Furin Gene Research Articles

Analysis of furin (FURIN) gene expression in the U-87 MG cell line as a potential target for gene inhibiting therapies in (auto-) immune diseases

Purpose: Furin is a proprotein convertase commonly found in the human body. The enzymatic activity of furin is necessary for the activation of numerous substrates including e.g. hormones and growth factors. Nevertheless, furin is involved in various pathological conditions caused by, among others, chronic inflammation. Therefore furin is considered as a potential target in autoimmune diseases therapy. We performed an experiment in which the expression of FURIN gene in U-87 MG astrocytoma cells was investigated. Additionally, this cell line contains some sequences coding human endogenous retroviruses (HERVs), including ERVW-1 and its receptor- SLC1A5. Deregulation of HERV expression has been observed in some neurodegenerative diseases as well as in inflammatory process. Material and Methods: Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot (WB) techniques were utilized for analysis. Phorbol 12-myristate 13-acetate (PMA) were used for cell stimulation. Short interfering RNAs (siRNA) were used for gene expression inhibition in U-87 MG cells in vitro. Results: Cell stimulation by PMA strongly increased FURIN expression, simultaneously downregulating ERVW-1 (p<0.01). Moreover addition of PMA significantly stimulates the autocatalytic action of cellular furin itself resulting in the dissociation of its propeptide that was clearly visible in a time-dependent manner. SiRNA-mediated expression inhibition of ERVW-1 and FURIN influenced the mRNA level for SLC1A5 (ASCT2) - primary syncytin-1 receptor, that was significantly lower. FURIN inhibition by siRNA caused strong upregulation of ERVW-1 expression (p<0.01). Conclusion: Our results showed that stimulation by PMA and inhibition expression by siRNA affects the expression of FURIN in U-87 MG astrocytoma cells. Moreover, furin shows a complex relationship on the expression of ERVW-1 and SLC1A5 genes, as well as on the form (precursor or mature) and the amount of the final translation products of the transcripts. The regulation of FURIN may pose a potential therapeutic strategy in the treatment of neurodegenerative diseases caused by autoimmunity.

The kpc-1 3'UTR facilitates dendritic transport and translation efficiency of mRNAs for dendrite arborization of a mechanosensory neuron important for male courtship.

A recently reported Schizophrenia-associated genetic variant in the 3'UTR of the human furin gene, a homolog of C. elegans kpc-1, highlights an important role of the furin 3'UTR in neuronal development. We isolate three kpc-1 mutants that display abnormal dendrite arborization in PVD neurons and defective male mating behaviors. We show that the kpc-1 3'UTR participates in dendrite branching and self-avoidance. The kpc-1 3'UTR facilitates mRNA localization to branching points and contact points between sibling dendrites and promotes translation efficiency. A predicted secondary structural motif in the kpc-1 3'UTR is required for dendrite self-avoidance. Animals with over-expression of DMA-1, a PVD dendrite receptor, exhibit similar dendrite branching and self-avoidance defects that are suppressed with kpc-1 over-expression. Our results support a model in which KPC-1 proteins are synthesized at branching points and contact points to locally down-regulate DMA-1 receptors to promote dendrite branching and self-avoidance of a mechanosensory neuron important for male courtship.

FURIN, IFNL4, and TLR2 gene polymorphisms in relation to COVID-19 severity: a case-control study in Egyptian patients.

