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| COVID-19 research v1.52 | IFNG |
Sarah Leigh changed review comment from: IFNG was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). "Illumina review: From OMIM: Interferon-gamma (IFNG), or type II interferon, is a cytokine critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumor control. The importance of IFNG in the immune system stems in part from its ability to inhibit viral replication directly, but most importantly derives from its immunostimulatory and immunomodulatory effects. IFNG is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 (186940) and CD8 (see 186910) cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops (PMID: 178981204; Schoenborn and Wilson, 2007). From OMIM: PMID: 17215375: Huang et al. (2007) The IFNG gene SNP, -764 C>G (rs2069707) in the proximal promoter region next to the binding motif for HSF1 , was significantly associated with sustained virologic response to IFNA therapy in a cohort of hepatitis C virus-positive patients compared to a cohorts who had spontaneously cleared HCV infection or who had chronic HCV infection. Luciferase reporter and EMSA analyses showed that the -764G allele had 2- to 3-fold higher promoter activity and stronger binding affinity for HSF1 than the -764C allele. Huang et al. (2007) concluded that the -764C-G SNP is functionally important in determining viral clearance and treatment response in HCV-infected patients. From OMIM PMID: 12854077: An et al. (2003) reported an association between a SNP in the IFNG promoter region, -173 G>T, and progression to AIDS. In individuals with the rare -179T allele, but not in those with the -179G allele, IFNG is inducible by TNF. An et al. (2003) studied 298 African American HIV-1 seroconverters and found that the -179T allele was associated with accelerated progression to a CD4 cell count below 200 and to AIDS. They noted that the SNP is present in 4% of African Americans and in only 0.02% of European Americans. PMID: 26458193 Wei et al. (2017) Eleven independent case-control studies were selected for the meta-analysis, comprising a total of 1527 HBV cases and 1467 healthy subjects. carriers of the IFN-γ A allele were more likely to develop HBV infection than those without in all five genetic models (all p < 0.05). According to the ethnicity-based sub-group analysis, a significant difference of the IFN-γ rs2430561 T > A (IFN-γ +874T/A) polymorphism was detected associated with the increased risk of HBV infection in Asians and European-derived populations in the majority of the groups. ; to: IFNG was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: From OMIM: Interferon-gamma (IFNG), or type II interferon, is a cytokine critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumor control. The importance of IFNG in the immune system stems in part from its ability to inhibit viral replication directly, but most importantly derives from its immunostimulatory and immunomodulatory effects. IFNG is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 (186940) and CD8 (see 186910) cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops (PMID: 17981204; Schoenborn and Wilson, 2007). From OMIM: PMID: 17215375: Huang et al. (2007) The IFNG gene SNP, -764 C>G (rs2069707) in the proximal promoter region next to the binding motif for HSF1 , was significantly associated with sustained virologic response to IFNA therapy in a cohort of hepatitis C virus-positive patients compared to a cohorts who had spontaneously cleared HCV infection or who had chronic HCV infection. Luciferase reporter and EMSA analyses showed that the -764G allele had 2- to 3-fold higher promoter activity and stronger binding affinity for HSF1 than the -764C allele. Huang et al. (2007) concluded that the -764C-G SNP is functionally important in determining viral clearance and treatment response in HCV-infected patients. From OMIM PMID: 12854077: An et al. (2003) reported an association between a SNP in the IFNG promoter region, -173 G>T, and progression to AIDS. In individuals with the rare -179T allele, but not in those with the -179G allele, IFNG is inducible by TNF. An et al. (2003) studied 298 African American HIV-1 seroconverters and found that the -179T allele was associated with accelerated progression to a CD4 cell count below 200 and to AIDS. They noted that the SNP is present in 4% of African Americans and in only 0.02% of European Americans. PMID: 26458193 Wei et al. (2017) Eleven independent case-control studies were selected for the meta-analysis, comprising a total of 1527 HBV cases and 1467 healthy subjects. carriers of the IFN-γ A allele were more likely to develop HBV infection than those without in all five genetic models (all p < 0.05). According to the ethnicity-based sub-group analysis, a significant difference of the IFN-γ rs2430561 T > A (IFN-γ +874T/A) polymorphism was detected associated with the increased risk of HBV infection in Asians and European-derived populations in the majority of the groups. |
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| COVID-19 research v1.35 | IL7 |
Sarah Leigh changed review comment from: IL7 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility); to: IL7 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 1 grouping (clear GDA/viral susceptibility). Illumina review: PMID 25981006 – Horev et al. (2015) reported three cases from one consanguineous Arab family characterized by severe CD41T-cell lymphopenia, generalized verrucosis due to HPV infections, predisposition to opportunistic C. neoformans meningitis, and recurrent squamous cell carcinomas of the skin in sun-exposed areas. Whole exome sequencing analysis of one case (patient 3) identified a homozygous variant in the IL 7 gene, c.205A>T ( p.Arg69Ter). PMID: 31900472 Kosumi et al. (2020) reported two generalized verrucosis (GV) patients homozygous for a novel mutation in the start codon of IL7. IL-7 deficiency was not accompanied CD4 T lymphocytopenia, circulating CD4 T-cells were not depleted in one of the patients, suggesting a GV pathogenesis other than poor T-cell development. |
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| COVID-19 research v1.30 | IFNG |
