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Gräf, Stefan; Haimel, Matthias; Bleda, Marta; Hadinnapola, Charaka; Southgate, Laura; Li, Wei; Hodgson, Joshua; Liu, Bin; Salmon, Richard M.; Southwood, Mark; Machado, Rajiv D.; Martin, Jennifer M.; Treacy, Carmen M.; Yates, Katherine; Daugherty, Louise C.; Shamardina, Olga; Whitehorn, Deborah; Holden, Simon; Aldred, Micheala; Bogaard, Harm J.; Church, Colin; Coghlan, Gerry; Condliffe, Robin; Corris, Paul A.; [...]

Identification of rare sequence variation underlying heritable pulmonary arterial hypertension

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  • Medientyp: E-Artikel
  • Titel: Identification of rare sequence variation underlying heritable pulmonary arterial hypertension
  • Beteiligte: Gräf, Stefan; Haimel, Matthias; Bleda, Marta; Hadinnapola, Charaka; Southgate, Laura; Li, Wei; Hodgson, Joshua; Liu, Bin; Salmon, Richard M.; Southwood, Mark; Machado, Rajiv D.; Martin, Jennifer M.; Treacy, Carmen M.; Yates, Katherine; Daugherty, Louise C.; Shamardina, Olga; Whitehorn, Deborah; Holden, Simon; Aldred, Micheala; Bogaard, Harm J.; Church, Colin; Coghlan, Gerry; Condliffe, Robin; Corris, Paul A.; [...]
  • Erschienen: Springer Science and Business Media LLC, 2018
  • Erschienen in: Nature Communications
  • Sprache: Englisch
  • DOI: 10.1038/s41467-018-03672-4
  • ISSN: 2041-1723
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title><jats:p>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 (<jats:italic>BMPR2</jats:italic>), 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 <jats:italic>ATP13A3, AQP1</jats:italic> and <jats:italic>SOX17</jats:italic>, and provide independent validation of a critical role for <jats:italic>GDF2</jats:italic> in PAH. We demonstrate familial segregation of mutations in <jats:italic>SOX17</jats:italic> and <jats:italic>AQP1</jats:italic> with PAH. Mutations in <jats:italic>GDF2</jats:italic>, 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.</jats:p>
  • Zugangsstatus: Freier Zugang