scholarly journals Rare loss-of-function mutations of PTGIR identified in fibromuscular dysplasia and spontaneous coronary artery dissection

2020 ◽  
Vol 12 (2-4) ◽  
pp. 216
Author(s):  
A. Georges ◽  
J. Albuisson ◽  
T. Berrandou ◽  
D. Dupré ◽  
A. Lorthioir ◽  
...  
2019 ◽  
Author(s):  
Adrien Georges ◽  
Juliette Albuisson ◽  
Takiy Berrandou ◽  
Délia Dupré ◽  
Aurélien Lorthioir ◽  
...  

AbstractBackgroundFibromuscular 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.ObjectivesWe aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD.MethodsWe analyzed 29 exomes that included familial and sporadic FMD. Follow-up was conducted by targeted or Sanger sequencing (1,071 FMD and 365 SCAD patients) or lookups in exome (264 FMD) or genome sequences (488 SCAD), all independent and unrelated. We used TRAPD burden test to test for enrichment in patients compared to gnomAD controls. The biological effects of variants on receptor signaling and protein expression were characterized using transient overexpression in human cells.ResultsWe identified one rare loss-of-function variant (LoF) (MAFgnomAD=0.000075) shared by two FMD sisters in the prostaglandin I2 receptor (hIP) gene (PTGIR), a key player in vascular remodeling. Follow-up in >1,300 FMD patients revealed four additional LoF allele carriers and a putative enrichment in FMD (PTRAPD=8×10−4), in addition to several rare missense variants. We confirmed the LoFs (Q163X and P17RfsX6) and one missense (L67P) to severely impair hIP function in vitro. Genetic analyses of PTGIR in SCAD revealed one patient who carries Q163X, one with L67P and one carrying a rare splicing mutation (c.768+1C>G), but not a significant enrichment (PTRAPD=0.12) in SCAD.ConclusionsOur study shows that rare genetic mutations in PTGIR are enriched among FMD patients and found in SCAD patients, suggesting a role for prostacyclin signaling in non-atherosclerotic stenosis and dissection.Condensed abstractFibromuscular Dysplasia (FMD) and Spontaneous Coronary Artery Dissection (SCAD) are non-atherosclerotic arterial diseases predominantly affecting women. Their mechanisms and genetic causes are poorly understood. We identified rare loss-of-function mutations of the prostacyclin receptor gene (PTGIR) in several FMD and SCAD patients, including two affected sisters, and several unrelated patients. We also showed that a rare missense mutation of PTGIR severely impairs prostacyclin receptor function in vitro. Our data provide evidence for a role for prostacyclin signaling in the etiology of FMD and SCAD providing leads towards this mechanism.


2021 ◽  
Vol 39 (Supplement 1) ◽  
pp. e262-e263
Author(s):  
Adrien Georges ◽  
Juliette Albuisson ◽  
Takiy Berrandou ◽  
Délia Dupré ◽  
Aurélien Lorthioir ◽  
...  

Circulation ◽  
2015 ◽  
Vol 132 (suppl_3) ◽  
Author(s):  
Daniel M Shivapour ◽  
Phillip Erwin ◽  
Heather L Gornik ◽  
Esther S Kim

Introduction: Non-atherosclerotic spontaneous coronary artery dissection (SCAD) primarily affects women and may be associated with arteriopathies such as fibromuscular dysplasia (FMD). We aimed to describe patient characteristics, management, and outcome of SCAD at a large referral center. Methods: We queried our institutional cardiac cath database for SCAD diagnoses from 2000-2014. The electronic medical record was also queried for consecutive SCAD patients seen in a specialty arteriopathy clinic from 2010-2015. Details regarding presentation, treatment, and outcome of SCAD were collected. Trends in management over two time periods (2000-2009, 2010-2015) were compared. Results: There were 96 SCAD events in 75 patients (16 patients had one recurrence, one had three events, and one had four distinct events). Mean age at presentation was 47 years, 83% were female, and 84% presented with ACS. The LAD was the most commonly affected vessel (54%). Most SCAD events were treated medically (52%). Of 41 events treated with PCI, 19 were complicated by hematoma extension. Four PCI patients required subsequent CABG. Imaging of other arterial beds increased over time, with 2/3 patients receiving vascular ultrasound to evaluate for renal or carotid FMD in the more recent time period (Table). Of those evaluated for FMD, 45% had imaging findings compatible with multifocal FMD. Significant carotid tortuosity was present in 38%, with four demonstrating a classic “S surve” appearance recently shown to be a variant presentation of FMD. All patients survived to index hospitalization discharge, however, 24% of patients had at least one recurrence. Conclusions: SCAD affects predominantly young females and often manifests as ACS. Findings of FMD or carotid tortuosity are frequent and recognition of SCAD as a potential manifestation of FMD is increasing in our institution. In support of other reports, recurrence of SCAD is not rare and PCI attempts are complicated nearly half of the time.


2013 ◽  
Vol 6 (6) ◽  
pp. 638 ◽  
Author(s):  
Fernando Alfonso ◽  
Manuel Paulo ◽  
Vera Lennie ◽  
Bárbara Das-Neves ◽  
Mauro Echavarría-Pinto

2013 ◽  
Vol 61 (10) ◽  
pp. E76 ◽  
Author(s):  
Jacqueline W.L. Saw ◽  
Andrew Starovoytov ◽  
Tara Sedlak ◽  
Donald Ricci ◽  
Christopher E. Buller

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