Sarah Leigh changed review comment from: IFNG was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: IFNG was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). "Illumina review: From OMIM: Interferon-gamma (IFNG), or type II interferon, is a cytokine critical for innate and adaptive immunity against viral and intracellular bacterial infections and for tumor control. The importance of IFNG in the immune system stems in part from its ability to inhibit viral replication directly, but most importantly derives from its immunostimulatory and immunomodulatory effects. IFNG is produced predominantly by natural killer (NK) and natural killer T (NKT) cells as part of the innate immune response, and by CD4 (186940) and CD8 (see 186910) cytotoxic T lymphocyte (CTL) effector T cells once antigen-specific immunity develops (PMID: 178981204; Schoenborn and Wilson, 2007). From OMIM: PMID: 17215375: Huang et al. (2007) The IFNG gene SNP, -764 C>G (rs2069707) in the proximal promoter region next to the binding motif for HSF1 , was significantly associated with sustained virologic response to IFNA therapy in a cohort of hepatitis C virus-positive patients compared to a cohorts who had spontaneously cleared HCV infection or who had chronic HCV infection. Luciferase reporter and EMSA analyses showed that the -764G allele had 2- to 3-fold higher promoter activity and stronger binding affinity for HSF1 than the -764C allele. Huang et al. (2007) concluded that the -764C-G SNP is functionally important in determining viral clearance and treatment response in HCV-infected patients. From OMIM PMID: 12854077: An et al. (2003) reported an association between a SNP in the IFNG promoter region, -173 G>T, and progression to AIDS. In individuals with the rare -179T allele, but not in those with the -179G allele, IFNG is inducible by TNF. An et al. (2003) studied 298 African American HIV-1 seroconverters and found that the -179T allele was associated with accelerated progression to a CD4 cell count below 200 and to AIDS. They noted that the SNP is present in 4% of African Americans and in only 0.02% of European Americans. PMID: 26458193 Wei et al. (2017) Eleven independent case-control studies were selected for the meta-analysis, comprising a total of 1527 HBV cases and 1467 healthy subjects. carriers of the IFN-γ A allele were more likely to develop HBV infection than those without in all five genetic models (all p < 0.05). According to the ethnicity-based sub-group analysis, a significant difference of the IFN-γ rs2430561 T > A (IFN-γ +874T/A) polymorphism was detected associated with the increased risk of HBV infection in Asians and European-derived populations in the majority of the groups. |
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| COVID-19 research v1.21 | CX3CR1 |
Sarah Leigh changed review comment from: CX3CR1 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility); to: CX3CR1 was identified through an OMIM search for potential viral susceptibility genes. Initial triage by Illumina (Alison Coffey and team) was given a Tier 3 grouping (experimental evidence and association data consistent with viral susceptibility). Illumina review: Receptor for the CX3C chemokine fractalkine (CX3CL1); binds to CX3CL1 and mediates both its adhesive and migratory functions. Acts as coreceptor with CD4 for HIV-1 virus envelope protein (in vitro) (PMID:9726990). Associated with rapid progression to AIDS from HIV1 infection. PMID:14607932: Garin et al. (2003) - identified two novel isoforms of the human chemokine receptor CX3CR1, produced by alternative splicing that appear to be more potent HIV coreceptors. PMID:10731151: Faure et al. (2000) - CX3CR1 is an HIV coreceptor as well as a leukocyte chemotactic/adhesion receptor for fractalkine. Faure et al. (2000) identified 2 single nucleotide polymorphisms in the CX3CR1 gene in Caucasians and demonstrated that HIV-infected patients homozygous for I249/M280 progressed to AIDS more rapidly than those with other haplotypes (relative risk = 2.13, P = 0.039). Functional CX3CR1 analysis showed that fractalkine binding is reduced among patients homozygous for this particular haplotype. Concluded that CX3CR1-I249/M280 is a recessive genetic risk factor for HIV/AIDS. PMID 28228284: Zhivaki et al. (2017) - Upregulated in RSV infection affecting severity of infection. Respiratory syncytial virus (RSV) is the major cause of lower respiratory tract infections in infants and is characterized by pulmonary infiltration of B cells in fatal cases. Identified a population of neonatal regulatory B lymphocytes (nBreg cells) that produced interleukin 10 (IL-10) in response to RSV infection. The polyreactive B cell receptor of nBreg cells interacted with RSV protein F and induced upregulation of chemokine receptor CX3CR1. CX3CR1 interacted with RSV glycoprotein G, leading to nBreg cell infection and IL-10 production that dampened T helper 1 (Th1) cytokine production. In the respiratory tract of neonates with severe RSV-induced acute bronchiolitis, RSV-infected nBreg cell frequencies correlated with increased viral load and decreased blood memory Th1 cell frequencies. Thus, the frequency of nBreg cells is predictive of the severity of acute bronchiolitis disease and nBreg cell activity may constitute an early-life host response that favors microbial pathogenesis. PMID unavailable: Strickland et al. (2020) - Pulmonary infection with C. neoformans (opportunistic fungal pathogen and leading cause of death in HIV-affected inividuals) enhanced CX3CR1 expression in the lung. Following infection, mice lacking CX3CR1 had significantly higher pulmonary fungal burdens, as well as decreased survival times compared to wild type mice. These infected CX3CR1 knockout mice also displayed higher expression of pro-inflammatory cytokines including MIP-2, MCP-1 and CCL7, but lower expression of anti-inflammatory cytokines such as IL-10. CX3CR1 deficiency resulted in mice having dramatically enhanced neutrophil accumulation in the lungs following infection.Depletion of neutrophils drastically improved lung CFU in infected knockout mice, indicating that excessive inflammation drove fungal growth. These data indicate that CX3CR1 expression is essential for host resistance to pulmonary cryptococcal infection by inhibiting excessive lung inflammation. |
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| COVID-19 research v0.348 | KLF2 |
