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Identification of rare sequence variation underlying heritable pulmonary arterial hypertension
Nature communications, 2018-04, Vol.9 (1), p.1416-16, Article 1416
2018

Details

Autor(en) / Beteiligte
Titel
Identification of rare sequence variation underlying heritable pulmonary arterial hypertension
Ist Teil von
  • Nature communications, 2018-04, Vol.9 (1), p.1416-16, Article 1416
Ort / Verlag
England: Nature Publishing Group
Erscheinungsjahr
2018
Link zum Volltext
Quelle
MEDLINE
Beschreibungen/Notizen
  • Pulmonary arterial hypertension (PAH) is a rare disorder with a poor prognosis. Deleterious variation within components of the transforming growth factor-β pathway, particularly the bone morphogenetic protein type 2 receptor (BMPR2), underlies most heritable forms of PAH. To identify the missing heritability we perform whole-genome sequencing in 1038 PAH index cases and 6385 PAH-negative control subjects. Case-control analyses reveal significant overrepresentation of rare variants in ATP13A3, AQP1 and SOX17, and provide independent validation of a critical role for GDF2 in PAH. We demonstrate familial segregation of mutations in SOX17 and AQP1 with PAH. Mutations in GDF2, encoding a BMPR2 ligand, lead to reduced secretion from transfected cells. In addition, we identify pathogenic mutations in the majority of previously reported PAH genes, and provide evidence for further putative genes. Taken together these findings contribute new insights into the molecular basis of PAH and indicate unexplored pathways for therapeutic intervention.
Sprache
Englisch
Identifikatoren
ISSN: 2041-1723
eISSN: 2041-1723
DOI: 10.1038/s41467-018-03672-4
Titel-ID: cdi_doaj_primary_oai_doaj_org_article_cb3171b4e79940aa9ab812b5a9ce621a
Format
–
Schlagworte
Adenosine Triphosphatases - chemistry, Adenosine Triphosphatases - genetics, Adenosine Triphosphatases - metabolism, Adult, Aquaporin 1, Aquaporin 1 - chemistry, Aquaporin 1 - genetics, Aquaporin 1 - metabolism, Base Sequence, Bone morphogenetic protein receptor type II, Bone Morphogenetic Protein Receptors, Type II - genetics, Bone Morphogenetic Protein Receptors, Type II - metabolism, Case-Control Studies, Familial Primary Pulmonary Hypertension - diagnosis, Familial Primary Pulmonary Hypertension - genetics, Familial Primary Pulmonary Hypertension - metabolism, Familial Primary Pulmonary Hypertension - pathology, Female, Gene Expression Regulation, Gene sequencing, Genes, Genetic Predisposition to Disease, Genomes, Growth Differentiation Factor 2, Growth Differentiation Factors - chemistry, Growth Differentiation Factors - genetics, Growth Differentiation Factors - metabolism, HEK293 Cells, Heritability, Humans, Hypertension, Life Sciences, Male, Membrane Transport Proteins - chemistry, Membrane Transport Proteins - genetics, Membrane Transport Proteins - metabolism, Models, Molecular, Mutation, Prognosis, Pulmonary hypertension, Secretion, Signal Transduction, SOXF Transcription Factors - chemistry, SOXF Transcription Factors - genetics, SOXF Transcription Factors - metabolism, Transforming growth factor, Transforming Growth Factor beta - genetics, Transforming Growth Factor beta - metabolism, Transforming growth factor-b, Whole Genome Sequencing

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