Neurodevelopmental disorders, such as autism spectrum disorders and schizophrenia, are complex disorders with a high degree of heritability. Genetic studies have identified several candidate genes associated with these disorders, including contactin-associated protein-like 2 (CNTNAP2). Traditionally, in animal models or in vitro, CNTNAP2 has been studied by genetic deletion or transcriptional knockdown, which reduces the expression of the entire gene; however, it remains unclear whether the mutations identified in clinical settings are sufficient to alter CNTNAP2 expression in human neurons. Here, using human induced pluripotent stem cells (hiPSCs) derived from two individuals with a large (289 kb) heterozygous deletion in CNTNAP2 (affecting exons 14–15) and discordant clinical outcomes, we have characterized CNTNAP2 expression patterns in hiPSC neural progenitor cells, two independent populations of hiPSC-derived neurons and hiPSC-derived oligodendrocyte precursor cells. First, we observed exon-specific changes in CNTNAP2 expression in both carriers; although the expression of exons 14–15 is significantly decreased, the expression of other exons is upregulated. Second, we observed significant differences in patterns of allele-specific expression in CNTNAP2 carriers that were consistent with the clinical outcome. Third, we observed a robust neural migration phenotype that correlated with diagnosis and exon- and allele-specific CNTNAP2 expression patterns, but not with genotype. In all, our data highlight the importance of considering the nature, location, and regulation of mutated alleles when attempting to connect genome wide association studies to gene function.
Variants in CNTNAP2, a member of the neurexin family of genes that function as cell adhesion molecules, have been associated with multiple neuropsychiatric conditions such as schizophrenia, autism spectrum disorder and intellectual disability; animal studies indicate a role for CNTNAP2 in axon guidance, dendritic arborization and synaptogenesis. We previously reprogrammed fibroblasts from a family trio consisting of two carriers of heterozygous intragenic CNTNAP2 deletions into human induced pluripotent stem cells (hiPSCs) and described decreased migration in the neural progenitor cells (NPCs) differentiated from the affected CNTNAP2 carrier in this trio. Here, we report the effect of this heterozygous intragenic deletion in CNTNAP2 on global gene expression and neuronal activity in the same cohort. Our findings suggest that heterozygous CNTNAP2 deletions affect genes involved in neuronal development and neuronal activity; however, these data reflect only one family trio and therefore more deletion carriers, with a variety of genetic backgrounds, will be needed to understand the molecular mechanisms underlying CNTNAP2 deletions.
BACKGROUND Early in the coronavirus disease 2019 (COVID-19) pandemic, there was a significant impact on routine medical care in the United States, including in fields of transplantation and oncology. AIM To analyze the impact and outcomes of early COVID-19 pandemic on liver transplantation (LT) for hepatocellular carcinoma (HCC) in the United States. METHODS WHO declared COVID-19 as a pandemic on March 11, 2020. We retrospectively analyzed data from the United Network for Organ Sharing (UNOS) database regarding adult LT with confirmed HCC on explant in 2019 and 2020. We defined pre-COVID period from March 11 to September 11, 2019, and early-COVID period as from March 11 to September 11, 2020. RESULTS Overall, 23.5% fewer LT for HCC were performed during the COVID period (518 vs 675, P < 0.05). This decrease was most pronounced in the months of March-April 2020 with a rebound in numbers seen from May-July 2020. Among LT recipients for HCC, concurrent diagnosis of non-alcoholic steatohepatitis significantly increased (23 vs 16%) and alcoholic liver disease (ALD) significantly decreased (18 vs 22%) during the COVID period. Recipient age, gender, BMI, and MELD score were statistically similar between two groups, while waiting list time decreased during the COVID period (279 days vs 300 days, P = 0.041). Among pathological characteristics of HCC, vascular invasion was more prominent during COVID period ( P < 0.01), while other features were the same. While the donor age and other characteristics remained same, the distance between donor and recipient hospitals was significantly increased ( P < 0.01) and donor risk index was significantly higher (1.68 vs 1.59, P < 0.01) during COVID period. Among outcomes, 90-day overall and graft survival were the same, but 180-day overall and graft were significantly inferior during COVID period (94.7 vs 97.0%, P = 0.048). On multivariable Cox-hazard regression analysis, COVID period emerged as a significant risk factor of post-transplant mortality (Hazard ratio 1.85; 95%CI: 1.28-2.68, P = 0.001). CONCLUSION During COVID period, there was a significant decrease in LTs performed for HCC. While early postoperative outcomes of LT for HCC were same, the overall and graft survival of LTs for HCC after 180 days were significantly inferior.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.