Rebecca Foulger commented on gene: KLF2: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): KLF2 is a member of the Kruppel-like factor (KLF) family of zinc finger transcription factors that function in cell differentiation, quiescence, and homeostasis. It also plays a regulatory role in inflammation-related pathways (Jha and Das 2017). Richardson et al. (2012) showed that KLF2 acts as a host factor that modulates CCR5 expression in CD4 T cells and influences susceptibility to infection with CCR5-dependent HIV-1 strains. Huang et al. (2017) showed through both network analyses and experimental results that KLF2 plays a central role in regulating many genes associated with acute respiratory distress syndrome (ARDS) identified by GWAS and that overexpression of KLF2 in vivo in mice could mitigate lung injury and expression of inflammatory genes, including that induced by influenza A virus. PMID 17141159: Lee et al. (2006) - KLF2 deficient mice die in prenatal stage due to vascular defects, highlighting its crucial role in embryonic development. Lethal high-output heart failure, as found in the KO mice, was also observed in zebrafish embryos after morpholino inhibition of the Klf2 ortholog klf2a. CD4+ T cells from KLF2-deficient mice expressed multiple inflammatory chemokine receptors, suggesting that loss of KLF2 leads to redirection of naïve T cells to nonlymphoid sites (Sebzda et al., 2008). PMID 19592277: Weinreich et al. (2009) - Demonstrated upregulation of the chemokine receptor CXCR3 on KLF2-deficient T cells (Fig. 1). KLF2-deficient T cells also overproduced IL-4 (Fig. 5). PMID 22988032: Richardson et al. (2012) - Tested whether the abundance of KLF2 after T cell activation regulates CCR5 expression and, thus, susceptibility of a T cell to CCR5-dependent HIV-1 strains (R5). Introduced small interfering RNA targeting KLF2 expression and demonstrated that reduced KLF2 expression also resulted in less CCR5 (Fig. 3). Introduction of KLF2 under control of a heterologous promoter could restore CCR5 expression and R5 susceptibility to CD3/28 costimulated T cells and some transformed cell lines (Fig. 5, 6). KLF2 is a host factor that modulates CCR5 expression in CD4 T cells and influences susceptibility to R5 infection. PMID 29125549: (review) Jha and Das (2017) - KLF2 also plays a critical regulatory role in various inflammatory diseases and their pathogenesis. PMID 27855271: Huang et al. (2017) - Animal and in vitro models of acute lung injury were used to characterize KLF2 expression and its downstream effects responding to influenza A virus (A/WSN/33 [H1N1]), tumor necrosis factor-α, LPS, mechanical stretch/ventilation, or microvascular flow to examine the role of the gene in endothelial barrier disruption and cytokine storm in experimental lung injury. Pulmonary Klf2 was down-regulated by inflammation induced by influenza A/WSN/H1N1 virus (H1N1) infection, LPS administration, or LPS administration followed by high tidal volume ventilation in vivo (Fig. 1). It was also down-regulated by pathologic stretch and inflammatory stimuli (Fig. 2). Knockdown of endogenous KLF2 reduces Rac1 activation in human pulmonary microvascular cells, whereas adenovirus-mediated transduction with KLF2 promoted Rac1 activation (Fig. 3). Computational predictive pathway analysis suggested that KLF2 acts to regulate ARDS-associated GWAS genes, including ACE, NAD(P)H, NQO1, SERPINE1/PAI-1, TNF, and NF-kappaB. Expression studies in mice confirmed this regulatory role (Fig. 8). Overexpression of KLF2 in vivo in mice could also mitigate lung injury and expression of inflammatory genes (Fig. 7). |
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| COVID-19 research v0.348 | DICER1 |
Rebecca Foulger changed review comment from: Evidence Summary from Illumina curation team: The DICER1 gene, located on chromosome 14, position q32.13, was discovered in 2001 by Bernstein and is a member of the RNase III family, (also known as dicer 1, ribonuclease III; dicer1, Dcr-1 homolog (Drosophila); multinodular goitre 1). DICER1 is involved in the generation of double-stranded microRNAs (miRNAs), short non-coding RNAs, the cleavage of dsRNA into siRNAs, along with the biogenesis of numerous other small RNAs. There is increasing evidence DICER1 is also involved in regulating many other essential cellular processes such as those related to chromatin remodeling, inflammation, apoptosis and cell survival (Kurzynska-Kokorniak et al. 2015; Song and Rossi, 2017). DICER1 encodes a ∼220-KDa protein (RNase III endoribonuclease) which is a crucial component of the RNA Induced Silencing Complex (RISC) loading complex (RLC), comprised of dicer, Argonaute-2 (AGO-2), and trans-activation-responsive RNA binding protein 2 (TARBP2). The encoded protein is required by the RNA interference (RNAi) and small temporal RNA (stRNA) pathways to produce the active small RNA component which has a role in modulating gene expression at the post-transcriptional level. Research has shown that expression levels of cellular transcript and protein dicer are strictly controlled, with aberrant regulation contributing to carcinogenesis, neurodegenerative, rheumatic and immune system disorders. Studies have concluded that the encoded dicer ribonuclease-dependent processing of dsRNA viral replication intermediates into successive siRNAs is a conserved mammalian immune response to infection by positive-strand RNA viruses (Svobodova et al. 2016 summary & fig1; Li et al. 2013; Ding et al. 2018). Moreover, miRNAs play an important role in host-virus interactions in mammals (See Maillard et al. 2019 REVIEW; Foulkes et al. 2014 REVIEW). IMMUNE SYSTEM The cre-lox method for dicer1 gene knockout has been employed for studies into the role of dicer1 in immune cell development and function. Studies of dicer1 fl/fl mice have indicated short survival times along with severely impaired GMP differentiation into monocytes, neutrophils, myeloid DCs & mature macrophages. (Devasthanam et al. 2014). Results conclude that dicer1 is important in immune response and also vital for cell survival and apoptosis pathways. Muljo et al. (2005) investigated a conditional allele of dicer-1 (dcr-1) within a mouse model and showed that specific dcr-1 deletion in the T-cell lineage, resulted in impaired development of T-cells & aberrant cell differentiation of T-helper cells & cytokine production. Dcr-1 deletion in the thymus resulted in severe block in development of CD8+ T cells and resulted in defective microRNA processing in CD4+ T-cells. The results demonstrate Dicer regulates diverse aspects of T-cell biology along with cytokine production during T-cell differentiation where dicer-deficient T-cells preferentially express interferon-ƴ. VIRUSES Research by Galiana-Arnoux et al. (2006), of DICER in drosophila (drosophila