RESUMO
Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant form of vascular dysplasia. Genetic diagnosis is made by identifying loss-of-function variants in genes, such as ENG and ACVRL1. However, the causal mechanisms of various variants of unknown significance remains unclear. In this study, we analyzed 12 Japanese patients from 11 families who were clinically diagnosed with HHT. Sequencing analysis identified 11 distinct variants in ACVRL1 and ENG. Three of the 11 were truncating variants, leading to a definitive diagnosis, whereas the remaining eight were splice-site and missense variants that required functional analyses. In silico splicing analyses demonstrated that three variants, c.526-3C > G and c.598C > G in ACVRL1, and c.690-1G > A in ENG, caused aberrant splicing, as confirmed by a minigene assay. The five remaining missense variants were p.Arg67Gln, p.Ile256Asn, p.Leu285Pro, and p.Pro424Leu in ACVRL and p.Pro165His in ENG. Nanoluciferase-based bioluminescence analyses demonstrated that these ACVRL1 variants impaired cell membrane trafficking, resulting in the loss of bone morphogenetic protein 9 (BMP9) signal transduction. In contrast, the ENG mutation impaired BMP9 signaling despite normal cell membrane expression. The updated functional analysis methods performed in this study will facilitate effective genetic testing and appropriate medical care for patients with HHT.
Assuntos
Telangiectasia Hemorrágica Hereditária , Humanos , Telangiectasia Hemorrágica Hereditária/genética , Endoglina/genética , Japão/epidemiologia , Mutação , Testes Genéticos , Receptores de Activinas Tipo II/genéticaRESUMO
This study investigates the impact of the COVID-19 pandemic on pediatric out-of-hospital cardiac arrest (OHCA) outcomes in Japan, aiming to address a critical research gap. Analyzing data from the All-Japan Utstein registry covering pediatric OHCA cases from 2018 to 2021, the study observed no significant changes in one-month survival, neurological outcomes, or overall performance when comparing the pre-pandemic (2018-2019) and pandemic (2020-2021) periods among 6765 cases. However, a notable reduction in pre-hospital return of spontaneous circulation (ROSC) during the pandemic (15.1-13.1%, p = .020) was identified. Bystander-initiated chest compressions and rescue breaths declined (71.1-65.8%, 22.3-13.0%, respectively; both p < .001), while bystander-initiated automated external defibrillator (AED) use increased (3.7-4.9%, p = .029). Multivariate logistic regression analyses identified factors associated with reduced pre-hospital ROSC during the pandemic. Post-pandemic, there was no noticeable change in the one-month survival rate. The lack of significant change in survival may be attributed to the negative effects of reduced chest compressions and ventilation being offset by the positive impact of widespread AED availability in Japan. These findings underscore the importance of innovative tools and systems for safe bystander cardiopulmonary resuscitation during a pandemic, providing insights to optimize pediatric OHCA care.
Assuntos
COVID-19 , Reanimação Cardiopulmonar , Parada Cardíaca Extra-Hospitalar , Sistema de Registros , Humanos , Parada Cardíaca Extra-Hospitalar/epidemiologia , Parada Cardíaca Extra-Hospitalar/terapia , Parada Cardíaca Extra-Hospitalar/mortalidade , Japão/epidemiologia , COVID-19/epidemiologia , Feminino , Criança , Masculino , Reanimação Cardiopulmonar/métodos , Pré-Escolar , Lactente , Adolescente , Pandemias , Desfibriladores , SARS-CoV-2/isolamento & purificação , Serviços Médicos de Emergência , Recém-Nascido , Retorno da Circulação Espontânea , Taxa de SobrevidaRESUMO
BACKGROUND: Peripheral pulmonary stenosis (PPS) is a condition characterized by the narrowing of the pulmonary arteries, which impairs blood flow to the lung. The mechanisms underlying PPS pathogenesis remain unclear. Thus, the aim of this study was to investigate the genetic background of patients with severe PPS to elucidate the pathogenesis of this condition. METHODS AND RESULTS: We performed genetic testing and functional analyses on a pediatric patient with PPS and Williams syndrome (WS), followed by genetic testing on 12 patients with WS and mild-to-severe PPS, 50 patients with WS but not PPS, and 21 patients with severe PPS but not WS. Whole-exome sequencing identified a rare PTGIS nonsense variant (p.E314X) in a patient with WS and severe PPS. Prostaglandin I2 synthase (PTGIS) expression was significantly downregulated and cell proliferation and migration rates were significantly increased in cells transfected with the PTGIS p.E314X variant-encoding construct when compared with that in cells transfected with the wild-type PTGIS-encoding construct. p.E314X reduced the tube formation ability in human pulmonary artery endothelial cells and caspase 3/7 activity in both human pulmonary artery endothelial cells and human pulmonary artery smooth muscle cells. Compared with healthy controls, patients with PPS exhibited downregulated pulmonary artery endothelial prostaglandin I2 synthase levels and urinary prostaglandin I metabolite levels. We identified another PTGIS rare splice-site variant (c.1358+2T>C) in another pediatric patient with WS and severe PPS. CONCLUSIONS: In total, 2 rare nonsense/splice-site PTGIS variants were identified in 2 pediatric patients with WS and severe PPS. PTGIS variants may be involved in PPS pathogenesis, and PTGIS represents an effective therapeutic target.
Assuntos
Sistema Enzimático do Citocromo P-450 , Oxirredutases Intramoleculares , Estenose da Valva Pulmonar , Síndrome de Williams , Adolescente , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Movimento Celular , Proliferação de Células , Células Cultivadas , Códon sem Sentido , Células Endoteliais/enzimologia , Células Endoteliais/metabolismo , Sequenciamento do Exoma , Predisposição Genética para Doença , Oxirredutases Intramoleculares/genética , Oxirredutases Intramoleculares/metabolismo , Fenótipo , Artéria Pulmonar/fisiopatologia , Artéria Pulmonar/enzimologia , Estenose da Valva Pulmonar/genética , Estenose da Valva Pulmonar/fisiopatologia , Índice de Gravidade de Doença , Síndrome de Williams/genética , Síndrome de Williams/fisiopatologia , Síndrome de Williams/enzimologiaRESUMO
[This corrects the article DOI: 10.3389/fcvm.2023.1212882.].