Circulation Journal
Online ISSN : 1347-4820
Print ISSN : 1346-9843
ISSN-L : 1346-9843
Pulmonary Circulation
Missense Mutations of the BMPR1B (ALK6) Gene in Childhood Idiopathic Pulmonary Arterial Hypertension
Ayako ChidaMasaki ShintaniTomotaka NakayamaYoshiyuki FurutaniEmiko HayamaKei InaiTsutomu SajiShigeaki NonoyamaToshio Nakanishi
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Supplementary material

2012 Volume 76 Issue 6 Pages 1501-1508


Background: Mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene, the activin receptor-like kinase 1 (ALK1) gene, and SMAD8 gene have been reported in heritable pulmonary arterial hypertension (HPAH) and in idiopathic pulmonary arterial hypertension (IPAH). However, almost 30% of HPAH cases and 60-90% of IPAH cases have no mutations in those genes. This suggests that there remain unidentified genes associated with HPAH and IPAH. Methods and Results: This study screened for mutations in endoglin, SMAD1, SMAD2, SMAD3, SMAD4, SMAD5, SMAD6, SMAD7, bone morphogenetic protein receptor type 1A (BMPR1A) and bone morphogenetic protein receptor type 1B (BMPR1B) genes in 43 IPAH patients who had no mutations in BMPR2, ALK1 and SMAD8. Two missense mutations (c.479 G>A S160N, c.1176 C>A F392L) in BMPR1B were each identified in 2 IPAH patients. Immunoblot analysis revealed that the BMPR1B F392L protein promoted SMAD8 phosphorylation. The response to BMP was analyzed using promoter-reporter activities. The transcriptional activation of the BMPR1B F392L protein with SMAD8 increased above that of wild-type BMPR1B with SMAD8, and those of BMPR1B S160N and F392L with SMAD8 and SMAD4 were each increased above those of the wild-type BMPR1B with SMAD8 and SMAD4. Conclusions: We identified 2 novel mutations in BMPR1B in 2 patients with IPAH. Our study suggests that BMPR1B mutations are associated with the pathogenesis of IPAH. (Circ J 2012; 76: 1501-1508)

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