scholarly journals Novel LOX Variants in Five Families with Aortic/Arterial Aneurysm and Dissection with Variable Connective Tissue Findings

2021 ◽  
Vol 22 (13) ◽  
pp. 7111
Author(s):  
Ilse Van Gucht ◽  
Alice Krebsova ◽  
Birgitte Rode Diness ◽  
Steven Laga ◽  
Dave Adlam ◽  
...  
Keyword(s):  
Connective Tissue ◽  
Catalytic Domain ◽  
Lysyl Oxidase ◽  
Artery Dissection ◽  
Arterial Aneurysm ◽  
Loss Of Function ◽  
Coronary Artery Dissection ◽  
Cardiovascular Morbidity And Mortality ◽  
Aortic Aneurysm And Dissection ◽  
Conserved Amino Acids

Thoracic aortic aneurysm and dissection (TAAD) is a major cause of cardiovascular morbidity and mortality. Loss-of-function variants in LOX, encoding the extracellular matrix crosslinking enzyme lysyl oxidase, have been reported to cause familial TAAD. Using a next-generation TAAD gene panel, we identified five additional probands carrying LOX variants, including two missense variants affecting highly conserved amino acids in the LOX catalytic domain and three truncating variants. Connective tissue manifestations are apparent in a substantial fraction of the variant carriers. Some LOX variant carriers presented with TAAD early in life, while others had normal aortic diameters at an advanced age. Finally, we identified the first patient with spontaneous coronary artery dissection carrying a LOX variant. In conclusion, our data demonstrate that loss-of-function LOX variants cause a spectrum of aortic and arterial aneurysmal disease, often combined with connective tissue findings.

scholarly journals Novel pathogenic SMAD2 variants in five families with arterial aneurysm and dissection: further delineation of the phenotype

2018 ◽  
Vol 56 (4) ◽  
pp. 220-227 ◽  
Author(s):  
Elyssa Cannaerts ◽  
Marlies Kempers ◽  
Alessandra Maugeri ◽  
Carlo Marcelis ◽  
Thatjana Gardeitchik ◽  
...  
Keyword(s):  
Connective Tissue ◽  
Aortic Root ◽  
Transforming Growth Factor ◽  
Premature Stop Codon ◽  
Missense Variant ◽  
Artery Dissection ◽  
Aortic Dilatation ◽  
Arterial Aneurysm ◽  
Missense Variants ◽  
Aortic Root Dilatation

BackgroundMissense variants in SMAD2, encoding a key transcriptional regulator of transforming growth factor beta signalling, were recently reported to cause arterial aneurysmal disease.ObjectivesThe aims of the study were to identify the genetic disease cause in families with aortic/arterial aneurysmal disease and to further define SMAD2 genotype–phenotype correlations.Methods and resultsUsing gene panel sequencing, we identified a SMAD2 nonsense variant and four SMAD2 missense variants, all affecting highly conserved amino acids in the MH2 domain. The premature stop codon (c.612dup; p.(Asn205*)) was identified in a marfanoid patient with aortic root dilatation and in his affected father. A p.(Asn318Lys) missense variant was found in a Marfan syndrome (MFS)-like case who presented with aortic root aneurysm and in her affected daughter with marfanoid features and mild aortic dilatation. In a man clinically diagnosed with Loeys-Dietz syndrome (LDS) that presents with aortic root dilatation and marked tortuosity of the neck vessels, another missense variant, p.(Ser397Tyr), was identified. This variant was also found in his affected daughter with hypertelorism and arterial tortuosity, as well as his affected mother. The third missense variant, p.(Asn361Thr), was discovered in a man presenting with coronary artery dissection. Variant genotyping in three unaffected family members confirmed its absence. The last missense variant, p.(Ser467Leu), was identified in a man with significant cardiovascular and connective tissue involvement.ConclusionTaken together, our data suggest that heterozygous loss-of-function SMAD2 variants can cause a wide spectrum of autosomal dominant aortic and arterial aneurysmal disease, combined with connective tissue findings reminiscent of MFS and LDS.

