title: Investigation of second genetic hits at the BMPR2 locus as a modulator of disease progression in familial pulmonary arterial hypertension.
abstract: BACKGROUND
  Primary pulmonary arterial hypertension (PAH) is a potentially devastating condition resulting from occlusion of the pulmonary arterioles by the formation of vascular lesions. Heterozygous mutations in the gene encoding the bone morphogenetic protein receptor type II (BMPR2) have been identified in both familial (FPAH) and idiopathic PAH. Mutant alleles are typically of low penetrance, indicating that other factors are required for the onset of PAH. Previous reports have suggested that the characteristic plexiform lesions in affected lungs are akin to neoplasia, showing monoclonal expansion and microsatellite instability. We hypothesized that in patients with germline mutations, BMPR2 might behave as a classic tumor suppressor gene, with somatic loss of the wild-type allele contributing to disease progression.
  
  
  RESULTS
  To test this hypothesis, plexiform and concentric vascular lesions were serially microdissected from lung explant tissue derived from 7 FPAH cases. DNA was analyzed for loss of heterozygosity at BMPR2 and for microsatellite instability (MSI) at 5 loci. MSI was detected in 1 of 37 lesions at a single locus, BAT-26, whereas heterozygosity at BMPR2 was retained at all informative loci. We also describe a FPAH patient carrying biallelic constitutional missense mutations of BMPR2 who manifested disease at a stage and manner similar to heterozygous patients.
  
  
  CONCLUSIONS
  Taken together, these data demonstrate that MSI is uncommon in FPAH and suggest that somatic loss of the remaining wild-type BMPR2 allele in heterozygous mutation carriers likely does not play a significant role in modulating the onset or progression of FPAH.
authors.affiliation: Division of Medical Genetics, Department of Genetics, University of Leicester, Leicester, UK.
authors.forename: Rajiv D
authors.initials: RD
authors.lastname: Machado
authors.forename: Victoria
authors.initials: V
authors.lastname: James
authors.forename: Mark
authors.initials: M
authors.lastname: Southwood
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Harrison
authors.forename: Carl
authors.initials: C
authors.lastname: Atkinson
authors.forename: Susan
authors.initials: S
authors.lastname: Stewart
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Morrell
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.forename: Micheala A
authors.initials: MA
authors.lastname: Aldred
mesh_terms: D000328:Adult; D000483:Alleles; D052006:Bone Morphogenetic Protein Receptors, Type II; D004252:DNA Mutational Analysis; D018450:Disease Progression; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000473:pathology; D019656:Loss of Heterozygosity; D008168:Lung / Q000601:surgery; D042282:Microdissection; D018895:Microsatellite Repeats; D009154:Mutation; D020125:Mutation, Missense; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D017346:Protein Serine-Threonine Kinases; C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II