Identification of rare sequence variation underlying heritable pulmonary arterial hypertension

Nat Commun. 2018 Apr 12;9(1):1416. doi: 10.1038/s41467-018-03672-4.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphatases / chemistry*
  • Adenosine Triphosphatases / genetics
  • Adenosine Triphosphatases / metabolism
  • Adult
  • Aquaporin 1 / chemistry*
  • Aquaporin 1 / genetics
  • Aquaporin 1 / metabolism
  • Base Sequence
  • 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
  • Genetic Predisposition to Disease
  • Growth Differentiation Factor 2
  • Growth Differentiation Factors / chemistry*
  • Growth Differentiation Factors / genetics
  • Growth Differentiation Factors / metabolism
  • HEK293 Cells
  • Humans
  • Male
  • Membrane Transport Proteins / chemistry*
  • Membrane Transport Proteins / genetics
  • Membrane Transport Proteins / metabolism
  • Models, Molecular
  • Mutation*
  • Prognosis
  • SOXF Transcription Factors / chemistry*
  • SOXF Transcription Factors / genetics
  • SOXF Transcription Factors / metabolism
  • Signal Transduction
  • Transforming Growth Factor beta / genetics
  • Transforming Growth Factor beta / metabolism
  • Whole Genome Sequencing

Substances

  • AQP1 protein, human
  • GDF2 protein, human
  • Growth Differentiation Factor 2
  • Growth Differentiation Factors
  • Membrane Transport Proteins
  • SOX17 protein, human
  • SOXF Transcription Factors
  • Transforming Growth Factor beta
  • Aquaporin 1
  • BMPR2 protein, human
  • Bone Morphogenetic Protein Receptors, Type II
  • ATP13A3 protein, human
  • Adenosine Triphosphatases