A wide range of clinical manifestations and outcomes, including liver injury, have been reported in COVID-19 patients. We investigated the association of three substantial gene polymorphisms (FURIN, IFNL4, and TLR2) with COVID-19 disease susceptibility and severity to help predict prognosis. 150 adult COVID-19-assured cases were categorized as follows: 78 patients with a non-severe presentation, 39 patients with severe disease, and 33 critically ill patients. In addition, 74 healthy controls were included. Clinical and laboratory evaluations were carried out, including complete and differential blood counts, D-dimer, lactate dehydrogenase (LDH), C-reactive protein (CRP), procalcitonin, ferritin, interleukin-6 (Il-6), and liver and kidney functions. FURIN (rs6226), IFNL4 (rs12979860), and TLR2 (rs3804099) genotyping allelic discrimination assays were conducted using real-time PCR. The FURIN, IFNL4, and TLR2 genotypes and their alleles differed significantly between COVID-19 patients and controls, as well as between patients with severe or critical illness and those with a non-severe presentation. According to a multivariable regression analysis, FURIN (C/T + T/T) and TLR2 (T/C + C/C) mutants were associated with COVID-19 susceptibility, with odds ratios of 3.293 and 2.839, respectively. FURIN C/C and IFNL4 T/T mutants were significantly linked to severe and critical illnesses. Multivariate regression analysis showed that FURIN (G/C + C/C) genotypes and IFNL4 T/T homozygosity were independent risk factors associated with increased mortality. FURIN, IFNL4, and TLR2 gene variants are associated with the risk of COVID-19 occurrence as well as increased severity and poor outcomes in Egyptian patients.

Novel genetic association of the Furin gene polymorphism rs1981458 with COVID-19 severity among Indian populations

SARS CoV-2, the causative agent for the ongoing COVID-19 pandemic, it enters the host cell by activating the ACE2 receptor with the help of two proteasesi.e., Furin and TMPRSS2. Therefore, variations in these genes may account for differential susceptibility and severity between populations. Previous studies have shown that the role of ACE2 and TMPRSS2 gene variants in understanding COVID-19 susceptibility among Indian populations. Nevertheless, a knowledge gap exists concerning the COVID-19 susceptibility of Furin gene variants among diverse South Asian ethnic groups. Investigating the role of Furin gene variants and their global phylogeographic structure is essential to comprehensively understanding COVID-19 susceptibility in these populations. We have used 450 samples from diverse Indian states and performed linear regression to analyse the Furin gene variant's with COVID-19 Case Fatality Rate (CFR) that could be epidemiologically associated with disease severity outcomes. Associated genetic variants were further evaluated for their expression and regulatory potential through various Insilco analyses. Additionally, we examined the Furin gene using next-generation sequencing (NGS) data from 393 diverse global samples, with a particular emphasis on South Asia, to investigate its Phylogeographic structure among diverse world populations. We found a significant positive association for the SNP rs1981458 with COVID-19 CFR (p < 0.05) among diverse Indian populations at different timelines of the first and second waves. Further, QTL and other regulatory analyses showed various significant associations for positive regulatory roles of rs1981458 and Furin gene, mainly in Immune cells and virus infection process, highlighting their role in host immunity and viral assembly and processing. The Furin protein–protein interaction suggested that COVID-19 may contribute to Pulmonary arterial hypertension via a typical inflammation mechanism. The phylogeographic architecture of the Furin gene demonstrated a closer genetic affinity of South Asia with West Eurasian populations. Therefore, it is worth proposing that for the Furin gene, the COVID-19 susceptibility of South Asians will be more similar to the West Eurasian population. Our previous studies on the ACE2 and TMPRSS2 genes showed genetic affinity of South Asian with East Eurasians and West Eurasians, respectively. Therefore, with the collective information from these three important genes (ACE2, TMPRSS2 and Furin) we modelled COVID-19 susceptibilityof South Asia in between these two major ancestries with an inclination towards West Eurasia. In conclusion, this study, for the first time, concluded the role of rs1981458 in COVID-19 severity among the Indian population and outlined its regulatory potential.This study also highlights that the genetic structure for COVID-19 susceptibilityof South Asia is distinct, however, inclined to the West Eurasian population. We believe this insight may be utilised as a genetic biomarker to identify vulnerable populations, which might be directly relevant for developing policies and allocating resources more effectively during an epidemic.

Gα11 deficiency increases fibroblast growth factor 23 levels in a mouse model of familial hypocalciuric hypercalcemia.

