<i>FHIT</i>, a Novel Modifier Gene in Pulmonary Arterial Hypertension

Prosseda, Svenja Dannewitz; Tian, Xuefei; Kuramoto, K.; Böehm, Matthias; Sudheendra, Deepti; Miyagawa, Kazuya; Zhang, Fan; Solow-Cordero, David E.; Saldivar, Joshua C.; Austin, Eric D.; Loyd, James E.; Wheeler, Lisa; Andruska, Adam; Donato, Michèle; Wang, Lingli; Huebner, Kay; Metzger, Ross J.; Khatri, Purvesh; Spiekerkoetter, Edda

doi:10.1164/rccm.201712-2553oc

Cited by 39 publications

(46 citation statements)

References 85 publications

(99 reference statements)

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“…More recently, FHIT was identified as a potentially clinically relevant BMPR2 modifier gene through an siRNA screen of BMPR2 signaling regulatory genes combined with publicly available PAH RNA expression data. Subsequently, the authors showed that pharmaceutical upregulation of FHIT prevented and reversed experimental pulmonary hypertension in a rat model [ 70 ]. Rhodes and colleagues utilized metabolomics to identify circulating metabolites that distinguish PAH cases from healthy controls, to predict outcomes among PAH cases, and to monitor metabolite levels over time to determine whether correction could affect outcomes [ 71 ].…”

Section: Genetics Of Pediatric Pah—current Knowledgementioning

confidence: 99%

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Welch

Chung

2020

Genes

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Pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. The disease is caused by both genetic and environmental factors and likely gene–environment interactions. While PAH can manifest across the lifespan, pediatric-onset disease is particularly challenging because it is frequently associated with a more severe clinical course and comorbidities including lung/heart developmental anomalies. In light of these differences, it is perhaps not surprising that emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to ~42% of pediatric-onset PAH compared to ~12.5% of adult-onset PAH. De novo variants are frequently associated with PAH in children and contribute to at least 15% of all pediatric cases. The standard of medical care for pediatric PAH patients is based on extrapolations from adult data. However, increased etiologic heterogeneity, poorer prognosis, and increased genetic burden for pediatric-onset PAH calls for a dedicated pediatric research agenda to improve molecular diagnosis and clinical management. A genomics-first approach will improve the understanding of pediatric PAH and how it is related to other rare pediatric genetic disorders.

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Section: Genetics Of Pediatric Pah—current Knowledgementioning

confidence: 99%

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Welch

Chung

2020

Genes

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“…Additionally, we are just now beginning to understand the genetic underpinnings of BMPR2 transcriptional regulation. Elucidating BMPR2 potentiating modifier genes such as FHIT can reveal novel pharmacologic therapies [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

“…There is evidence for genetic regulation of BMPR2 by “BMPR2 modifier genes”. We have identified fragile histadine triad ( FHIT ) as one such gene, which, when targeted by the drug Enzastaurin, ameliorates PAH in animal models [ 48 ].…”

Section: Mechanisms For Bmpr2 Deficiencymentioning

confidence: 99%

Consequences of BMPR2 Deficiency in the Pulmonary Vasculature and Beyond: Contributions to Pulmonary Arterial Hypertension

Andruska

Spiekerkoetter

2018

IJMS

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Since its association with familial pulmonary arterial hypertension (PAH) in 2000, Bone Morphogenetic Protein Receptor II (BMPR2) and its related signaling pathway have become recognized as a key regulator of pulmonary vascular homeostasis. Herein, we define BMPR2 deficiency as either an inactivation of the receptor, decreased receptor expression, or an impairment of the receptor’s downstream signaling pathway. Although traditionally the phenotypic consequences of BMPR2 deficiency in PAH have been thought to be limited to the pulmonary vasculature, there is evidence that abnormalities in BMPR2 signaling may have consequences in many other organ systems and cellular compartments. Revisiting how BMPR2 functions throughout health and disease in cells and organs beyond the lung vasculature may provide insight into the contribution of these organ systems to PAH pathogenesis as well as the potential systemic manifestation of PAH. Here we review our knowledge of the consequences of BMPR2 deficiency across multiple organ systems.

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“…As reduced BMPR2 signalling is a known phenomenon even in patients without the mutation, targeting BMPR2 modifier genes might be an effective rescue mechanism. Enzastaurin was shown to rescue the BMPR2 modifier gene, fragile histidine triad ( FHIT ) and reverse animal PH 183 . Ligand traps inhibiting negative BMPR2 regulation are another therapeutic option.…”

Section: Clinical Utility and Therapeutic Implications Of Genetic Tesmentioning

confidence: 99%

The role of genomics and genetics in pulmonary arterial hypertension

Swietlik¹,

Gräf²,

Morrell³

2020

gcsp

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[No abstract. Showing first paragraph of article]Although pulmonary hypertension (PH) had been recognised for centuries, it was not until the invention of cardiac catheterisation in the 1950s that enabled an accurate gene encoding bone morphogenetic protein receptor type 2, in patients with familial and clinical diagnosis. The discovery of heterozygous germline mutations in BMPR2, the idiopathic forms of pulmonary arterial hypertension (PAH) was another breakthrough in understanding the disease and initiated a new era in care of patients with this condition.

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FHIT, a Novel Modifier Gene in Pulmonary Arterial Hypertension

Abstract: This study highlights the importance of the novel BMPR2 modifier FHIT in PH and the clinical value of the repurposed drug Enzastaurin as a potential novel therapeutic strategy to improve PAH.

Cited by 39 publications

References 85 publications

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Genetics and Genomics of Pediatric Pulmonary Arterial Hypertension

Consequences of BMPR2 Deficiency in the Pulmonary Vasculature and Beyond: Contributions to Pulmonary Arterial Hypertension

The role of genomics and genetics in pulmonary arterial hypertension

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