title: BMPR2 mutations have short lifetime expectancy in primary pulmonary hypertension.
abstract: In a nationwide study, we identified a total of 59 patients diagnosed with primary pulmonary hypertension (PPH) in Finland between the years 1987 and 1999. These data support a minimum estimate for a PPH population prevalence of 5.8 cases/million with an incidence of 0.2-1.3 cases/million/year. The male-to-female ratio among the patients was 1:4, while 7% (4/59) of the PPH probands had a known family history of the disorder. Familial or sporadic PPH showed no geographic clustering to any region of Finland. Sequencing of the coding regions and exon-intron boundaries of the bone morphogenetic protein receptor type 2 (BMPR2) identified heterozygous BMPR2 mutations in 12% (3/26) of the sporadic and 33% (1/3) of the familial patients. All four mutations were different, and two of those have been previously reported in other populations. Pathogenic defects in BMPR2 include a novel missense mutation (c.2696G>C encoding R899P), located within the receptor intracellular cytoplasmic domain whose function has been poorly characterized. Our analysis demonstrates that this mutant, while localizing to the cell surface, does not impact on SMAD-mediated (mothers against decapentaplegic homolog) intracellular signaling, but leads to constitutive activation of the p38(MAPK) pathway. The absence of a founder mutation in a genetically homogeneous population, such as the Finns, suggests that all identified BMPR2 mutations have to be rather young while the ancestral (if any) mutations have been lost either due to repetitive genetic bottlenecks or due to significant negative selection. Hum Mutat 26(2), 1-6, 2005. (c) 2005 Wiley-Liss, Inc.
authors.affiliation: Department of Medical Genetics, University of Helsinki, Helsinki, Finland. marja.sankelo@helsinki.fi
authors.forename: Marja
authors.initials: M
authors.lastname: Sankelo
authors.forename: Julia A
authors.initials: JA
authors.lastname: Flanagan
authors.forename: Rajiv
authors.initials: R
authors.lastname: Machado
authors.forename: Rachel
authors.initials: R
authors.lastname: Harrison
authors.forename: Nung
authors.initials: N
authors.lastname: Rudarakanchana
authors.forename: Nicholas
authors.initials: N
authors.lastname: Morrell
authors.forename: Morag
authors.initials: M
authors.lastname: Dixon
authors.forename: Maija
authors.initials: M
authors.lastname: Halme
authors.forename: Hannu
authors.initials: H
authors.lastname: Puolijoki
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: Outi
authors.initials: O
authors.lastname: Elomaa
authors.forename: Markku
authors.initials: M
authors.lastname: Kupari
authors.forename: Anne
authors.initials: A
authors.lastname: Räisänen-Sokolowski
authors.forename: Richard C
authors.initials: RC
authors.lastname: Trembath
authors.forename: Tarja
authors.initials: T
authors.lastname: Laitinen
mesh_terms: D000293:Adolescent; D000328:Adult; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D006976:Hypertension, Pulmonary / Q000235:genetics* / Q000401:mortality*; D008136:Longevity; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D015398:Signal Transduction
chemical_list: C498218:BMPR2 protein, human; D052006:Bone Morphogenetic Protein Receptors, Type II