Fibroblast growth factor 23 (FGF23) production has recently been shown to increase downstream of Gαq/11-PKC signaling in osteocytes. Inactivating mutations in the gene encoding Gα11 (GNA11) cause familial hypocalciuric hypercalcemia (FHH) due to impaired calcium-sensing receptor signaling. We explored the effect of Gα11 deficiency on FGF23 production in mice with heterozygous (Gna11+/-) or homozygous (Gna11-/-) ablation of Gna11. Both Gna11+/- and Gna11-/- mice demonstrated hypercalcemia and mildly raised parathyroid hormone levels, consistent with FHH. Strikingly, these mice also displayed increased serum levels of total and intact FGF23 and hypophosphatemia. Gna11-/- mice showed augmented Fgf23 mRNA levels in the liver and heart, but not in bone or bone marrow, and also showed evidence of systemic inflammation with elevated serum IL-1β levels. Furin gene expression was significantly increased in the Gna11-/- liver, suggesting enhanced FGF23 cleavage despite the observed rise in circulating intact FGF23 levels. Gna11-/- mice had normal renal function and reduced serum levels of glycerol-3-phosphate, excluding kidney injury as the primary cause of elevated intact FGF23 levels. Thus, Gα11 ablation caused systemic inflammation and excess serum FGF23 in mice, suggesting that patients with FHH - at least those with GNA11 mutations - may be at risk for these complications.

The impact of wound-healing assay, phorbol myristate acetate (PMA) stimulation and siRNA-mediated FURIN gene silencing on endogenous retroviral ERVW-1 expression level in U87-MG astrocytoma cells

PurposeHuman endogenous retroviruses (HERVs) are ubiquitous genomic sequences. Normally dormant HERVs, undergo reactivation by environmental factors. This deregulation of HERVs’ transcriptional equilibrium correlates with medical conditions such as multiple sclerosis (MS). Here we sought to explore whether exposing the U-87 MG astrocytoma cells to traumatic injury deregulates the expression of HERV-W family member ERVW-1 encoding syncytin-1. We also examined the expression of FURIN gene that is crucial in syncytin-1 synthesis. Material and methodsScratch assay was used as a model of cells injury in U-87 MG cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR), western blot (WB) and migration assay using Boyden chamber were used. Phorbol 12-myristate 13-acetate (PMA) and small interfering RNA (siRNA) were used for cell stimulation and gene expression inhibition, respectively. ResultsResults revealed reduced ERVW-1 expression in cells exposed to injury (p ​< ​0.05) while GFAP gene - a marker of active astrocytes, was upregulated (p ​< ​0.01). These findings were confirmed by both WB and RT-qPCR. Expression of FURIN gene was not altered after injury, but cell stimulation by PMA strongly increased FURIN expression, simultaneously downregulating ERVW-1 (p ​< ​0.01). SiRNA-mediated expression inhibition of ERVW-1 and FURIN influenced the mRNA level for SLC1A5 (ASCT2) - primary syncytin-1 receptor, that was significantly lower. FURIN inhibition by siRNA caused strong upregulation of ERVW-1 expression (p ​< ​0.01). ConclusionResults showed that mechanical impact affects the expression of endogenous retroviruses in U-87 MG astrocytoma cells by scratch assay. Regulation of FURIN, a crucial enzyme in ERVW-1 turnover may support the therapy of some neurological conditions.

The possible effects of COVID-19 on the human reproductive system

Spike surface glycoprotein and small envelope matrix-nucleocapsid proteins, is from the Coronaviridae family and binds to host receptors via spike surface proteins. Although it shows its symptoms especially on the respiratory tract, various studies have been carried out considering that it also affects other systems in the body. For the virus to enter the host cell, it must bind to ACE2 (angiotensin converting enzyme 2). ACE2 is a key protein involved in balancing Ang I and Ang II levels. With receptors such as TMPRSS2 (transmembrane serine protease 2), the effects of the virus on the human reproductive system are much better understood. Since human germ cells and early embryos express ACE2, there is a potential risk of the Coronavirus associated with germ cells. Studies show that the coronavirus changes the amount and density of hormones in the human reproductive system. The fact that most of the partners of 35 female patients who had SARS-CoV-2 in the studies were infected individuals suggests that sexual transmission may be possible. It was determined that TMPRSS4, Cathepsin B and L, FURIN, MX1 and BSG gene expressions were high in the menstrual cycle, while ACE 2 and TMPRSS2 were moderately expressed. It has been shown that the ACE2 enzyme is most intensely expressed is the testes. Studies have shown that sperm DNA (deoxyribonucleic acid) fragmentation, changes in hormone levels and the formation of anti-sperm antibodies are an important cause of male infertility. Infected men have been found to have an impaired spermatogenesis. This rewiew; it aims to draw attention to the possible effects of the corona virus on the human reproductive system and to reveal new mechanisms for new research to be done.

