RT Journal Article
T1 Characterization of rare ABCC8 variants identified in Spanish pulmonary arterial hypertension patients
A1 Lago Docampo, Mauro
A1 Tenorio Castaño, Jair Antonio
A1 Hernández González, Ignacio
A1 Pérez Olivares, Carmen
A1 Escribano Subías, Pilar
A1 Pousada, Guillermo
A1 Baloira, Adolfo
A1 Arenas Busto, Miguel
A1 Lapunzina, Pablo
A1 Valverde Pérez, Diana
K1 3207.04 Patología Cardiovascular
K1 3205.08 Enfermedades Pulmonares
K1 2410 Biología Humana
K1 2409 Genética
AB Pulmonary Arterial Hypertension (PAH) is a rare and fatal disease where knowledge about its genetic basis continues to increase. In this study, we used targeted panel sequencing in a cohort of 624 adult and pediatric patients from the Spanish PAH registry. We identified 11 rare variants in the ATP-binding Cassette subfamily C member 8 (ABCC8) gene, most of them with splicing alteration predictions. One patient also carried another variant in SMAD1 gene (c.27delinsGTAAAG). We performed an ABCC8 in vitro biochemical analyses using hybrid minigenes to confirm the correct mRNA processing of 3 missense variants (c.211C > T p.His71Tyr, c.298G > A p.Glu100Lys and c.1429G > A p.Val477Met) and the skipping of exon 27 in the novel splicing variant c.3394G > A. Finally, we used structural protein information to further assess the pathogenicity of the variants. The results showed 11 novel changes in ABCC8 and 1 in SMAD1 present in PAH patients. After in silico and in vitro biochemical analyses, we classified 2 as pathogenic (c.3288_3289del and c.3394G > A), 6 as likely pathogenic (c.211C > T, c.1429G > A, c.1643C > T, c.2422C > A, c.2694 + 1G > A, c.3976G > A and SMAD1 c.27delinsGTAAAG) and 3 as Variants of Uncertain Significance (c.298G > A, c.2176G > A and c.3238G > A). In all, we show that coupling in silico tools with in vitro biochemical studies can improve the classification of genetic variants.
PB Scientific Reports
SN 20452322
YR 2020
FD 2020-09-15
LK http://hdl.handle.net/11093/2125
UL http://hdl.handle.net/11093/2125
LA eng
NO Scientific Reports, 10(1): 15135 (2020)
NO Instituto de Salud Carlos III | Ref. RD06/0003/0012
DS Investigo
RD 28-nov-2023