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Original Research: Pulmonary Vascular Disease |

Characteristics of Pulmonary Arterial Hypertension in Affected Carriers of a Mutation Located in the Cytoplasmic Tail of Bone Morphogenetic Protein Receptor Type 2Mutation Affecting the Cytoplasmic Tail of BMPRII

Barbara Girerd, PhD; Florence Coulet, PharmD, PhD; Xavier Jaïs, MD; Mélanie Eyries, PhD; Cathelijne Van Der Bruggen, BSc; Frances De Man, PhD; Arjan Houweling, MD, PhD; Peter Dorfmüller, MD, PhD; Laurent Savale, MD, PhD; Olivier Sitbon, MD, PhD; Anton Vonk-Noordegraaf, MD, PhD; Florent Soubrier, MD, PhD; Gérald Simonneau, MD; Marc Humbert, MD, PhD; David Montani, MD, PhD
Author and Funding Information

From the University Paris-Sud (Drs Girerd, Jaïs, Dorfmüller, Savale, Sitbon, Simonneau, Humbert, and Montani), Le Kremlin-Bicêtre, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie (Drs Girerd, Jaïs, Dorfmüller, Savale, Sitbon, Simonneau, Humbert, and Montani), Centre de Référence de l’Hypertension Pulmonaire Sévère, DHU Thorax Innovation, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; Institut National de la Santé et de la Recherche Médicale (INSERM) U999 (Drs Girerd, Jaïs, Dorfmüller, Savale, Sitbon, Simonneau, Humbert, and Montani), LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France; the Genetics Department (Drs Coulet, Eyries, and Soubrier), Hôpital Pitié-Salpêtrière, AP-HP, Paris, France; the ICAN Institute for Cardiometabolism and Nutrition (Drs Eyries and Soubrier), Paris, France; the Unité Mixte de Recherche en Santé (UMR_S 1166) (Drs Eyries and Soubrier), UPMC - Université Paris-Sorbonne, and INSERM, Paris, France; and the Departments of Pulmonary Medicine (Ms Van Der Bruggen and Drs De Man and Vonk-Noordegraaf), Institute for Cardiovascular Research, and the Department of Clinical Genetics (Dr Houweling), VU University Medical Center, Amsterdam, The Netherlands.

CORRESPONDENCE TO: David Montani, MD, PhD, Université Paris-Sud, Service de Pneumologie, Centre de Référence de l’Hypertension Pulmonaire Sévère, Hôpital de Bicêtre, 78 rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France; e-mail: david.montani@bct.aphp.fr


FUNDING/SUPPORT: Dr Montani received a young investigator award for this work from the 5th World Symposium on Pulmonary Hypertension, February 27-March 1, 2013, Nice, France.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;147(5):1385-1394. doi:10.1378/chest.14-0880
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BACKGROUND:  Mutations in BMPR2 encoding bone morphogenetic protein receptor type 2 (BMPRII) is the main genetic risk factor for heritable pulmonary arterial hypertension (PAH). The suspected mechanism is considered to be a defect of BMP signaling. The BMPRII receptor exists in a short isoform without a cytoplasmic tail, which has preserved BMP signaling.

METHODS:  This cohort study compared age at PAH diagnosis and severity between patients carrying a BMPR2 mutation affecting the cytoplasmic tail of BMPRII and affected carriers of a mutation upstream of this domain.

RESULTS:  We identified 171 carriers affected with PAH with a mutated BMPR2. Twenty-three were carriers of a point mutation located on the cytoplasmic tail of BMPRII. This population was characterized by having an older age at diagnosis compared with other BMPR2 mutation carriers (43.2 ± 12.1 years and 35.7 ± 14.6 years, P = .040), a lower pulmonary vascular resistance (13.3 ± 3.5 and 17.4 ± 6.7, P = .023), and a higher proportion of acute vasodilator responders with a long-term response to calcium channel blockers (8.7% and 0%, P = .02). No statistically significant differences were observed in survival. An in vitro assay showed that mutations located in the cytoplasmic tail led to normal activation of the Smad pathway, whereas activation was abolished in the presence of mutations located in the kinase domain.

CONCLUSIONS:  Patients carrying a mutation affecting the cytoplasmic tail of BMPRII were characterized by an older age at diagnosis compared with other BMPR2 mutation carriers, less severe hemodynamic characteristics, and a greater chance of being a long-term responder to calcium channel blockers. Further investigations are needed to better understand the consequences of these BMPR2 mutations in BMPRII signaling pathways and their possible role in pulmonary arterial remodeling.

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