Expression of key SARS-CoV-2 entry molecules in surgically obtained human retinal biopsies.

To investigate the presence of ACE2, TMPRSS2 and Furin, i.e., a key player in the ocular infection with SARS-COV-2, in surgically obtained human retinal tissue samples from SARS-CoV-2-negative patients, using gene expression analysis. The mechanisms and entry paths of ocular infections have been ill-defined so far. To better understand the possible entry routes, we used surgically explanted retinal tissue from nine patients that were not infected with SARS-CoV-2 and analyzed the message expression of the three key molecules that confer viral entry into cells using polymerase chain reaction. The median age of the patients (n = 9) included in the study was 52years (IQR 48, 55). Eight patients underwent surgery for rhegmatogenous retinal detachment and one patient for tractional retinal detachment. Gene expression for the proteins studied was detected in all nine patients. The results of analysis by Livak's method (2001) demonstrated a median TMPRSS2 gene expression value of 20.9 (IQR 11.7, 33.7), a median ACE2 gene expression value of 2.09 (IQR 1.14, 2.79) and a median Furin gene expression value of 8.33 (IQR 5.90, 11.8). In conclusion, TMPRSS2, Furin and ACE2 are expressed in the retina and may contribute to the retinal involvement in COVID-19 patients. Expression may vary among individuals, which may explain why some patients may be more prone to retinal involvement during SARS-CoV-2 infection COVID-19 patients than others. Variability in the expression of TMPRSS2, Furin and ACE2 proteins themselves may also explain the presence or development of retinal symptoms of varying severity.

Identification of potential biomarkers for SLE through mRNA expression profiling

ABSTRACT Background: Systemic lupus erythematosus (SLE) is an autoimmune disease that influences numerous body systems. Furin, tristetraprolin (TTP), and NOD, LRR, and pyrin domain-containing protein 3 (NLRP3) contribute in developing autoimmune illnesses. Aim: Understandthe role of furin, TTP, and NLRP3 mRNA gene expression in SLE pathogenesis and prognosis. Methods: Total 210 individuals were enrolled, divided in two group: cases and control; 105 participants in each group. Real-time quantitative PCR for furin, TTP,and NLRP3 mRNA gene expression were determined for each subject. Results: SLE patients showed significantly higher serum furin [median 20.10 (0.0–162.88) in comparison with control group [median 1.10 (0.33–8.64)] with significant pvalue (p < 0.001), for NLRP3 expression [median 7.03 (0.0–282.97) compared to control group [median 1.0 (0.44–9.48)] with significant p value (p = 0.006)but lower TTP [median 2.37 (0.0–30.13)] in comparison with control group [median 7.90 (1.0–29.29)] with significant p value (p < 0.001) . Elevated levels of Furin and NLRP3 and low levels of TTP were linked to increased illness activity. Conclusion: Furin and NLRP increase in SLE and higher with illness activity. TTP is lowerin SLE and negatively correlates with disease activity.

1,25-Dihydroxyvitamin D3 regulates furin-mediated FGF23 cleavage.