have two dicer genes) have identified that DICER genes (Dcr1, miRNA pathway and Dcr2, RNAi pathway) control production of siRNA and a loss-of-function mutation in Dcr2 resulted in increased susceptibility to three different families of RNA viruses. Qi et al. (2012) research into RNAi gene silencing mechanism show that the B2 protein in Wuhan nodavirus (WhNV) suppresses Dcr2 in drosophila by direct interaction with the PAZ and RNAse III domains therefore blocking processing of dsRNA and siRNA. Evidence of a dicer antiviral system was also reported by Machitani et al. (2016) for mammalian human adenoviruses where DICER1 gene knockdown increased the copy number of adenovirus-encoding small RNAs (VA-RNAs) leading to the promotion of adenovirus replication; conversely, dicer overexpression significantly inhibited viral replication. Modai et al. (2019) conclude that HIV-1 infection inhibits DICER1 by altering miRNA expression. They conclude that upon HIV-1 infection, human miR-186, 210 and 222 directly regulate DICER1 gene expression causing down-regulation of the gene contributing to impaired cell-mediated immunity (fig6). Other methods of inhibition are from viral proteins, termed viral suppressors of RNA silencing, which interact and inhibit dicer ribonuclease activity in HIV-1 and hepatitis C infections. These viral proteins may mediate proteasomal degradation of endoribonuclease dicer through CRL4DCAF1 ubiquitin ligase complex (Klockow et al. 2013), interact directly via the core protein (Chen et al. 2008) or HIV-1 transactivation of transcription (Bennasser and Jeang, 2006). Through these methods they can block dicer interactions with TRBP2 or ADAR1, boost macrophage infection, and subsequently reduce the function of short hairpin RNAs (shRNAs) which thus inhibit RNA silencing. Ultimately these viruses, though various methods, supress the ability of dicer to process dsRNAs into siRNAs boosting viral infection and pathogenesis. Downregulation of DICER1 gene expression has additionally been found in cord blood of infants with severe respiratory syncytial virus (RSV), prior to RSV exposure, indicating this reduced expression may predispose newborns to RSV disease. Inchley et al. (2011) theorize that this occurs via disruption of leukocyte gene regulation of miRNA and direct anti-viral RNAi mechanisms. (Inchley et al. 2011 see section on “Dicer Gene Expression”). Otsuka et al. (2007) have shown using gene-trap methods to obtain viable dicer1 fl/fl mice where dicer1 deficiency caused impairment of miR24 and miR93 production resulting in susceptibility to vesticular stomatitis virus (VSV) and herpes simplex-1 virus, but not other viruses tested. SARS CoV & SARS CoV-2 Recently, Pasquier and Robichon, 2020 (preprint) have investigated the Dicer host immunity system regarding SARs-CoV-2 within a computational approach, concluding SARS-CoV2 may manipulate this system of immunity against its host, requiring further research. Mu et al., 2020 suggest SARs-CoV2 suppresses RNAi thus preventing recognition by the encoded ribonuclease dicer protein Viral suppressors of RNA silencing (VSRs) suppress RNAi at pre or post-dicer level to overcome host defense and establish infection. Cui et al. (2015) from Wuhan University laboratory of virology, identified a novel VSR from coronaviruses (CoVs) including Severe acute respiratory syndrome coronavirus (SARS-CoV) and showed that the coronavirus nucelocaspid protein (N-protein), conserved and expressed in all coronaviruses, suppressed RNAi triggered by either short hairpin RNAs or small interfering RNAs in mammalian cells. They went on to show using mouse hepatitis virus A-59 (MHV-A59) which is closely linked to SARS-CoV in the family coronaviridae, that the viral replication was increased when the N proteins (novel VSR) were expressed but that knockdown of DICER1 gene or Ago2 transcripts facilitated the viral replication specifically in mammalian cells. They demonstrate that the N-protein of CoVs could efficiently inhibit dicer-mediated dsRNA cleavage and post-Dicer activities by sequestering dsRNAs and siRNAs. Kannan et al. (2020) performed clustal W analysis of N-Protein for SARS-CoV and COVID-19 demonstrating 90% sequence identity from an NCBI amino acid blast of both nucleocapsid (N) protein sequences (figure2). They suggest that the N-protein of COVID-19 may also function as a VSR for RNAi to overcome host defense. Ding et al. (2017) show that both MHV and SARS-CoV N proteins can also disrupt protein activator of protein kinase R (PACT), a cellular dsRNA-binding protein which binds to RIG-I and MDA5 to activate interferon (IFN) production to prevent antiviral host response. Literature Review PMID: 17181864: Bennasser and Jeang, 2006 • HIV-1 Tat Interaction With Dicer: Requirement for RNA • Tat-Dicer interaction depends on RNA, requires the helicase domain of Dicer, and is independent of Tat's transactivation domain. PMID: 18325616: Chen et al., 2008 • HCV Core Protein Interacts With Dicer to Antagonize RNA Silencing PMID: 26085159: Cui et al., 2015 • The Nucleocapsid Protein of Coronaviruses Acts as a Viral Suppressor of RNA Silencing in Mammalian Cells PMID: 24303839: Devasthanam et al, 2014 • This study investigates the role of the dicer protein in immune cell development and function using dicer1 cre-lox knockout models to conditionally ablate dicer1 in different immune cell subsets. PMID: 28591694: Ding et al., 2017 • The nucleocapsid proteins of mouse hepatitis virus and severe acute respiratory syndrome coronavirus share the same IFN-β antagonizing mechanism: attenuation of PACT-mediated RIG-I/MDA5 activation PMID: 30015086: Ding et al., 2018 • Antiviral RNA Interference in Mammals: Indicates infection of plants and insects with RNA and DNA viruses triggers Dicer-dependent production of virus-derived small interfering RNAs (vsiRNAs), which subsequently guide specific virus clearance by RNA interference (RNAi). PMID: 25176334: Foulkes et al., 2012-REVIEW • Review of DICER1: DICER1 Mutations, microRNAs and Mechanisms PMID: 16554838: Galiana-Arnoux et al., 2006 • Essential function in vivo for Dicer-2 in host defense against RNA viruses in drosophila. • https://pubmed.ncbi.nlm.nih.gov/16554838/ or https://www.nature.com/articles/ni1335 PMID: 21385408: Inchley et al., 2011 • Investigates ribonuclease Dicer and analyzed the gene expression of Dicer in newborns of which 37 infants had sufficient cord blood RNA with confirmed RSV disease <1yr. Demonstrates