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Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects
Ist Teil von
Human mutation, 2015-12, Vol.36 (12), p.1113-1127
Ort / Verlag
United States: Blackwell Publishing Ltd
Erscheinungsjahr
2015
Quelle
Wiley Online Library All Journals
Beschreibungen/Notizen
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.
Pulmonary arterial hypertension is an often fatal vascular disorder.
The figure illustrates the key pathways implicated in disease pathogenesis, both convergent and distinct. Key elements harbouring deleterious mutations are indicated by asterisks. This report is the first of its kind to provide a comprehensive record of all identified mutations in causal genes including novel variation.