Intact fibroblast growth factor 23 (iFGF23) is a phosphaturic hormone that is cleaved by furin into N-terminal and C-terminal fragments. Several studies have implicated vitamin D in regulating furin in infections. Thus, we investigated the effect of 1,25-dihydroxyvitamin D3 [1,25(OH)2D] and the vitamin D receptor (VDR) on furin-mediated iFGF23 cleavage. Mice lacking VDR (Vdr-/-) had a 25-fold increase in iFGF23 cleavage, with increased furin levels and activity compared with wild-type (WT) littermates. Inhibition of furin activity blocked the increase in iFGF23 cleavage in Vdr-/- animals and in a Vdr-knockdown osteocyte OCY454 cell line. Chromatin immunoprecipitation revealed VDR binding to DNA upstream of the Furin gene, with more transcription in the absence of VDR. In WT mice, furin inhibition reduced iFGF23 cleavage, increased iFGF23, and reduced serum phosphate levels. Similarly, 1,25(OH)2D reduced furin activity, decreased iFGF23 cleavage, and increased total FGF23. In a post hoc analysis of a randomized clinical trial, we found that ergocalciferol treatment, which increased serum 1,25(OH)2D, significantly decreased serum furin activity and iFGF23 cleavage, compared with placebo. Thus, 1,25(OH)2D inhibits iFGF23 cleavage via VDR-mediated suppression of Furin expression, thereby providing a mechanism by which vitamin D can augment phosphaturic iFGF23 levels.

Allele-Specific Epigenetic Regulation of FURIN Expression at a Coronary Artery Disease Susceptibility Locus.

Genome-wide association studies have revealed an association between the genetic variant rs17514846 in the FURIN gene and coronary artery disease. We investigated the mechanism through which rs17514846 modulates FURIN expression. An analysis of isogenic monocytic cell lines showed that the cells of the rs17514846 A/A genotype expressed higher levels of FURIN than cells of the C/C genotype. Pyrosequencing showed that the cytosine (in a CpG motif) at the rs17514846 position on the C allele was methylated. Treatment with the DNA methylation inhibitor 5-aza-2'-deoxycytidine increased FURIN expression. An electrophoretic mobility super-shift assay with a probe corresponding to the DNA sequence at and around the rs17514846 position of the C allele detected DNA-protein complex bands that were altered by an anti-MeCP2 antibody. A chromatin immunoprecipitation assay with the anti-MeCP2 antibody showed an enrichment of the DNA sequence containing the rs17514846 site. siRNA-mediated knockdown of MeCP2 caused an increase in FURIN expression. Furthermore, MeCP2 knockdown increased monocyte migration and proliferation, and this effect was diminished by a FURIN inhibitor. The results of our study suggest that DNA methylation inhibits FURIN expression and that the coronary artery disease-predisposing variant rs17514846 modulates FURIN expression and monocyte migration via an allele-specific effect on DNA methylation.

Interplay between Furin and Sialoglycans in Modulating Adeno-Associated Viral Cell Entry.

Adeno-associated viruses (AAVs) are small, helper-dependent, single-stranded DNA viruses that exploit a broad spectrum of host factors for cell entry. During the course of infection, several AAV serotypes have been shown to transit through the trans-Golgi network within the host cell. In the current study, we investigated whether the Golgi-localized, calcium-dependent protease furin influences AAV transduction. While CRISPR/Cas9-mediated knockout (KO) of the Furin gene minimally affected the transduction efficiency of most recombinant AAV serotypes tested, we observed a striking increase in transgene expression (~2 log orders) for the African green monkey isolate AAV4. Interrogation of different steps in the infectious pathway revealed that AAV4 binding, uptake, and transcript levels are increased in furin KO cells, but postentry steps such as uncoating or nuclear entry remain unaffected. Recombinant furin does not cleave AAV4 capsid proteins nor alter cellular expression levels of essential factors such as AAVR or GPR108. Interestingly, fluorescent lectin screening revealed a marked increase in 2,3-O-linked sialoglycan staining on the surface and perinuclear space of furin KO cells. The essential nature of increased sialoglycan expression in furin KO cells in enhancing AAV4 transduction was further corroborated by (i) increased transduction by the closely related isolates AAVrh.32.33 and sea lion AAV and (ii) selective blockade or removal of cellular 2,3-O-linked sialoglycans by specific lectins or neuraminidase, respectively. Based on the overall findings, we postulate that furin likely plays a key role in regulating expression of cellular sialoglycans, which in turn can influence permissivity to AAVs and possibly other viruses. IMPORTANCE Adeno-associated viruses (AAVs) are a proven recombinant vector platform for gene therapy and have demonstrated success in the clinic. Continuing to improve our knowledge of AAV-host cell interactions is critical for improving the safety and efficacy. The current study dissects the interplay between furin, a common intracellular protease, and certain cell surface sialoglycans that serve as viral attachment factors for cell entry. Based on the findings, we postulate that differential expression of furin in host cells and tissues is likely to influence gene expression by certain recombinant AAV serotypes.