significant reduced Dicer expression in cord blood prior to severe disease in infants <1yr later. Conclude downregulation may predispose infants to RSV disease. PMID: 32141569: Kannan et al., 2020 • COVID-19 (Novel Coronavirus 2019) - Recent Trends • Perform W cluster analysis of COVID-19 and SARS-CoV nucleocapsid (N) protein sequences of the viruses showing 90% amino acid sequence similarity. Suggest the N-protein may be a VSR in RNAi by targeting DICER. PMID: 23849790: Klockow et al., 2013 • The HIV-1 Protein Vpr Targets the Endoribonuclease Dicer for Proteasomal Degradation to Boost Macrophage Infection PMID: 25883138: Kurzynska-Kokorniak et al., 2015 • Investigating the complexity of the mechanisms regulating Dicer gene expression and enzyme activities PMID: 24115437: Li et al, 2013 • Investigates RNA interference pathways in antiviral immunity in mammals overviewing dicer processing of dsRNA viral replication intermediates into siRNAs. PMID: 27273616: Machitani et al., 2016 • Dicer functions as an antiviral system against human adenoviruses via cleavage of adenovirus-encoded noncoding RNA PMID: 30872283: Maillard et al., 2019- REVIEW • Reviewing DICER1 within the anti-viral RNAi pathway in mammals PMID: 30682089: Modai et al, 2019 • HIV-1 infection increases miRNAs which inhibit Dicer PMID: 32291557: Mu et al, 2020 • SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells PMID: 16009718: Muljo et al., 2005 • Indicates absence of dicer results in abberant T-cell differentiation. PMID: 17613256: Otsuka, et al 2007 • Hypersusceptibility to Vesicular Stomatitis Virus Infection in Dicer1-Deficient Mice Is Due to Impaired miR24 and miR93 Expression No PMID: Preprint : Pasquier and Rubichon, 2020 • SARS-CoV-2 might manipulate against its host the immunity RNAi/Dicer/Ago system PMID: 22438534: Qi et al., 2012 • Targeting of Dicer-2 and RNA by a Viral RNA Silencing Suppressor in Drosophila Cells PMID: 28473628: Song and Rossi, 2017 • Molecular Mechanisms of Dicer: Endonuclease and Enzymatic Activity; to: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): The DICER1 gene, located on chromosome 14, position q32.13, was discovered in 2001 by Bernstein and is a member of the RNase III family, (also known as dicer 1, ribonuclease III; dicer1, Dcr-1 homolog (Drosophila); multinodular goitre 1). DICER1 is involved in the generation of double-stranded microRNAs (miRNAs), short non-coding RNAs, the cleavage of dsRNA into siRNAs, along with the biogenesis of numerous other small RNAs. There is increasing evidence DICER1 is also involved in regulating many other essential cellular processes such as those related to chromatin remodeling, inflammation, apoptosis and cell survival (Kurzynska-Kokorniak et al. 2015; Song and Rossi, 2017). DICER1 encodes a ∼220-KDa protein (RNase III endoribonuclease) which is a crucial component of the RNA Induced Silencing Complex (RISC) loading complex (RLC), comprised of dicer, Argonaute-2 (AGO-2), and trans-activation-responsive RNA binding protein 2 (TARBP2). The encoded protein is required by the RNA interference (RNAi) and small temporal RNA (stRNA) pathways to produce the active small RNA component which has a role in modulating gene expression at the post-transcriptional level. Research has shown that expression levels of cellular transcript and protein dicer are strictly controlled, with aberrant regulation contributing to carcinogenesis, neurodegenerative, rheumatic and immune system disorders. Studies have concluded that the encoded dicer ribonuclease-dependent processing of dsRNA viral replication intermediates into successive siRNAs is a conserved mammalian immune response to infection by positive-strand RNA viruses (Svobodova et al. 2016 summary & fig1; Li et al. 2013; Ding et al. 2018). Moreover, miRNAs play an important role in host-virus interactions in mammals (See Maillard et al. 2019 REVIEW; Foulkes et al. 2014 REVIEW). IMMUNE SYSTEM The cre-lox method for dicer1 gene knockout has been employed for studies into the role of dicer1 in immune cell development and function. Studies of dicer1 fl/fl mice have indicated short survival times along with severely impaired GMP differentiation into monocytes, neutrophils, myeloid DCs & mature macrophages. (Devasthanam et al. 2014). Results conclude that dicer1 is important in immune response and also vital for cell survival and apoptosis pathways. Muljo et al. (2005) investigated a conditional allele of dicer-1 (dcr-1) within a mouse model and showed that specific dcr-1 deletion in the T-cell lineage, resulted in impaired development of T-cells & aberrant cell differentiation of T-helper cells & cytokine production. Dcr-1 deletion in the thymus resulted in severe block in development of CD8+ T cells and resulted in defective microRNA processing in CD4+ T-cells. The results demonstrate Dicer regulates diverse aspects of T-cell biology along with cytokine production during T-cell differentiation where dicer-deficient T-cells preferentially express interferon-ƴ. VIRUSES Research by Galiana-Arnoux et al. (2006), of DICER in drosophila (drosophila have two dicer genes) have identified that DICER genes (Dcr1, miRNA pathway and Dcr2, RNAi pathway) control production of siRNA and a loss-of-function mutation in Dcr2 resulted in increased susceptibility to three different families of RNA viruses. Qi et al. (2012) research into RNAi gene silencing mechanism show that the B2 protein in Wuhan nodavirus (WhNV) suppresses Dcr2 in drosophila by direct interaction with the PAZ and RNAse III domains therefore blocking processing of dsRNA and siRNA. Evidence of a dicer antiviral system was also reported by Machitani et al. (2016) for mammalian human adenoviruses where DICER1 gene knockdown increased the copy number of adenovirus-encoding small RNAs (VA-RNAs) leading to the promotion of adenovirus replication; conversely, dicer overexpression significantly inhibited viral replication. Modai et al. (2019) conclude that HIV-1 infection inhibits DICER1 by altering miRNA expression. They conclude that upon HIV-1 infection, human miR-186, 210 and 222 directly regulate DICER1 gene expression causing down-regulation of the gene contributing to impaired cell-mediated immunity (fig6). Other methods of inhibition are from viral proteins, termed viral suppressors of RNA silencing, which interact and inhibit dicer ribonuclease activity in HIV-1 and hepatitis C infections. These viral proteins may mediate proteasomal degradation