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Biallelic variants in the calpain regulatory subunit CAPNS1 cause pulmonary arterial hypertension

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Biallelic variants in the calpain regulatory subunit CAPNS1 cause pulmonary arterial hypertension. / Postma, Alex V; Rapp, Christina K; Knoflach, Katrin; Volk, Alexander E; Lemke, Johannes R; Ackermann, Maximilian; Regamey, Nicolas; Latzin, Philipp; Celant, Lucas; Jansen, Samara M A; Bogaard, Harm J; Ilgun, Aho; Alders, Mariëlle; van Spaendonck-Zwarts, Karin Y; Jonigk, Danny; Klein, Christoph; Gräf, Stefan; Kubisch, Christian; Houweling, Arjan C; Griese, Matthias.

in: Genetics in medicine open, Jahrgang 1, Nr. 1, 2023, S. 100811.

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

Harvard

Postma, AV, Rapp, CK, Knoflach, K, Volk, AE, Lemke, JR, Ackermann, M, Regamey, N, Latzin, P, Celant, L, Jansen, SMA, Bogaard, HJ, Ilgun, A, Alders, M, van Spaendonck-Zwarts, KY, Jonigk, D, Klein, C, Gräf, S, Kubisch, C, Houweling, AC & Griese, M 2023, 'Biallelic variants in the calpain regulatory subunit CAPNS1 cause pulmonary arterial hypertension', Genetics in medicine open, Jg. 1, Nr. 1, S. 100811. https://doi.org/10.1016/j.gimo.2023.100811

APA

Postma, A. V., Rapp, C. K., Knoflach, K., Volk, A. E., Lemke, J. R., Ackermann, M., Regamey, N., Latzin, P., Celant, L., Jansen, S. M. A., Bogaard, H. J., Ilgun, A., Alders, M., van Spaendonck-Zwarts, K. Y., Jonigk, D., Klein, C., Gräf, S., Kubisch, C., Houweling, A. C., & Griese, M. (2023). Biallelic variants in the calpain regulatory subunit CAPNS1 cause pulmonary arterial hypertension. Genetics in medicine open, 1(1), 100811. https://doi.org/10.1016/j.gimo.2023.100811

Vancouver

Postma AV, Rapp CK, Knoflach K, Volk AE, Lemke JR, Ackermann M et al. Biallelic variants in the calpain regulatory subunit CAPNS1 cause pulmonary arterial hypertension. Genetics in medicine open. 2023;1(1):100811. https://doi.org/10.1016/j.gimo.2023.100811

Bibtex

@article{c9bbce9748794669abd451c603dee0f8,
title = "Biallelic variants in the calpain regulatory subunit CAPNS1 cause pulmonary arterial hypertension",
abstract = "PURPOSE: The aim of this study was to identify the monogenic cause of pulmonary arterial hypertension (PAH), a multifactorial and often fatal disease, in 2 unrelated consanguine families.METHODS: We performed exome sequencing and validated variant pathogenicity by whole-blood RNA and protein expression analysis in both families. Further RNA sequencing of preserved lung tissue was performed to investigate the consequences on selected genes that are involved in angiogenesis, proliferation, and apoptosis.RESULTS: We identified 2 rare biallelic variants in CAPNS1, encoding the regulatory subunit of calpain. The variants cosegregated with PAH in the families. Both variants lead to loss of function (LoF), which is demonstrated by aberrant splicing resulting in the complete absence of the CAPNS1 protein in affected patients. No other LoF CAPNS1 variant was identified in the genome data of more than 1000 patients with unresolved PAH.CONCLUSION: The calpain holoenzyme was previously linked to pulmonary vascular development and progression of PAH in patients. We demonstrated that biallelic LoF variants in CAPNS1 can cause idiopathic PAH by the complete absence of CAPNS1 protein. Screening of this gene in patients who are affected by PAH, especially with suspected autosomal recessive inheritance, should be considered.",
author = "Postma, {Alex V} and Rapp, {Christina K} and Katrin Knoflach and Volk, {Alexander E} and Lemke, {Johannes R} and Maximilian Ackermann and Nicolas Regamey and Philipp Latzin and Lucas Celant and Jansen, {Samara M A} and Bogaard, {Harm J} and Aho Ilgun and Mari{\"e}lle Alders and {van Spaendonck-Zwarts}, {Karin Y} and Danny Jonigk and Christoph Klein and Stefan Gr{\"a}f and Christian Kubisch and Houweling, {Arjan C} and Matthias Griese",
note = "{\textcopyright} 2023 The Authors.",
year = "2023",
doi = "10.1016/j.gimo.2023.100811",
language = "English",
volume = "1",
pages = "100811",
journal = "Genetics in medicine open",
issn = "2949-7744",
number = "1",