Host Genetic Variants Linked to COVID-19 Neurological Complications and Susceptibility in Young Adults-A Preliminary Analysis.

To date, multiple efforts have been made to use genome-wide association studies (GWAS) to untangle the genetic basis for SARS-CoV-2 infection susceptibility and severe COVID-19. However, data on the genetic-related effects of SARS-CoV-2 infection on the presence of accompanying and long-term post-COVID-19 neurological symptoms in younger individuals remain absent. We aimed to examine the possible association between SNPs found in a GWAS of COVID-19 outcomes and three phenotypes: SARS-CoV-2 infection, neurological complications during disease progression, and long-term neurological complications in young adults with a mild-to-moderate disease course. University students (N = 336, age 18-25 years, European ancestry) with or without COVID-19 and neurological symptoms in anamnesis comprised the study sample. Logistic regression was performed with COVID-19-related phenotypes as outcomes, and the top 25 SNPs from GWAS meta-analyses and an MR study linking COVID-19 and cognitive deficits were found. We replicated previously reported associations of the FURIN and SLC6A20 gene variants (OR = 2.36, 95% CI 1.31-4.24) and OR = 1.94, 95% CI 1.08-3.49, respectively) and remaining neurological complications (OR = 2.12, 95% CI 1.10-4.35 for SLC6A20), while NR1H2 (OR = 2.99, 95% CI 1.39-6.69) and TMPRSS2 (OR = 2.03, 95% CI 1.19-3.50) SNPs were associated with neurological symptoms accompanying COVID-19. Our findings indicate that genetic variants related to a severe COVID-19 course in adults may contribute to the occurrence of neurological repercussions in individuals at a young age.

Proprotein Convertase Furin Regulates Melanogenesis via the Notch Signaling Pathway.

Furin is a calcium-dependent serine protease found in almost all mammals. It plays an important role in embryogenesis, tissue homeostasis, tumors pathogenesis, viral infectious diseases, and neurodegenerative diseases. However, whether furin directly regulates melanin synthesis and transport has rarely been evaluated yet. The present study aimed to investigate furin potential function and mechanisms in melanogenesis. Short hairpin RNAs targeting furin gene (sh-furin RNAs) were used to inhibit furin gene expression in human melanoma cell line MNT-1 cells. Then, intracellular melanin content was measured using a sodium hydroxide method. Extracellular melanin content was measured determining cell culture medium absorbance at 450 nm. Levodopa (L-DOPA) oxidation rate was measured to assess the tyrosinase activity. Quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting (WB) were performed to measure melanogenesis-related genes and Notch pathway-related genes expression levels. Human primary melanocytes (MCs) were extracted from foreskin tissues and were stimulated with a furin inhibitor. Then, the extracellular and intracellular melanin content, tyrosinase activity and molecules related to melanogenesis and the Notch pathway expression were measured in MCs with or without a furin inhibitor. Additionally, morpholino technology was used to inhibit furin in zebrafish. Zebrafish pigmentary phenotypes in the control group and furin inhibition group were observed with a stereo microscope. Then, MCs number in the tail and head of the zebrafish were counted using Image J software (version 1.53t, National Institute of Health, Bethesda, MD, USA). Meanwhile, melanin content, tyrosinase activity, and molecules related to melanogenesis and the Notch pathway expression levels were measured. Subsequently, valproic acid (VPA), a Notch pathway agonist, was used in MNT-1 melanoma cells treated with or without sh-furin lentiviral vectors for rescue experiments. Furin inhibition enhanced intracellular and extracellular melanin content, and cellular tyrosinase activity in MNT-1 cells and MCs. Additionally, furin inhibition increased melanin synthesis-associated and transport-associated proteins expression levels while inhibiting Notch pathway-relevant proteins. After using VPA to activate the Notch pathway in MNT-1 cells transfected with a sh-furin RNA, the biological effects resulting from furin knockdown were reversed. In addition, the results of in vivo experiments using morpholino to knock down furin gene in zebrafish further confirmed that furin knockdown regulated melanogenesis and impaired the Notch pathway. This study clarified that furin affected the synthesis and transport of melanin via Notch pathway. Notch pathway may be a potential therapeutic target for pigmented skin diseases.