of endoribonuclease dicer through CRL4DCAF1 ubiquitin ligase complex (Klockow et al. 2013), interact directly via the core protein (Chen et al. 2008) or HIV-1 transactivation of transcription (Bennasser and Jeang, 2006). Through these methods they can block dicer interactions with TRBP2 or ADAR1, boost macrophage infection, and subsequently reduce the function of short hairpin RNAs (shRNAs) which thus inhibit RNA silencing. Ultimately these viruses, though various methods, supress the ability of dicer to process dsRNAs into siRNAs boosting viral infection and pathogenesis. Downregulation of DICER1 gene expression has additionally been found in cord blood of infants with severe respiratory syncytial virus (RSV), prior to RSV exposure, indicating this reduced expression may predispose newborns to RSV disease. Inchley et al. (2011) theorize that this occurs via disruption of leukocyte gene regulation of miRNA and direct anti-viral RNAi mechanisms. (Inchley et al. 2011 see section on “Dicer Gene Expression”). Otsuka et al. (2007) have shown using gene-trap methods to obtain viable dicer1 fl/fl mice where dicer1 deficiency caused impairment of miR24 and miR93 production resulting in susceptibility to vesticular stomatitis virus (VSV) and herpes simplex-1 virus, but not other viruses tested. SARS CoV & SARS CoV-2 Recently, Pasquier and Robichon, 2020 (preprint) have investigated the Dicer host immunity system regarding SARs-CoV-2 within a computational approach, concluding SARS-CoV2 may manipulate this system of immunity against its host, requiring further research. Mu et al., 2020 suggest SARs-CoV2 suppresses RNAi thus preventing recognition by the encoded ribonuclease dicer protein Viral suppressors of RNA silencing (VSRs) suppress RNAi at pre or post-dicer level to overcome host defense and establish infection. Cui et al. (2015) from Wuhan University laboratory of virology, identified a novel VSR from coronaviruses (CoVs) including Severe acute respiratory syndrome coronavirus (SARS-CoV) and showed that the coronavirus nucelocaspid protein (N-protein), conserved and expressed in all coronaviruses, suppressed RNAi triggered by either short hairpin RNAs or small interfering RNAs in mammalian cells. They went on to show using mouse hepatitis virus A-59 (MHV-A59) which is closely linked to SARS-CoV in the family coronaviridae, that the viral replication was increased when the N proteins (novel VSR) were expressed but that knockdown of DICER1 gene or Ago2 transcripts facilitated the viral replication specifically in mammalian cells. They demonstrate that the N-protein of CoVs could efficiently inhibit dicer-mediated dsRNA cleavage and post-Dicer activities by sequestering dsRNAs and siRNAs. Kannan et al. (2020) performed clustal W analysis of N-Protein for SARS-CoV and COVID-19 demonstrating 90% sequence identity from an NCBI amino acid blast of both nucleocapsid (N) protein sequences (figure2). They suggest that the N-protein of COVID-19 may also function as a VSR for RNAi to overcome host defense. Ding et al. (2017) show that both MHV and SARS-CoV N proteins can also disrupt protein activator of protein kinase R (PACT), a cellular dsRNA-binding protein which binds to RIG-I and MDA5 to activate interferon (IFN) production to prevent antiviral host response. Literature Review PMID: 17181864: Bennasser and Jeang, 2006 • HIV-1 Tat Interaction With Dicer: Requirement for RNA • Tat-Dicer interaction depends on RNA, requires the helicase domain of Dicer, and is independent of Tat's transactivation domain. PMID: 18325616: Chen et al., 2008 • HCV Core Protein Interacts With Dicer to Antagonize RNA Silencing PMID: 26085159: Cui et al., 2015 • The Nucleocapsid Protein of Coronaviruses Acts as a Viral Suppressor of RNA Silencing in Mammalian Cells PMID: 24303839: Devasthanam et al, 2014 • This study investigates the role of the dicer protein in immune cell development and function using dicer1 cre-lox knockout models to conditionally ablate dicer1 in different immune cell subsets. PMID: 28591694: Ding et al., 2017 • The nucleocapsid proteins of mouse hepatitis virus and severe acute respiratory syndrome coronavirus share the same IFN-β antagonizing mechanism: attenuation of PACT-mediated RIG-I/MDA5 activation PMID: 30015086: Ding et al., 2018 • Antiviral RNA Interference in Mammals: Indicates infection of plants and insects with RNA and DNA viruses triggers Dicer-dependent production of virus-derived small interfering RNAs (vsiRNAs), which subsequently guide specific virus clearance by RNA interference (RNAi). PMID: 25176334: Foulkes et al., 2012-REVIEW • Review of DICER1: DICER1 Mutations, microRNAs and Mechanisms PMID: 16554838: Galiana-Arnoux et al., 2006 • Essential function in vivo for Dicer-2 in host defense against RNA viruses in drosophila. • https://pubmed.ncbi.nlm.nih.gov/16554838/ or https://www.nature.com/articles/ni1335 PMID: 21385408: Inchley et al., 2011 • Investigates ribonuclease Dicer and analyzed the gene expression of Dicer in newborns of which 37 infants had sufficient cord blood RNA with confirmed RSV disease <1yr. Demonstrates significant reduced Dicer expression in cord blood prior to severe disease in infants <1yr later. Conclude downregulation may predispose infants to RSV disease. PMID: 32141569: Kannan et al., 2020 • COVID-19 (Novel Coronavirus 2019) - Recent Trends • Perform W cluster analysis of COVID-19 and SARS-CoV nucleocapsid (N) protein sequences of the viruses showing 90% amino acid sequence similarity. Suggest the N-protein may be a VSR in RNAi by targeting DICER. PMID: 23849790: Klockow et al., 2013 • The HIV-1 Protein Vpr Targets the Endoribonuclease Dicer for Proteasomal Degradation to Boost Macrophage Infection PMID: 25883138: Kurzynska-Kokorniak et al., 2015 • Investigating the complexity of the mechanisms regulating Dicer gene expression and enzyme activities PMID: 24115437: Li et al, 2013 • Investigates RNA interference pathways in antiviral immunity in mammals overviewing dicer processing of dsRNA viral replication intermediates into siRNAs. PMID: 27273616: Machitani et al., 2016 • Dicer functions as an antiviral system against human adenoviruses via cleavage of adenovirus-encoded noncoding RNA PMID: 30872283: Maillard et al., 2019- REVIEW • Reviewing DICER1 within the anti-viral RNAi pathway in mammals PMID: 30682089: Modai et al, 2019 • HIV-1 infection increases miRNAs which inhibit Dicer PMID: 32291557: Mu et al, 2020 • SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells PMID: 16009718: Muljo et al., 2005 • Indicates absence of dicer results in abberant T-cell differentiation. PMID: 17613256: Otsuka, et al 2007 • Hypersusceptibility to Vesicular Stomatitis Virus Infection in Dicer1-Deficient Mice Is Due to Impaired miR24 and miR93 Expression No PMID: Preprint : Pasquier and Rubichon, 2020 • SARS-CoV-2 might manipulate against its host the immunity RNAi/Dicer/Ago system PMID: 22438534: Qi et al., 2012 • Targeting of Dicer-2 and RNA by a Viral RNA Silencing Suppressor in Drosophila Cells PMID: 28473628: Song and Rossi, 2017 • Molecular Mechanisms of Dicer: Endonuclease and Enzymatic Activity |
