title: Characteristics of pulmonary arterial hypertension in affected carriers of a mutation located in the cytoplasmic tail of bone morphogenetic protein receptor type 2.
abstract: 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.
authors.affiliation: University Paris-Sud, Le Kremlin-Bicêtre, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie, 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, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Barbara
authors.initials: B
authors.lastname: Girerd
authors.affiliation: Genetics Department, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Coulet
authors.affiliation: University Paris-Sud, Le Kremlin-Bicêtre, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie, 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, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Xavier
authors.initials: X
authors.lastname: Jaïs
authors.affiliation: Genetics Department, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France; ICAN Institute for Cardiometabolism and Nutrition, Paris, France; Unité Mixte de Recherche en Santé (UMR_S 1166), UPMC - Université Paris-Sorbonne, and INSERM, Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Eyries
authors.affiliation: Departments of Pulmonary Medicine, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Cathelijne
authors.initials: C
authors.lastname: Van Der Bruggen
authors.affiliation: Departments of Pulmonary Medicine, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Frances
authors.initials: F
authors.lastname: De Man
authors.affiliation: Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Arjan
authors.initials: A
authors.lastname: Houweling
authors.affiliation: University Paris-Sud, Le Kremlin-Bicêtre, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie, 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, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Peter
authors.initials: P
authors.lastname: Dorfmüller
authors.affiliation: University Paris-Sud, Le Kremlin-Bicêtre, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie, 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, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Savale
authors.affiliation: University Paris-Sud, Le Kremlin-Bicêtre, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie, 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, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Sitbon
authors.affiliation: Departments of Pulmonary Medicine, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Anton
authors.initials: A
authors.lastname: Vonk-Noordegraaf
authors.affiliation: Genetics Department, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France; ICAN Institute for Cardiometabolism and Nutrition, Paris, France; Unité Mixte de Recherche en Santé (UMR_S 1166), UPMC - Université Paris-Sorbonne, and INSERM, Paris, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Soubrier
authors.affiliation: University Paris-Sud, Le Kremlin-Bicêtre, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie, 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, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Gérald
authors.initials: G
authors.lastname: Simonneau
authors.affiliation: University Paris-Sud, Le Kremlin-Bicêtre, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie, 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, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.affiliation: University Paris-Sud, Le Kremlin-Bicêtre, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Service de Pneumologie, 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, LabEx LERMIT, Centre Chirurgical Marie Lannelongue, Le Plessis Robinson, France. Electronic address: david.montani@bct.aphp.fr.
authors.forename: David
authors.initials: D
authors.lastname: Montani
mesh_terms: D000328:Adult; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D006579:Heterozygote; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics*; D008297:Male; D009154:Mutation
chemical_list: C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II