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, Vol. 1, No. 1, 2023, p. 100811.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -