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Characterization of rare ABCC8 variants identified in Spanish pulmonary arterial hypertension patients.

ABSTRACT: 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.

SUBMITTER: Lago-Docampo M

PROVIDER: S-EPMC7492224 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Characterization of rare ABCC8 variants identified in Spanish pulmonary arterial hypertension patients.

Lago-Docampo Mauro M Tenorio Jair J Hernández-González Ignacio I Pérez-Olivares Carmen C Escribano-Subías Pilar P Pousada Guillermo G Baloira Adolfo A Arenas Miguel M Lapunzina Pablo P Valverde Diana D

Scientific reports 20200915 1

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 i ...[more]

PMID: 32934261

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Project description:ImportanceIdiopathic pulmonary arterial hypertension (IPAH) is a fatal disease with high heritability; however, the bone morphogenetic protein receptor 2 (BMPR2) gene only accounts for 17% of IPAH. The genetic basis of IPAH needs further investigation.ObjectiveTo identify novel IPAH susceptibility genes other than BMPR2.Design, setting, and participantsThis 2-stage, case-control genetic association study enrolled 230 patients with IPAH from 2 referral pulmonary hypertension centers in China. Eligible patients had no BMPR2 variants and were compared with 968 healthy control participants. Data were collected from January 1, 2000, to July 31, 2015, and analyzed from August 1, 2015, to May 30, 2018.ExposuresPTGIS rare variants.Main outcomes and measuresWhole-genome sequencing was performed to identify putative IPAH genes in a discovery cohort, with validation in an independent referral cohort. Correlation of genotype and hemodynamic characteristics was then evaluated at baseline and after pulmonary vasodilator testing. Functional assessments were conducted to analyze the effects of identified genetic variants on transcript splicing, enzymatic activity, and endothelial cell phenotypes.ResultsAmong 230 patients with IPAH (164 female [71.3%]; mean [SD] age, 34 [18] years), an enrichment of rare variants in a gene encoding prostacyclin synthase (PTGIS) was identified in the discovery cohort. The association of PTGIS rare variants with IPAH was confirmed in the replication cohort. In the combined data set, PTGIS rare variants were found in 14 of 230 cases (6.1%) and 8 of 968 controls (0.8%) (odds ratio, 7.8; 95% CI, 3.2-18.8; P = 5 × 10-6, logistic regression). Compared with patients without PTGIS variants, inhaled iloprost induced a more significant decrease of pulmonary vascular resistance (difference in the least square mean, -21.7%; 95% CI, -31.4% to -12.0%; P < .001, linear regression model) and an increase of cardiac index (difference in the least square mean, 18.3%; 95% CI, 8.8%-27.8%; P < .001, linear regression model) in patients with PTGIS variants. The minigene assay indicated that the c.521 + 1G>A variant resulted in aberrant messenger RNA transcripts. The functional studies showed that the 2 missense rare variants (R252Q and A447T) resulted in a decrease in prostacyclin production and increased cell death of pulmonary microvascular endothelial cells.Conclusions and relevanceThis study identified 3 rare loss-of-function variants in the PTGIS gene from 2 independent cohorts with IPAH. The genetic variants of PTGIS predispose pulmonary vascular responses to the iloprost stimulation. These findings suggest that PTGIS variants may be involved in the pathogenesis of IPAH.

Dataset Information

Characterization of rare ABCC8 variants identified in Spanish pulmonary arterial hypertension patients.

Publications

Characterization of rare ABCC8 variants identified in Spanish pulmonary arterial hypertension patients.

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