Familial Pulmonary Hypertension

Epidemiology

  • 20% of famiial pulmonary hypertension cases have no detectable mutations in the currently known disease-associated genes

Etiologic Genetic Mutations

  • Bone Morphogenetic Protein Receptor Type 2 (BMPR2) Gene Mutation
    • Epidemiology
      • BMPR2 mutation is present in 80% of familial pulmonary hypertension cases
      • All patients with BMPR2 mutations are considered to have heritable disease, whether the patient is the first identified case, possibly with a de novo mutation, or other family members were previously diagnosed with PAH
    • Physiology: BMPR2 is a member of the tumor growth factor (TGF) beta super family
  • Activin-Like Receptor Kinase-1 (ALK1) Gene Mutation
    • Physiology: member of TGF beta super family
  • Endoglin (ENG) Gene Mutation
    • Physiology: member of TGF beta super family
  • Mothers Against Decapentaplegic 9 (Smad 9) Gene Mutation
    • Physiology: member of TGF beta super family
  • Caveolin-1 (CAV1) Gene Mutation
    • Physiology: encodes for a membrane protein of caveolae, abundant in lung endothelial cells
  • KCNK3 Gene Mutation:
    • Physiology: encodes for potassium channel super family K member-3

Clinical


References

  • Sporadic primary pulmonary hypertension is associated with germline mutations of the gene encoding BMPR-II, a receptor member of the TGF-beta family. J Med Genet 2000;37:741–5 [MEDLINE]
  • Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia. N Engl J Med 2001; 345:325–34 [MEDLINE]
  • Endoglin germline mutation in a patient with hereditary haemorrhagic telangiectasia and dexfenfluramine associated pulmonary arterial hypertension. Thorax 2004;59: 446–8 [MEDLINE]
  • High frequency of BMPR2 exonic deletions/duplications in familial pulmonary arterial hypertension. Am J Respir Crit Care Med 2006;174:590-8 [MEDLINE]
  • BMPR2 gene rearrangements account for a significant proportion of mutations in familial and idiopathic pulmonary arterial hypertension. Hum Mutat 2006;27:212–3 [MEDLINE]
  • Relationship of BMPR2 mutations to vasoreactivity in pulmonary arterial hypertension. Circulation 2006;113:2509–15 [MEDLINE]
  • Mutations of the TGF-beta type II receptor BMPR2 in pulmonary arterial hypertension. Hum Mutat 2006;27:121–32 [MEDLINE]
  • Clinical outcomes of pulmonary arterial hypertension in carriers of BMPR2 mutation. Am J Respir Crit Care Med 2008;177:1377–83 [MEDLINE]
  • Clinical implications of determining BMPR2 mutation status in a large cohort of children and adults with pulmonary arterial hypertension. J Heart Lung Transplant 2008;27:668–74 [MEDLINE]
  • Clinical outcomes of pulmonary arterial hypertension in patients carrying an ACVRL1 (ALK1) mutation. Am J Respir Crit Care Med. 2010 Apr 15;181(8):851-61 [MEDLINE]