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Circ Cardiovasc Genet ; 7(6): 920-9, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25373139

RESUMO

BACKGROUND: Human variation in susceptibility to hypoxia-induced pulmonary hypertension is well recognized. High-altitude residents who do not develop pulmonary hypertension may host protective gene mutations. METHODS AND RESULTS: Exome sequencing was conducted on 24 unrelated Kyrgyz highlanders living 2400 to 3800 m above sea level, 12 (10 men; mean age, 54 years) with an elevated mean pulmonary artery pressure (mean±SD, 38.7±2.7 mm Hg) and 12 (11 men; mean age, 52 years) with a normal mean pulmonary artery pressure (19.2±0.6 mm Hg) to identify candidate genes that may influence the pulmonary vascular response to hypoxia. A total of 140 789 exomic variants were identified and 26 116 (18.5%) were classified as novel or rare. Thirty-three novel or rare potential pathogenic variants (frameshift, essential splice-site, and nonsynonymous) were found exclusively in either ≥3 subjects with high-altitude pulmonary hypertension or ≥3 highlanders with a normal mean pulmonary artery pressure. A novel missense mutation in GUCY1A3 in 3 subjects with a normal mean pulmonary artery pressure encodes an α1-A680T soluble guanylate cyclase (sGC) variant. Expression of the α1-A680T sGC variant in reporter cells resulted in higher cyclic guanosine monophosphate production compared with the wild-type enzyme and the purified α1-A680T sGC exhibited enhanced sensitivity to nitric oxide in vitro. CONCLUSIONS: The α1-A680T sGC variant may contribute to protection against high-altitude pulmonary hypertension and supports sGC as a pharmacological target for reducing pulmonary artery pressure in humans at altitude.


Assuntos
Doença da Altitude/genética , Guanilato Ciclase/genética , Hipertensão Pulmonar/genética , Receptores Citoplasmáticos e Nucleares/genética , Alelos , Doença da Altitude/patologia , Sequência de Aminoácidos , Animais , GMP Cíclico/metabolismo , Feminino , Genótipo , Guanilato Ciclase/metabolismo , Células HEK293 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hipertensão Pulmonar/patologia , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Óxido Nítrico/metabolismo , Filogenia , Polimorfismo de Nucleotídeo Único , Receptores Citoplasmáticos e Nucleares/metabolismo , Alinhamento de Sequência , Análise de Sequência de DNA , Transdução de Sinais , Guanilil Ciclase Solúvel
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