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Hum Mutat. 2015 Dec;36(12):1113-27. doi: 10.1002/humu.22904. Epub 2015 Oct 12.

Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects.

Author information

1
School of Life Sciences, University of Lincoln, Lincoln, United Kingdom.
2
Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, United Kingdom.
3
Division of Genetics & Molecular Medicine, King's College London, London, United Kingdom.
4
Centre for Pulmonary Hypertension, Thoraxclinic at the University Hospital Heidelberg, Heidelberg, Germany.
5
Institute of Human Genetics, Heidelberg University, Heidelberg, Germany.
6
Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio.
7
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.
8
Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah.
9
ARUP Institute for Clinical and Experimental Pathology, ARUP Laboratories, Salt Lake City, Utah.
10
Departments of Pediatrics and Medicine, Columbia University Medical Center, New York, New York.
11
Departments of Medicine, Intermountain Medical Center and the University of Utah School of Medicine, Salt Lake City, Utah.
12
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.
13
Genetics Department, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.
14
Institute for Cardiometabolism and Nutrition (ICAN), Paris, France.
15
Department of Medicine, University of Cambridge, Cambridge, United Kingdom.
16
Department of Haematology, University of Cambridge, Cambridge, United Kingdom.
17
Université Paris-Sud, Faculté de Médecine, Paris, France.
18
Département Hospitalo-Universitaire (DHU) Thorax Innovation (TORINO), Service de Pneumologie, Hôpital Bicêtre, AP-HP, Paris, France.
19
INSERM UMR_S 999, Laboratoire d'Excellence en Recherche sur le Médicament et l'Innovation Thérapeutique (LERMIT), Centre Chirurgical Marie Lannelongue, Paris, France.
20
Quest Diagnostics, Action from Insight, San Juan Capistrano, California.
21
Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
22
Addenbrooke's & Papworth Hospitals, Cambridge, United Kingdom.

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.

KEYWORDS:

ACVRL1; BMPR2; CAV1; EIF2AK4; ENG; KCNA5; KCNK3; SMAD1; SMAD4; SMAD9; haploinsufficiency; locus heterogeneity

PMID:
26387786
PMCID:
PMC4822159
DOI:
10.1002/humu.22904
[Indexed for MEDLINE]
Free PMC Article

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