Analysis of Genetic Mutations Related to TGF-β/BMP Signaling in Children and Adults with Pulmonary Arterial Hypertension

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type:TOHO University Scholarly Publication

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Background: Pulmonary arterial hypertension (PAH) is a vascular disorder characterized by increased pulmonary vascular resistance and right heart failure. Mutations in the bone morphogenic protein receptor 2(BMPR2), endoglin(ENG), and activin receptor-like kinase 1(ALK1) genes, which belong to the transforming growth factor-β (TGF-β) superfamily, have been implicated in PAH pathogenesis. In a previous study, we identified 18 BMPR2 mutations and seven ALK1 mutations in 57 pediatric cases. In further screening of mutations in 11 genes (ENG, SMAD1-8, ALK3, ALK6) in the TGF-β superfamily, we found one mutation in SMAD8 and two mutations in BMPR1B (ALK6) among PAH patients who had no mutations in BMPR2, ENG, or ALK1. We thus examined the correlation with TGF-β/bone morphogenic protein (BMP) signaling in the present study. Methods: In this study, we conducted a genetic analysis of BMPR2, ALK1, ENG, SMAD8, and ALK6 in 21 adults with PAH, then further analyzed SMAD1-7, ALK2-5, and ALK7 in those with no mutations in BMPR2, ALK1, ENG, SMAD8, or ALK6. In addition to our previous study, we screened mutations of four genes (ALK2, ALK4, ALK5, and ALK7) in 29 children with PAH but no mutations in BMPR2, ALK1, ALK3, ALK6, ENG, or SMAD1-8. Results: In this study, we identified nine BMPR2 mutations and one ALK1 mutation in adult PAH. We analyzed 11 adult patients with idiopathic PAH (IPAH) and no mutations in BMPR2, ALK1, ENG, SMAD8, ALK6, or 12 other genes (SMAD1-7, ALK2-5, ALK7) and 29 child patients with IPAH and no mutations in BMPR2, ALK1, ALK3, ALK6, ENG, SMAD1-8, or four other genes (ALK2, ALK4, ALK5, ALK7). No genetic mutations were found. The ALK1 mutation was 2.6 times as frequent in children (12.3%; 7/57) as in adults (4.8%; 1/21). However, PAH symptom severity was not correlated with the presence or absence of genetic mutations. Conclusion: In adults with IPAH, we identified mutations in BMPR2 and ALK1 but not in other genes belonging to the TGF-β superfamily. A few new disease-related genes were recently found in an expanded analysis; however, it is likely that as yet undiscovered mutations are involved in PAH pathogenesis.

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