Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.

  • Abdalla S
  • Flanagan J
  • Räisänen-Sokolowski A
 et al. 
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BACKGROUND: Mutations of the transforming growth factor beta (TGFbeta) receptor components ENDOGLIN and ALK-1 cause the autosomal dominant vascular disorder hereditary haemorrhagic telangiectasia (HHT). Heterozygous mutations of the type II receptor BMPR2 underlie familial primary pulmonary hypertension. OBJECTIVE: To investigate kindreds presenting with both pulmonary hypertension and HHT. METHODS: Probands and families were identified by specialist pulmonary hypertension centres in five countries. DNA sequence analysis of ALK-1, ENDOGLIN, and BMPR2 was undertaken. Cellular localisation was investigated by heterologous overexpression of mutant constructs in both BAEC and HeLa cells. The impact of a novel sequence variant was assessed through comparative analysis and computer modelling. RESULTS: Molecular analysis of 11 probands identified eight missense mutations of ALK-1, one of which was observed in two families. Mutations were located within exons 5 to 10 of the ALK-1 gene. The majority of ALK-1 mutant constructs appeared to be retained within the cell cytoplasm, in the endoplasmic reticulum. A novel GS domain mutation, when overexpressed, reached the cell surface but is predicted to disrupt conformational changes owing to loss of a critical hydrogen bond. Two novel missense mutations were identified in ENDOGLIN. CONCLUSIONS: The association of pulmonary arterial hypertension and HHT identifies an important disease complication and appears most common among subjects with defects in ALK-1 receptor signalling. Future studies should focus on detailed molecular analysis of the common cellular pathways disrupted by mutations of ALK-1 and BMPR2 that cause inherited pulmonary vascular disease.

Author-supplied keywords

  • Activin Receptors
  • Adolescent
  • Adult
  • Aged
  • Amino Acid Sequence
  • Antigens
  • Bone Morphogenetic Protein Receptors
  • CD
  • Cell Surface
  • DNA Mutational Analysis
  • Endoplasmic Reticulum
  • Endoplasmic Reticulum: chemistry
  • Female
  • Genetic Predisposition to Disease
  • Hereditary Hemorrhagic
  • Hereditary Hemorrhagic: complicati
  • Hereditary Hemorrhagic: diagnosis
  • Hereditary Hemorrhagic: genetics
  • Humans
  • Hypertension
  • Male
  • Middle Aged
  • Missense
  • Models
  • Molecular
  • Mutation
  • Protein
  • Protein-Serine-Threonine Kinases
  • Protein-Serine-Threonine Kinases: genetics
  • Pulmonary
  • Pulmonary: diagnosis
  • Pulmonary: genetics
  • Receptors
  • Structural Homology
  • Telangiectasia
  • Type I
  • Type I: analysis
  • Type I: chemistry
  • Type I: genetics
  • Type II
  • Vascular Cell Adhesion Molecule-1
  • Vascular Cell Adhesion Molecule-1: genetics

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  • S.A. Abdalla

  • J A Flanagan

  • A Räisänen-Sokolowski

  • R E Harrison

  • M Sankelo

  • J Rowell

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