title: Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects.
abstract: Pulmonary arterial hypertension (PAH) is an often fatal disorder resulting from several causes including heterogeneous genetic defects. While mutations in the bone morphogenetic protein receptor type II (BMPR2) gene are the single most common causal factor for hereditary cases, pathogenic mutations have been observed in approximately 25% of idiopathic PAH patients without a prior family history of disease. Additional defects of the transforming growth factor beta pathway have been implicated in disease pathogenesis. Specifically, studies have confirmed activin A receptor type II-like 1 (ACVRL1), endoglin (ENG), and members of the SMAD family as contributing to PAH both with and without associated clinical phenotypes. Most recently, next-generation sequencing has identified novel, rare genetic variation implicated in the PAH disease spectrum. Of importance, several identified genetic factors converge on related pathways and provide significant insight into the development, maintenance, and pathogenetic transformation of the pulmonary vascular bed. Together, these analyses represent the largest comprehensive compilation of BMPR2 and associated genetic risk factors for PAH, comprising known and novel variation. Additionally, with the inclusion of an allelic series of locus-specific variation in BMPR2, these data provide a key resource in data interpretation and development of contemporary therapeutic and diagnostic tools.
authors.affiliation: School of Life Sciences, University of Lincoln, Lincoln, United Kingdom.
authors.forename: Rajiv D
authors.initials: RD
authors.lastname: Machado
authors.affiliation: Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.|Division of Genetics & Molecular Medicine, King's College London, London, United Kingdom.
authors.forename: Laura
authors.initials: L
authors.lastname: Southgate
authors.affiliation: Centre for Pulmonary Hypertension, Thoraxclinic at the University Hospital Heidelberg, Heidelberg, Germany.|Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Christina A
authors.initials: CA
authors.lastname: Eichstaedt
authors.affiliation: Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio.
authors.forename: Micheala A
authors.initials: MA
authors.lastname: Aldred
authors.affiliation: Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.
authors.forename: Eric D
authors.initials: ED
authors.lastname: Austin
authors.affiliation: Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah.|ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, Utah.
authors.forename: D Hunter
authors.initials: DH
authors.lastname: Best
authors.affiliation: Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, New York.
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.affiliation: Centre for Pulmonary Hypertension, Thoraxclinic at the University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Nicola
authors.initials: N
authors.lastname: Benjamin
authors.affiliation: Departments of Medicine, Intermountain Medical Center and the University of Utah School of Medicine, Salt Lake City, Utah.
authors.forename: C Gregory
authors.initials: CG
authors.lastname: Elliott
authors.affiliation: Unité Mixte de Recherche en Santé (UMR_S 1166), Université Pierre and Marie Curie Université Paris 06 (UPMC) and Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.|Genetics Department, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.|Institute for Cardiometabolism and Nutrition (ICAN), Paris, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Eyries
authors.affiliation: Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Fischer
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, United Kingdom.|Department of Haematology, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Stefan
authors.initials: S
authors.lastname: Gräf
authors.affiliation: Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Hinderhofer
authors.affiliation: Université Paris-Sud, Faculté de Médecine, Paris, France.|Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO), Service de Pneumologie, Hôpital Bicêtre, AP-HP, Paris, France.|INSERM UMR_S 999, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique (LERMIT), Centre Chirurgical Marie Lannelongue, Paris, France.
authors.forename: Marc
authors.initials: M
authors.lastname: Humbert
authors.affiliation: Quest Diagnostics, Action from Insight, San Juan Capistrano, California.
authors.forename: Steven B
authors.initials: SB
authors.lastname: Keiles
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: James E
authors.initials: JE
authors.lastname: Loyd
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge, United Kingdom.|Addenbrooke's & Papworth Hospitals, Cambridge, United Kingdom.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.affiliation: Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
authors.forename: John H
authors.initials: JH
authors.lastname: Newman
authors.affiliation: Unité Mixte de Recherche en Santé (UMR_S 1166), Université Pierre and Marie Curie Université Paris 06 (UPMC) and Institut National de la Santé et de la Recherche Médicale (INSERM), Paris, France.|Genetics Department, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.|Institute for Cardiometabolism and Nutrition (ICAN), Paris, France.
authors.forename: Florent
authors.initials: F
authors.lastname: Soubrier
authors.affiliation: Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.affiliation: Centre for Pulmonary Hypertension, Thoraxclinic at the University Hospital Heidelberg, Heidelberg, Germany.|Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
authors.forename: Rebecca Rodríguez
authors.initials: RR
authors.lastname: Viales
authors.affiliation: Centre for Pulmonary Hypertension, Thoraxclinic at the University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Ekkehard
authors.initials: E
authors.lastname: Grünig
mesh_terms: D000818:Animals; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D056726:Genetic Association Studies; D005817:Genetic Counseling; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D005810:Multigene Family; D009154:Mutation; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
chemical_list: D016212:Transforming Growth Factor beta; D052006:Bone Morphogenetic Protein Receptors, Type II
keywords: ACVRL1; BMPR2; CAV1; EIF2AK4; ENG; KCNA5; KCNK3; SMAD1; SMAD4; SMAD9; haploinsufficiency; locus heterogeneity