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| COVID-19 research v0.348 | DICER1 |
Rebecca Foulger commented on gene: DICER1: Evidence Summary from Illumina curation team: The DICER1 gene, located on chromosome 14, position q32.13, was discovered in 2001 by Bernstein and is a member of the RNase III family, (also known as dicer 1, ribonuclease III; dicer1, Dcr-1 homolog (Drosophila); multinodular goitre 1). DICER1 is involved in the generation of double-stranded microRNAs (miRNAs), short non-coding RNAs, the cleavage of dsRNA into siRNAs, along with the biogenesis of numerous other small RNAs. There is increasing evidence DICER1 is also involved in regulating many other essential cellular processes such as those related to chromatin remodeling, inflammation, apoptosis and cell survival (Kurzynska-Kokorniak et al. 2015; Song and Rossi, 2017). DICER1 encodes a ∼220-KDa protein (RNase III endoribonuclease) which is a crucial component of the RNA Induced Silencing Complex (RISC) loading complex (RLC), comprised of dicer, Argonaute-2 (AGO-2), and trans-activation-responsive RNA binding protein 2 (TARBP2). The encoded protein is required by the RNA interference (RNAi) and small temporal RNA (stRNA) pathways to produce the active small RNA component which has a role in modulating gene expression at the post-transcriptional level. Research has shown that expression levels of cellular transcript and protein dicer are strictly controlled, with aberrant regulation contributing to carcinogenesis, neurodegenerative, rheumatic and immune system disorders. Studies have concluded that the encoded dicer ribonuclease-dependent processing of dsRNA viral replication intermediates into successive siRNAs is a conserved mammalian immune response to infection by positive-strand RNA viruses (Svobodova et al. 2016 summary & fig1; Li et al. 2013; Ding et al. 2018). Moreover, miRNAs play an important role in host-virus interactions in mammals (See Maillard et al. 2019 REVIEW; Foulkes et al. 2014 REVIEW). IMMUNE SYSTEM The cre-lox method for dicer1 gene knockout has been employed for studies into the role of dicer1 in immune cell development and function. Studies of dicer1 fl/fl mice have indicated short survival times along with severely impaired GMP differentiation into monocytes, neutrophils, myeloid DCs & mature macrophages. (Devasthanam et al. 2014). Results conclude that dicer1 is important in immune response and also vital for cell survival and apoptosis pathways. Muljo et al. (2005) investigated a conditional allele of dicer-1 (dcr-1) within a mouse model and showed that specific dcr-1 deletion in the T-cell lineage, resulted in impaired development of T-cells & aberrant cell differentiation of T-helper cells & cytokine production. Dcr-1 deletion in the thymus resulted in severe block in development of CD8+ T cells and resulted in defective microRNA processing in CD4+ T-cells. The results demonstrate Dicer regulates diverse aspects of T-cell biology along with cytokine production during T-cell differentiation where dicer-deficient T-cells preferentially express interferon-ƴ. VIRUSES Research by Galiana-Arnoux et al. (2006), of DICER in drosophila (drosophila have two dicer genes) have identified that DICER genes (Dcr1, miRNA pathway and Dcr2, RNAi pathway) control production of siRNA and a loss-of-function mutation in Dcr2 resulted in increased susceptibility to three different families of RNA viruses. Qi et al. (2012) research into RNAi gene silencing mechanism show that the B2 protein in Wuhan nodavirus (WhNV) suppresses Dcr2 in drosophila by direct interaction with the PAZ and RNAse III domains therefore blocking processing of dsRNA and siRNA. Evidence of a dicer antiviral system was also reported by Machitani et al. (2016) for mammalian human adenoviruses where DICER1 gene knockdown increased the copy number of adenovirus-encoding small RNAs (VA-RNAs) leading to the promotion of adenovirus replication; conversely, dicer overexpression significantly inhibited viral replication. Modai et al. (2019) conclude that HIV-1 infection inhibits DICER1 by altering miRNA expression. They conclude that upon HIV-1 infection, human miR-186, 210 and 222 directly regulate DICER1 gene expression causing down-regulation of the gene contributing to impaired cell-mediated immunity (fig6). Other methods of inhibition are from viral proteins, termed viral suppressors of RNA silencing, which interact and inhibit dicer ribonuclease activity in HIV-1 and hepatitis C infections. These viral proteins may mediate proteasomal degradation of endoribonuclease dicer through CRL4DCAF1 ubiquitin ligase complex (Klockow et al. 2013), interact directly via the core protein (Chen et al. 2008) or HIV-1 transactivation of transcription (Bennasser and Jeang, 2006). Through these methods they can block dicer interactions with TRBP2 or ADAR1, boost macrophage infection, and subsequently reduce the function of short hairpin RNAs (shRNAs) which thus inhibit RNA silencing. Ultimately these viruses, though various methods, supress the ability of dicer to process dsRNAs into siRNAs boosting viral infection and pathogenesis. Downregulation of DICER1 gene expression has additionally been found in cord blood of infants with severe respiratory syncytial virus (RSV), prior to RSV exposure, indicating this reduced expression may predispose newborns to RSV disease. Inchley et al. (2011) theorize that this occurs via disruption of leukocyte gene regulation of miRNA and direct anti-viral RNAi mechanisms. (Inchley et al. 2011 see section on “Dicer Gene Expression”). Otsuka et al. (2007) have shown using gene-trap methods to obtain viable dicer1 fl/fl mice where dicer1 deficiency caused impairment of miR24 and miR93 production resulting in susceptibility to vesticular stomatitis virus (VSV) and herpes simplex-1 