Loss-of-Function ABCC8 Mutations in Pulmonary Arterial Hypertension.
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Bohnen Michael S, Ma Lijiang, Zhu Na, Qi Hongjian, McClenaghan Conor, Gonzaga-Jauregui Claudia, Dewey Frederick E, Overton John D, Reid Jeffrey G, Shuldiner Alan R, Baras Aris, Sampson Kevin J, Bleda Marta, Hadinnapola Charaka, Haimel Matthias, Bogaard Harm J, Church Colin, Coghlan Gerry, Corris Paul A, Eyries Mélanie, Gibbs J Simon R, Girerd Barbara, Houweling Arjan C, Humbert Marc, Guignabert Christophe, Kiely David G, Lawrie Allan, MacKenzie Ross Rob V, Martin Jennifer M, Montani David, Peacock Andrew J, Pepke-Zaba Joanna, Soubrier Florent, Suntharalingam Jay, Toshner Mark, Treacy Carmen M, Trembath Richard C, Vonk Noordegraaf Anton, Wharton John, Wilkins Martin R, Wort Stephen J, Yates Katherine, Gräf Stefan, Morrell Nicholas W, Krishnan Usha, Rosenzweig Erika B, Shen Yufeng, Nichols Colin G, Kass Robert S, Chung Wendy K
Аннотация
METHODS: Exome sequencing was performed to identify novel genes in a cohort of 99 pediatric and 134 adult-onset group I PAH patients. Novel rare variants in the gene identified were independently identified in a cohort of 680 adult-onset patients. Variants were expressed in COS cells and function assessed by patch-clamp and rubidium flux analysis.
RESULTS: We identified a de novo novel heterozygous predicted deleterious missense variant c.G2873A (p.R958H) in ABCC8 in a child with idiopathic PAH. We then evaluated all individuals in the original and a second cohort for rare or novel variants in ABCC8 and identified 11 additional heterozygous predicted damaging ABCC8 variants. ABCC8 encodes SUR1 (sulfonylurea receptor 1)-a regulatory subunit of the ATP-sensitive potassium channel. We observed loss of ATP-sensitive potassium channel function for all ABCC8 variants evaluated and pharmacological rescue of all channel currents in vitro by the SUR1 activator, diazoxide.
CONCLUSIONS: Novel and rare missense variants in ABCC8 are associated with PAH. Identified ABCC8 mutations decreased ATP-sensitive potassium channel function, which was pharmacologically recovered.