebastian Clauss and Ina Klier and Stefan K{\"a}{\"a}b and Andreas Schulz and Wild, {Philipp S} and Adil Ghrib and Tanja Zeller and Schnabel, {Renate B} and Steffen Just and Rappold, {Gudrun A}",
year = "2019",
doi = "10.3389/fgene.2019.00648",
language = "English",
volume = "10",
pages = "648",
journal = "FRONT GENET",
issn = "1664-8021",
publisher = "Lausanne : Frontiers Research Foundation",

}

RIS

TY - JOUR

T1 - Functional Characterization of Rare Variants in the SHOX2 Gene Identified in Sinus Node Dysfunction and Atrial Fibrillation

AU - Hoffmann, Sandra

AU - Paone, Christoph

AU - Sumer, Simon A

AU - Diebold, Sabrina

AU - Weiss, Birgit

AU - Roeth, Ralph

AU - Clauss, Sebastian

AU - Klier, Ina

AU - Kääb, Stefan

AU - Schulz, Andreas

AU - Wild, Philipp S

AU - Ghrib, Adil

AU - Zeller, Tanja

AU - Schnabel, Renate B

AU - Just, Steffen

AU - Rappold, Gudrun A

PY - 2019

Y1 - 2019

N2 - Sinus node dysfunction (SND) and atrial fibrillation (AF) often coexist; however, the molecular mechanisms linking both conditions remain elusive. Mutations in the homeobox-containing SHOX2 gene have been recently associated with early-onset and familial AF. Shox2 is a key regulator of sinus node development, and its deficiency leads to bradycardia, as demonstrated in animal models. To provide an extended SHOX2 gene analysis in patients with distinct arrhythmias, we investigated SHOX2 as a susceptibility gene for SND and AF by screening 98 SND patients and 450 individuals with AF. The functional relevance of the novel mutations was investigated in vivo and in vitro, together with the previously reported p.H283Q variant. A heterozygous missense mutation (p.P33R) was identified in the SND cohort and four heterozygous variants (p.G77D, p.L129=, p.L130F, p.A293=) in the AF cohort. Overexpression of the pathogenic predicted mutations in zebrafish revealed pericardial edema for p.G77D and the positive control p.H283Q, whereas the p.P33R and p.A293= variants showed no effect. In addition, a dominant-negative effect with reduced heart rates was detected for p.G77D and p.H283Q. In vitro reporter assays demonstrated for both missense variants p.P33R and p.G77D significantly impaired transactivation activity, similar to the described p.H283Q variant. Also, a reduced Bmp4 target gene expression was revealed in zebrafish hearts upon overexpression of the p.P33R mutant. This study associates additional rare variants in the SHOX2 gene implicated in the susceptibility to distinct arrhythmias and allows frequency estimations in the AF cohort (3/990). We also demonstrate for the first time a genetic link between SND and AF involving SHOX2. Moreover, our data highlight the importance of functional investigations of rare variants.

AB - Sinus node dysfunction (SND) and atrial fibrillation (AF) often coexist; however, the molecular mechanisms linking both conditions remain elusive. Mutations in the homeobox-containing SHOX2 gene have been recently associated with early-onset and familial AF. Shox2 is a key regulator of sinus node development, and its deficiency leads to bradycardia, as demonstrated in animal models. To provide an extended SHOX2 gene analysis in patients with distinct arrhythmias, we investigated SHOX2 as a susceptibility gene for SND and AF by screening 98 SND patients and 450 individuals with AF. The functional relevance of the novel mutations was investigated in vivo and in vitro, together with the previously reported p.H283Q variant. A heterozygous missense mutation (p.P33R) was identified in the SND cohort and four heterozygous variants (p.G77D, p.L129=, p.L130F, p.A293=) in the AF cohort. Overexpression of the pathogenic predicted mutations in zebrafish revealed pericardial edema for p.G77D and the positive control p.H283Q, whereas the p.P33R and p.A293= variants showed no effect. In addition, a dominant-negative effect with reduced heart rates was detected for p.G77D and p.H283Q. In vitro reporter assays demonstrated for both missense variants p.P33R and p.G77D significantly impaired transactivation activity, similar to the described p.H283Q variant. Also, a reduced Bmp4 target gene expression was revealed in zebrafish hearts upon overexpression of the p.P33R mutant. This study associates additional rare variants in the SHOX2 gene implicated in the susceptibility to distinct arrhythmias and allows frequency estimations in the AF cohort (3/990). We also demonstrate for the first time a genetic link between SND and AF involving SHOX2. Moreover, our data highlight the importance of functional investigations of rare variants.

U2 - 10.3389/fgene.2019.00648

DO - 10.3389/fgene.2019.00648

M3 - SCORING: Journal article

C2 - 31354791

VL - 10

SP - 648

JO - FRONT GENET

JF - FRONT GENET

SN - 1664-8021

ER -