title: Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.
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.
authors.affiliation: Division of Medical Genetics, University of Leicester, Leicester, UK.
authors.forename: R E
authors.initials: RE
authors.lastname: Harrison
authors.forename: J A
authors.initials: JA
authors.lastname: Flanagan
authors.forename: M
authors.initials: M
authors.lastname: Sankelo
authors.forename: S A
authors.initials: SA
authors.lastname: Abdalla
authors.forename: J
authors.initials: J
authors.lastname: Rowell
authors.forename: R D
authors.initials: RD
authors.lastname: Machado
authors.forename: C G
authors.initials: CG
authors.lastname: Elliott
authors.forename: I M
authors.initials: IM
authors.lastname: Robbins
authors.forename: H
authors.initials: H
authors.lastname: Olschewski
authors.forename: V
authors.initials: V
authors.lastname: McLaughlin
authors.forename: E
authors.initials: E
authors.lastname: Gruenig
authors.forename: F
authors.initials: F
authors.lastname: Kermeen
authors.forename: M
authors.initials: M
authors.lastname: Halme
authors.forename: A
authors.initials: A
authors.lastname: Räisänen-Sokolowski
authors.forename: T
authors.initials: T
authors.lastname: Laitinen
authors.forename: N W
authors.initials: NW
authors.lastname: Morrell
authors.forename: R C
authors.initials: RC
authors.lastname: Trembath
mesh_terms: D030201:Activin Receptors, Type I / Q000032:analysis / Q000737:chemistry / Q000235:genetics*; D030301:Activin Receptors, Type II; D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D015703:Antigens, CD; D052006:Bone Morphogenetic Protein Receptors, Type II; D004252:DNA Mutational Analysis; D000071063:Endoglin; D004721:Endoplasmic Reticulum / Q000737:chemistry; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D006976:Hypertension, Pulmonary / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D011956:Receptors, Cell Surface; D040681:Structural Homology, Protein; D013683:Telangiectasia, Hereditary Hemorrhagic / Q000150:complications* / Q000175:diagnosis / Q000235:genetics; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
chemical_list: D015703:Antigens, CD; C064206:ENG protein, human; D000071063:Endoglin; D011956:Receptors, Cell Surface; D019010:Vascular Cell Adhesion Molecule-1; D017346:Protein Serine-Threonine Kinases; C425364:ACVRL1 protein, human; D030201:Activin Receptors, Type I; D030301:Activin Receptors, Type II; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II