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

J Med Genet. 2003 Dec;40(12):865-71. doi: 10.1136/jmg.40.12.865.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Antigens, CD
  • ENG protein, human
  • Endoglin
  • Receptors, Cell Surface
  • Vascular Cell Adhesion Molecule-1
  • Protein Serine-Threonine Kinases
  • ACVRL1 protein, human
  • Activin Receptors, Type I
  • Activin Receptors, Type II
  • BMPR2 protein, human
  • Bone Morphogenetic Protein Receptors, Type II

Associated data

  • OMIM/178600
  • OMIM/187300
  • OMIM/600376