Rare loss-of-function mutations of PTGIR are enriched in fibromuscular dysplasia

Georges, Adrien and Albuisson, Juliette and Berrandou, Takiy and Dupré, Délia and Lorthioir, Aurélien and D’Escamard, Valentina and Di Narzo, Antonio F and Kadian-Dodov, Daniella and Olin, Jeffrey W and Warchol-Celinska, Ewa and Prejbisz, Aleksander and Januszewicz, Andrzej and Bruneval, Patrick and Baranowska, Anna A and Webb, Tom R and Hamby, Stephen E and Samani, Nilesh J and Adlam, David and Fendrikova-Mahlay, Natalia and Hazen, Stanley and Wang, Yu and Yang, Min-Lee and Hunker, Kristina and Combaret, Nicolas and Motreff, Pascal and Chédid, Antoine and Fiquet, Béatrice and Plouin, Pierre-François and Mousseaux, Elie and Azarine, Arshid and Amar, Laurence and Azizi, Michel and Gornik, Heather L and Ganesh, Santhi K and Kovacic, Jason C and Jeunemaitre, Xavier and Bouatia-Naji, Nabila (2020) Rare loss-of-function mutations of PTGIR are enriched in fibromuscular dysplasia. Cardiovascular Research, 117 (4). pp.1154-1165. ISSN 0008-6363

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Link to published document: http://doi.org/10.1093/cvr/cvaa161

Abstract

AIMS: Fibromuscular dysplasia (FMD) and spontaneous coronary artery dissection (SCAD) are related, non-atherosclerotic arterial diseases mainly affecting middle-aged women. Little is known about their physiopathological mechanisms. We aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD. METHODS AND RESULTS: We analysed 29 exomes that included familial and sporadic FMD. We identified one rare loss-of-function variant (LoF) (frequencygnomAD = 0.000075) shared by two FMD sisters in the prostaglandin I2 receptor gene (PTGIR), a key player in vascular remodelling. Follow-up was conducted by targeted or Sanger sequencing (1071 FMD and 363 SCAD patients) or lookups in exome (264 FMD) or genome sequences (480 SCAD), all independent and unrelated. It revealed four additional LoF allele carriers, in addition to several rare missense variants, among FMD patients, and two LoF allele carriers among SCAD patients, including one carrying a rare splicing mutation (c.768 + 1C>G). We used burden test to test for enrichment in patients compared to gnomAD controls, which detected a putative enrichment in FMD (PTRAPD = 8 x 10-4), but not a significant enrichment (PTRAPD = 0.12) in SCAD. The biological effects of variants on human prostaclycin receptor (hIP) signalling and protein expression were characterized using transient overexpression in human cells. We confirmed the LoFs (Q163X and P17RfsX6) and one missense (L67P), identified in one FMD and one SCAD patient, to severely impair hIP function in vitro. CONCLUSIONS: Our study shows that rare genetic mutations in PTGIR are enriched among FMD patients and found in SCAD patients, suggesting a role for prostacyclin signalling in non-atherosclerotic stenosis and dissection.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 22 Apr 2021 04:52
Last Modified: 01 Aug 2021 04:40
URI: http://eprints.victorchang.edu.au/id/eprint/1070

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