Loss of the Schizophrenia-Linked Furin Protein from Drosophila Mushroom Body Neurons Results in Antipsychotic-Reversible Habituation Deficits.

Habituation is a conserved adaptive process essential for incoming information assessment, which drives the behavioral response decrement to recurrent inconsequential stimuli and does not involve sensory adaptation or fatigue. Although the molecular mechanisms underlying the process are not well understood, habituation has been reported to be defective in a number of disorders including schizophrenia. We demonstrate that loss of furin1, the Drosophila homolog of a gene whose transcriptional downregulation has been linked to schizophrenia, results in defective habituation to recurrent footshocks in mixed sex populations. The deficit is reversible by transgenic expression of the Drosophila or human Furin in adult α'/β' mushroom body neurons and by acute oral delivery of the typical antipsychotic haloperidol and the atypical clozapine, which are commonly used to treat schizophrenic patients. The results validate the proposed contribution of Furin downregulation in schizophrenia and suggest that defective footshock habituation is a Drosophila protophenotype of the human disorder.SIGNIFICANCE STATEMENT Genome-wide association studies have revealed a number of loci linked to schizophrenia, but most have not been verified experimentally in a relevant behavioral task. Habituation deficits constitute a schizophrenia endophenotype. Drosophila with attenuated expression of the schizophrenia-linked highly conserved Furin gene present delayed habituation reversible with acute exposure to antipsychotics. This strongly suggests that footshock habituation defects constitute a schizophrenia protophenotype in Drosophila Furthermore, determination of the neurons whose regulated activity is required for footshock habituation provides a facile metazoan system to expediently validate putative schizophrenia genes and variants in a well understood simple brain.

FURIN gene variants (rs6224/rs4702) as potential markers of death and cardiovascular traits in severe COVID-19.

Furin is a protease that plays a key role in the infection cycle of SARS‐CoV‐2 by cleaving the viral proteins during the virus particle assembly. In addition, Furin regulates several physiological processes related to cardio‐metabolic traits. DNA variants in the FURIN gene are candidates to regulate the risk of developing these traits as well as the susceptibility to severe COVID‐19. We genotyped two functional FURIN variants (rs6224/rs4702) in 428 COVID‐19 patients in the intensive care unit. The association with death (N = 106) and hypertension, diabetes, and hyperlipidaemia was statistically evaluated. The risk of death was associated with age, hypertension, and hypercholesterolemia. The two FURIN alleles linked to higher expression (rs6224 T and rs4702 A) were significantly increased in the death cases (odds ratio= 1.40 and 1.43). Homozygosis for the two high expression genotypes (rs6224 TT and rs4702 AA) and for the T‐A haplotype was associated with an increased risk of hypercholesterolemia. In the multiple logistic regression both, hypercholesterolemia and the TT + AA genotype were significantly associated with death. In conclusion, besides its association with hypercholesterolemia, FURIN variants might be independent risk factors for the risk of death among COVID‐19 patients.