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

2020 ◽  
Author(s):  
Adrien Georges ◽  
Juliette Albuisson ◽  
Takiy Berrandou ◽  
Délia Dupré ◽  
Aurélien Lorthioir ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Fibromuscular Dysplasia ◽  
Biological Effects ◽  
Receptor Gene ◽  
Artery Dissection ◽  
Loss Of Function ◽  
Coronary Artery Dissection ◽  
Atherosclerotic Stenosis ◽  
Significant Enrichment

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 × 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.

scholarly journals Rare Loss-of-function Mutations of PTGIR Identified in Fibromuscular Dysplasia and Spontaneous Coronary Artery Dissection

2019 ◽  
Author(s):  
Adrien Georges ◽  
Juliette Albuisson ◽  
Takiy Berrandou ◽  
Délia Dupré ◽  
Aurélien Lorthioir ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Fibromuscular Dysplasia ◽  
Artery Dissection ◽  
Spontaneous Coronary Artery Dissection ◽  
Loss Of Function ◽  
Coronary Artery Dissection ◽  
Genetic Causes ◽  
Prostacyclin Receptor

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.

scholarly journals RARE LOSS-OF-FUNCTION MUTATIONS OF PTGIR IDENTIFIED IN FIBROMUSCULAR DYSPLASIA AND SPONTANEOUS CORONARY ARTERY DISSECTION

2021 ◽  
Vol 39 (Supplement 1) ◽  
pp. e262-e263
Author(s):  
Adrien Georges ◽  
Juliette Albuisson ◽  
Takiy Berrandou ◽  
Délia Dupré ◽  
Aurélien Lorthioir ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Fibromuscular Dysplasia ◽  
Artery Dissection ◽  
Spontaneous Coronary Artery Dissection ◽  
Loss Of Function ◽  
Coronary Artery Dissection

scholarly journals No direct involvement of Phactr-1 in non-atherosclerotic arteriopathies: results from 3 different Phactr-1 transgenic knockout mice

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
S Rubin ◽  
P Bougaran ◽  
S Martin ◽  
A Abelanet ◽  
V Delobel ◽  
...  
Keyword(s):  
Vascular Function ◽  
Association Studies ◽  
Vascular Diseases ◽  
Limb Ischemia ◽  
Artery Dissection ◽  
Genome Wide Association Studies ◽  
Loss Of Function ◽  
Coronary Artery Dissection ◽  
Tissue Specific ◽  
Vessel Morphology

Abstract Introduction Genome-wide association studies have revealed robust associations of common genetic polymorphisms in the Phactr1 locus (6p24) (encoding Phosphatase and Actin Regulator 1) with cervico-cerebral artery dissection (CCeAD), spontaneous coronary artery dissection (SCAD) and fibromuscular dysplasia (FMD). These common elements of genetic predisposition provide a proof of concept for important shared mechanisms at the molecular level between CCeAD, SCAD and FMD vascular diseases. Objective Deciphering genetic, molecular and physiological importance of PHACTR1. Method Using various tissue-specific Cre-driver mouse lines, Phactr1 was deleted either in endothelial cells (EC) using 2 tissue-specific Cre-driver (one of them was embryonic) and Smooth Muscle Cells (SMC) with a third tissue-specific Cre-driver to assess its role in the pathogenesis of CCeAD, SCAD or FMD. Results To test the efficacy of the Phactr1 deletion after cre-induction, we confirmed firstly, a decrease in Phactr1 transcription and Phactr1 expression in EC and SMC isolated from Phactr1iPDGFB and Phactr1iSMA mice. Irrespective to the tissue or the duration of the deletion, mice did not spontaneously display pathological phenotype or vascular impairment: mouse survival, growth, blood pressure, large vessel morphology or actin organization were not different in KO mice than their comparatives littermates. Challenging vascular function and repair either by angiotensin-II-induced hypertension or limb ischemia did not lead to vascular morphology or function impairment in Phactr1-deleted mice. Similarly, there was no more consequences of Phactr1 deletion during embryogenesis in ECs. Conclusion Loss of function of PHACTR-1 in the cell types mostly involved in vascular physiology does not appear to induce a pathological vascular phenotype. FUNDunding Acknowledgement Type of funding sources: None.