}

RIS

TY - JOUR

T1 - Biallelic variants in the calpain regulatory subunit CAPNS1 cause pulmonary arterial hypertension

AU - Postma, Alex V

AU - Rapp, Christina K

AU - Knoflach, Katrin

AU - Volk, Alexander E

AU - Lemke, Johannes R

AU - Ackermann, Maximilian

AU - Regamey, Nicolas

AU - Latzin, Philipp

AU - Celant, Lucas

AU - Jansen, Samara M A

AU - Bogaard, Harm J

AU - Ilgun, Aho

AU - Alders, Mariëlle

AU - van Spaendonck-Zwarts, Karin Y

AU - Jonigk, Danny

AU - Klein, Christoph

AU - Gräf, Stefan

AU - Kubisch, Christian

AU - Houweling, Arjan C

AU - Griese, Matthias

N1 - © 2023 The Authors.

PY - 2023

Y1 - 2023

N2 - PURPOSE: The aim of this study was to identify the monogenic cause of pulmonary arterial hypertension (PAH), a multifactorial and often fatal disease, in 2 unrelated consanguine families.METHODS: We performed exome sequencing and validated variant pathogenicity by whole-blood RNA and protein expression analysis in both families. Further RNA sequencing of preserved lung tissue was performed to investigate the consequences on selected genes that are involved in angiogenesis, proliferation, and apoptosis.RESULTS: We identified 2 rare biallelic variants in CAPNS1, encoding the regulatory subunit of calpain. The variants cosegregated with PAH in the families. Both variants lead to loss of function (LoF), which is demonstrated by aberrant splicing resulting in the complete absence of the CAPNS1 protein in affected patients. No other LoF CAPNS1 variant was identified in the genome data of more than 1000 patients with unresolved PAH.CONCLUSION: The calpain holoenzyme was previously linked to pulmonary vascular development and progression of PAH in patients. We demonstrated that biallelic LoF variants in CAPNS1 can cause idiopathic PAH by the complete absence of CAPNS1 protein. Screening of this gene in patients who are affected by PAH, especially with suspected autosomal recessive inheritance, should be considered.

AB - PURPOSE: The aim of this study was to identify the monogenic cause of pulmonary arterial hypertension (PAH), a multifactorial and often fatal disease, in 2 unrelated consanguine families.METHODS: We performed exome sequencing and validated variant pathogenicity by whole-blood RNA and protein expression analysis in both families. Further RNA sequencing of preserved lung tissue was performed to investigate the consequences on selected genes that are involved in angiogenesis, proliferation, and apoptosis.RESULTS: We identified 2 rare biallelic variants in CAPNS1, encoding the regulatory subunit of calpain. The variants cosegregated with PAH in the families. Both variants lead to loss of function (LoF), which is demonstrated by aberrant splicing resulting in the complete absence of the CAPNS1 protein in affected patients. No other LoF CAPNS1 variant was identified in the genome data of more than 1000 patients with unresolved PAH.CONCLUSION: The calpain holoenzyme was previously linked to pulmonary vascular development and progression of PAH in patients. We demonstrated that biallelic LoF variants in CAPNS1 can cause idiopathic PAH by the complete absence of CAPNS1 protein. Screening of this gene in patients who are affected by PAH, especially with suspected autosomal recessive inheritance, should be considered.

U2 - 10.1016/j.gimo.2023.100811

DO - 10.1016/j.gimo.2023.100811

M3 - SCORING: Journal article

C2 - 38230350

VL - 1

SP - 100811

JO - Genetics in medicine open

JF - Genetics in medicine open

SN - 2949-7744

IS - 1

ER -