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

Rajiv D Machado; Laura Southgate; Christina A Eichstaedt; Micheala A Aldred; Eric D Austin; D Hunter Best; Wendy K Chung; Nicola Benjamin; C Gregory Elliott; Mélanie Eyries; Christine Fischer; Stefan Gräf; Katrin Hinderhofer; Marc Humbert; Steven B Keiles; James E Loyd; Nicholas W Morrell; John H Newman; Florent Soubrier; Richard C Trembath; Rebecca Rodríguez Viales; Ekkehard Grünig

doi:10.1002/humu.22904

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

Rajiv D Machado, Laura Southgate, Christina A Eichstaedt, Micheala A Aldred, Eric D Austin, D Hunter Best, Wendy K Chung, Nicola Benjamin, C Gregory Elliott, Mélanie Eyries, Christine Fischer, Stefan Gräf, Katrin Hinderhofer, Marc Humbert, Steven B Keiles, James E Loyd, Nicholas W Morrell, John H Newman, Florent Soubrier, Richard C TrembathRebecca Rodríguez Viales, Ekkehard Grünig

Research output: Contribution to journal › Article › peer-review

195 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1113-27
Number of pages	15
Journal	Human Mutation
Volume	36
Issue number	12
DOIs	https://doi.org/10.1002/humu.22904
Publication status	Published - Dec 2015

Keywords

Animals
Bone Morphogenetic Protein Receptors, Type II
Disease Models, Animal
Genetic Association Studies
Genetic Counseling
Genetic Predisposition to Disease
Genetic Variation
High-Throughput Nucleotide Sequencing
Humans
Hypertension, Pulmonary
Multigene Family
Mutation
Signal Transduction
Transforming Growth Factor beta

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Machado, R. D., Southgate, L., Eichstaedt, C. A., Aldred, M. A., Austin, E. D., Best, D. H., Chung, W. K., Benjamin, N., Elliott, C. G., Eyries, M., Fischer, C., Gräf, S., Hinderhofer, K., Humbert, M., Keiles, S. B., Loyd, J. E., Morrell, N. W., Newman, J. H., Soubrier, F., ... Grünig, E. (2015). Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects. Human Mutation, 36(12), 1113-27. https://doi.org/10.1002/humu.22904

@article{221e802f1ba54f688e906963ccf5e917,

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.",

keywords = "Animals, Bone Morphogenetic Protein Receptors, Type II, Disease Models, Animal, Genetic Association Studies, Genetic Counseling, Genetic Predisposition to Disease, Genetic Variation, High-Throughput Nucleotide Sequencing, Humans, Hypertension, Pulmonary, Multigene Family, Mutation, Signal Transduction, Transforming Growth Factor beta",

author = "Machado, {Rajiv D} and Laura Southgate and Eichstaedt, {Christina A} and Aldred, {Micheala A} and Austin, {Eric D} and Best, {D Hunter} and Chung, {Wendy K} and Nicola Benjamin and Elliott, {C Gregory} and M{\'e}lanie Eyries and Christine Fischer and Stefan Gr{\"a}f and Katrin Hinderhofer and Marc Humbert and Keiles, {Steven B} and Loyd, {James E} and Morrell, {Nicholas W} and Newman, {John H} and Florent Soubrier and Trembath, {Richard C} and Viales, {Rebecca Rodr{\'i}guez} and Ekkehard Gr{\"u}nig",

note = "{\textcopyright} 2015 WILEY PERIODICALS, INC.",

year = "2015",

month = dec,

doi = "10.1002/humu.22904",

language = "English",

volume = "36",

pages = "1113--27",

journal = "Human Mutation",

issn = "1059-7794",

publisher = "Wiley",

number = "12",

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Machado, RD , Southgate, L, Eichstaedt, CA, Aldred, MA, Austin, ED, Best, DH, Chung, WK, Benjamin, N, Elliott, CG, Eyries, M, Fischer, C, Gräf, S, Hinderhofer, K, Humbert, M, Keiles, SB, Loyd, JE, Morrell, NW, Newman, JH, Soubrier, F, Trembath, RC, Viales, RR & Grünig, E 2015, 'Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects', Human Mutation, vol. 36, no. 12, pp. 1113-27. https://doi.org/10.1002/humu.22904

TY - JOUR

T1 - Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects

AU - Machado, Rajiv D

AU - Southgate, Laura

AU - Eichstaedt, Christina A

AU - Aldred, Micheala A

AU - Austin, Eric D

AU - Best, D Hunter

AU - Chung, Wendy K

AU - Benjamin, Nicola

AU - Elliott, C Gregory

AU - Eyries, Mélanie

AU - Fischer, Christine

AU - Gräf, Stefan

AU - Hinderhofer, Katrin

AU - Humbert, Marc

AU - Keiles, Steven B

AU - Loyd, James E

AU - Morrell, Nicholas W

AU - Newman, John H

AU - Soubrier, Florent

AU - Trembath, Richard C

AU - Viales, Rebecca Rodríguez

AU - Grünig, Ekkehard

PY - 2015/12

Y1 - 2015/12

N2 - 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.

AB - 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.

KW - Animals

KW - Bone Morphogenetic Protein Receptors, Type II

KW - Disease Models, Animal

KW - Genetic Association Studies

KW - Genetic Counseling

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - High-Throughput Nucleotide Sequencing

KW - Humans

KW - Hypertension, Pulmonary

KW - Multigene Family

KW - Mutation

KW - Signal Transduction

KW - Transforming Growth Factor beta

U2 - 10.1002/humu.22904

DO - 10.1002/humu.22904

M3 - Article

C2 - 26387786

SN - 1059-7794

VL - 36

SP - 1113

EP - 1127

JO - Human Mutation

JF - Human Mutation

IS - 12

ER -

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

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Keywords

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