Spontaneous coronary artery dissection and its association with heritable connective tissue disorders

Heart ◽  
2016 ◽  
Vol 102 (11) ◽  
pp. 876-881 ◽  
Author(s):  
Stanislav Henkin ◽  
Sara M Negrotto ◽  
Marysia S Tweet ◽  
Salman Kirmani ◽  
David R Deyle ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Connective Tissue ◽  
Artery Dissection ◽  
Spontaneous Coronary Artery Dissection ◽  
Connective Tissue Disorders ◽  
Coronary Artery Dissection ◽  
Heritable Connective Tissue Disorders

scholarly journals Spontaneous coronary artery dissection: novel pathophysiological insights from histological and ultrastructural tissue analysis

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Margaritis ◽  
F Saini ◽  
A Baranowska ◽  
S Parsons ◽  
A Vink ◽  
...  
Keyword(s):  
Coronary Artery ◽  
Connective Tissue ◽  
Inflammatory Cell ◽  
Vasa Vasorum ◽  
Artery Dissection ◽  
Inflammatory Cell Infiltrate ◽  
Funding Source ◽  
Spontaneous Coronary Artery Dissection ◽  
Cell Infiltrate ◽  
Coronary Artery Dissection

Abstract Introduction Spontaneous coronary artery dissection (SCAD) is a cause of acute coronary syndromes and rarely sudden cardiac death (SCD). SCAD is characterised by medial false lumen haematoma formation and periadventitial inflammatory cell infiltrate. Although SCAD has been linked to connective tissue disorders, its pathophysiology remains poorly understood and the role of inflammation unknown. Purpose We sought to establish the definitive histopathological features of SCAD and explore pathophysiological mechanisms through assessment of dermal connective tissue ultrastructure. Methods N=36 SCD cases diagnosed as SCAD on autopsy were identified in pathology archives at four international centres. Their demographic and clinical characteristics were compared with n=359 survivors recruited in a SCAD survivors cohort. Haematoxylin & eosin sections were examined under light microscope. Immunohistochemistry (IHC) was employed for quantification of inflammatory cell infiltrate (CD68, CD3) and vasa vasorum density (CD31) of SCAD cases (n=20) compared to age- and sex-matched controls (n=10). Dermal extracellular matrix components (EMC) of n=32 SCAD survivors and n=16 healthy volunteers (HV) were compared using electron microscopy (EM). Results The autopsy series cases were more likely to be male (p=0.0256) and had higher incidence of left main stem (p=0.0475) and proximal left anterior descending (p<0.001) disease compared to SCAD survivors. N=24 (66%) of SCAD autopsy case showed no evidence of myocardial necrosis. N=17 (47%) showed mild-moderate atherosclerotic changes but no features of fibromuscular dysplasia. There were no differences in vasa vasorum density between SCAD and control cases (A). The degree of inflammatory cell infiltrate varied greatly but significantly higher than controls (B), comprising CD68+ macrophages, eosinophils and CD3+ positive T-cells. There was a statistically significant association (p=0.006) between the degree of inflammatory cell infiltrate and the length of time from onset of symptoms to death (Panel C), as well as significantly (p<0.001) denser inflammatory cell infiltrate adjacent to the dissection plane (D, exemplary sections E&F). EM revealed no differences between SCAD and HV in dermal fibroblast size & activity or elastin size & damage indicators, but possible changes in subgroups with more extreme clinical phenotype or pregnancy-related SCAD (G). Conclusions To our knowledge this is the largest SCAD pathology case series so far. We show for the first time that periadvential inflammation in SCAD appears to be time-dependent and localising to the dissected coronary segment, suggesting healing response to injury rather than causal contribution. We found no evidence to suggest increased vasa vasorum density is pathophysiologically important. Connective tissue changes were only linked to a small proportion of cases. These novel findings may have important implications for the management of SCAD patients. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): British Heart Foundation, Leicester NIHR Biomedical Research Centre

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