Attachment Style Moderates Polygenic Risk for Incident Posttraumatic Stress in U.S. Military Veterans: A 7-Year, Nationally Representative, Prospective Cohort Study

BackgroundPosttraumatic stress disorder (PTSD) develops consequent to complex gene-by-environment interactions beyond the precipitating trauma. To date, however, no known study has used a prospective design to examine how polygenic risk scores (PRSs) interact with social-environmental factors such as attachment style to predict PTSD development. MethodsPRSs were derived from a genome-wide association study of PTSD symptoms (N = 186,689; Million Veteran Program cohort). We evaluated combined effects of PRS and attachment style in predicting incident PTSD in a 7-year, nationally representative cohort of trauma-exposed, European-American U.S. military veterans without PTSD (N = 1083). We also conducted multivariate gene-by-environment interaction and drug repositioning analyses to identify loci that interact with multiple environmental factors and potential pharmacotherapies that may be repurposed for this disorder. ResultsVeterans with higher PTSD PRS were more likely to have an incident-positive screen for PTSD over 7 years. A gene-by-environment interaction was also observed, such that higher PRS only predicted incident PTSD in veterans with an insecure attachment style and not those with a secure attachment style. At an individual locus level, the strongest gene-by-environment interaction was observed for the rs4702 variant of the FURIN gene with cumulative lifetime trauma burden. Drug repositioning revealed that genes implicated in PRS are perturbated by the drug doxylamine. ConclusionsAttachment style moderates polygenic risk for the development of PTSD in European-American veterans. These findings may inform PTSD prevention and treatment for veterans with high polygenic risk for PTSD and suggest a potential pharmacotherapeutic target for risk genes moderated by social-environmental factors.

Novel loci and potential mechanisms of major depressive disorder, bipolar disorder, and schizophrenia.

Different psychiatric disorders share genetic relationships and pleiotropic loci to certain extent. We integrated and analyzed datasets related to major depressive disorder (MDD), bipolar disorder (BIP), and schizophrenia (SCZ) from the Psychiatric Genomics Consortium using multitrait analysis of genome-wide association analysis (MTAG). MTAG significantly increased the effective sample size from 99,773 to 119,754 for MDD, from 909,061 to 1,450,972 for BIP, and from 856,677 to 940,613 for SCZ. We discovered 7, 32, and 43 novel lead single nucleotide polymorphisms (SNPs) and 1, 6, and 3 novel causal SNPs for MDD, BIP, and SCZ, respectively, after fine-mapping. We identified rs8039305 in the FURIN gene as a novel pleiotropic locus across the three disorders. We performed marker analysis of genomic annotation (MAGMA) and Hi-C-coupled MAGMA (H-MAGMA) based gene-set analysis and identified 101 genes associated with the three disorders, which were enriched in the regulation of postsynaptic membranes, postsynaptic membrane dopaminergic synapses, and Notch signaling pathway. Next, we performed Mendelian randomization analysis using different tools and detected a causal effect of BIP on SCZ. Overall, we demonstrated the usage of combined genome-wide association studies summary statistics for exploring potential novel mechanisms of the three psychiatric disorders, providing an alternative approach to integrate publicly available summary data.

Identification of Novel Genetic Regulatory Region for Proprotein Convertase FURIN and Interferon Gamma in T Cells.

The proprotein convertase enzyme FURIN promotes the proteolytic maturation of pro-proteins and thereby it serves as an important factor for maintaining cellular homeostasis. In T cells, FURIN is critical for maintaining the T regulatory cell dependent peripheral immune tolerance and intact T helper cell polarization. The enzymatic activity of FURIN is directly associated with its expression levels, but genetic determinants for cell-type specific Furin gene regulation have remained elusive. By exploring the histone acetyltransferase p300 binding patterns in T helper cells, a putative regulatory region at ca. 20kB upstream of Furin gene was identified. When this region was deleted with CRISPR/Cas9 the production of Furin mRNA was significantly reduced in activated mouse T cells. Genome-wide RNA profiling by sequencing revealed that the novel Furin regulator region also impacted the expression of several genes that have previously been associated with the Th1 type hall mark cytokine IFNγ regulation or function. Finally, Furin genetic regulatory region was found to specifically promote the secretion of IFNγ by activated T cells. In sum, our data unravels the presence of Furin expression regulatory region in T cells that has characteristics of a super-enhancer for Th1 cell fate.

Atopy is predictive of a decreased need for hospitalization for coronavirus disease 2019

Atopy is predictive of a decreased need for hospitalization for coronavirus disease 2019