Rare Loss-of-function Mutations ofPTGIRIdentified in Fibromuscular Dysplasia and Spontaneous Coronary Artery Dissection
Authors: Georges Adrien , Albuisson Juliette , Berrandou Takiy , Dupré Délia , Lorthioir Aurélien , D’Escamard Valentina , Di Narzo Antonio F , Kadian-Dodov Daniella , Olin Jeffrey W , Warchol-Celinska Ewa , Prejbisz Aleksander , Januszewicz Andrzej , Bruneval Patrick , Baranowska Anna A. , Webb Tom R. , Hamby Stephen E. , Samani Nilesh J. , Adlam David , Fendrikova-Mahlay Natalia , Hazen Stanley , Wang Yu , Yang Min-Lee , Hunker Kristina , Combaret Nicolas , Motreff Pascal , Chédid Antoine , Fiquet Béatrice , Plouin Pierre-François , Mousseaux Elie , Azarine Arshid , Amar Laurence , Azizi Michel , Gornik Heather L. , Ganesh Santhi K. , Kovacic Jason C. , Jeunemaitre Xavier , Bouatia-Naji Nabila 
Published: November 2019

Background

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.

Objectives

We aimed to identify rare genetic causes to elucidate molecular mechanisms implicated in FMD and SCAD.

Methods

We 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.

Results

We 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 functionin vitro. Genetic analyses ofPTGIRin 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.

Conclusions

Our study shows that rare genetic mutations inPTGIRare enriched among FMD patients and found in SCAD patients, suggesting a role for prostacyclin signaling in non-atherosclerotic stenosis and dissection.

Condensed abstract

Fibromuscular 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 ofPTGIRseverely impairs prostacyclin receptor functionin vitro. Our data provide evidence for a role for prostacyclin signaling in the etiology of FMD and SCAD providing leads towards this mechanism.