virus, but not other viruses tested. SARS CoV & SARS CoV-2 Recently, Pasquier and Robichon, 2020 (preprint) have investigated the Dicer host immunity system regarding SARs-CoV-2 within a computational approach, concluding SARS-CoV2 may manipulate this system of immunity against its host, requiring further research. Mu et al., 2020 suggest SARs-CoV2 suppresses RNAi thus preventing recognition by the encoded ribonuclease dicer protein Viral suppressors of RNA silencing (VSRs) suppress RNAi at pre or post-dicer level to overcome host defense and establish infection. Cui et al. (2015) from Wuhan University laboratory of virology, identified a novel VSR from coronaviruses (CoVs) including Severe acute respiratory syndrome coronavirus (SARS-CoV) and showed that the coronavirus nucelocaspid protein (N-protein), conserved and expressed in all coronaviruses, suppressed RNAi triggered by either short hairpin RNAs or small interfering RNAs in mammalian cells. They went on to show using mouse hepatitis virus A-59 (MHV-A59) which is closely linked to SARS-CoV in the family coronaviridae, that the viral replication was increased when the N proteins (novel VSR) were expressed but that knockdown of DICER1 gene or Ago2 transcripts facilitated the viral replication specifically in mammalian cells. They demonstrate that the N-protein of CoVs could efficiently inhibit dicer-mediated dsRNA cleavage and post-Dicer activities by sequestering dsRNAs and siRNAs. Kannan et al. (2020) performed clustal W analysis of N-Protein for SARS-CoV and COVID-19 demonstrating 90% sequence identity from an NCBI amino acid blast of both nucleocapsid (N) protein sequences (figure2). They suggest that the N-protein of COVID-19 may also function as a VSR for RNAi to overcome host defense. Ding et al. (2017) show that both MHV and SARS-CoV N proteins can also disrupt protein activator of protein kinase R (PACT), a cellular dsRNA-binding protein which binds to RIG-I and MDA5 to activate interferon (IFN) production to prevent antiviral host response. Literature Review PMID: 17181864: Bennasser and Jeang, 2006 • HIV-1 Tat Interaction With Dicer: Requirement for RNA • Tat-Dicer interaction depends on RNA, requires the helicase domain of Dicer, and is independent of Tat's transactivation domain. PMID: 18325616: Chen et al., 2008 • HCV Core Protein Interacts With Dicer to Antagonize RNA Silencing PMID: 26085159: Cui et al., 2015 • The Nucleocapsid Protein of Coronaviruses Acts as a Viral Suppressor of RNA Silencing in Mammalian Cells PMID: 24303839: Devasthanam et al, 2014 • This study investigates the role of the dicer protein in immune cell development and function using dicer1 cre-lox knockout models to conditionally ablate dicer1 in different immune cell subsets. PMID: 28591694: Ding et al., 2017 • The nucleocapsid proteins of mouse hepatitis virus and severe acute respiratory syndrome coronavirus share the same IFN-β antagonizing mechanism: attenuation of PACT-mediated RIG-I/MDA5 activation PMID: 30015086: Ding et al., 2018 • Antiviral RNA Interference in Mammals: Indicates infection of plants and insects with RNA and DNA viruses triggers Dicer-dependent production of virus-derived small interfering RNAs (vsiRNAs), which subsequently guide specific virus clearance by RNA interference (RNAi). PMID: 25176334: Foulkes et al., 2012-REVIEW • Review of DICER1: DICER1 Mutations, microRNAs and Mechanisms PMID: 16554838: Galiana-Arnoux et al., 2006 • Essential function in vivo for Dicer-2 in host defense against RNA viruses in drosophila. • https://pubmed.ncbi.nlm.nih.gov/16554838/ or https://www.nature.com/articles/ni1335 PMID: 21385408: Inchley et al., 2011 • Investigates ribonuclease Dicer and analyzed the gene expression of Dicer in newborns of which 37 infants had sufficient cord blood RNA with confirmed RSV disease <1yr. Demonstrates significant reduced Dicer expression in cord blood prior to severe disease in infants <1yr later. Conclude downregulation may predispose infants to RSV disease. PMID: 32141569: Kannan et al., 2020 • COVID-19 (Novel Coronavirus 2019) - Recent Trends • Perform W cluster analysis of COVID-19 and SARS-CoV nucleocapsid (N) protein sequences of the viruses showing 90% amino acid sequence similarity. Suggest the N-protein may be a VSR in RNAi by targeting DICER. PMID: 23849790: Klockow et al., 2013 • The HIV-1 Protein Vpr Targets the Endoribonuclease Dicer for Proteasomal Degradation to Boost Macrophage Infection PMID: 25883138: Kurzynska-Kokorniak et al., 2015 • Investigating the complexity of the mechanisms regulating Dicer gene expression and enzyme activities PMID: 24115437: Li et al, 2013 • Investigates RNA interference pathways in antiviral immunity in mammals overviewing dicer processing of dsRNA viral replication intermediates into siRNAs. PMID: 27273616: Machitani et al., 2016 • Dicer functions as an antiviral system against human adenoviruses via cleavage of adenovirus-encoded noncoding RNA PMID: 30872283: Maillard et al., 2019- REVIEW • Reviewing DICER1 within the anti-viral RNAi pathway in mammals PMID: 30682089: Modai et al, 2019 • HIV-1 infection increases miRNAs which inhibit Dicer PMID: 32291557: Mu et al, 2020 • SARS-CoV-2-encoded nucleocapsid protein acts as a viral suppressor of RNA interference in cells PMID: 16009718: Muljo et al., 2005 • Indicates absence of dicer results in abberant T-cell differentiation. PMID: 17613256: Otsuka, et al 2007 • Hypersusceptibility to Vesicular Stomatitis Virus Infection in Dicer1-Deficient Mice Is Due to Impaired miR24 and miR93 Expression No PMID: Preprint : Pasquier and Rubichon, 2020 • SARS-CoV-2 might manipulate against its host the immunity RNAi/Dicer/Ago system PMID: 22438534: Qi et al., 2012 • Targeting of Dicer-2 and RNA by a Viral RNA Silencing Suppressor in Drosophila Cells PMID: 28473628: Song and Rossi, 2017 • Molecular Mechanisms of Dicer: Endonuclease and Enzymatic Activity |
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| COVID-19 research v0.348 | CD28 |
Rebecca Foulger commented on gene: CD28: Evidence Summary from Illumina curation team: CD28 is a transmembrane receptor expressed on the surface of T cells and is required for the immune cell activation and proliferation of naïve and memory T cells. CD28 knockout mice have an increased susceptibility to ECTV, a host specific virus which causes mousepox. Upon infection, CD28 deficient mice showed a 40% mortality within 14 days while wild-type control mice did not show any symptoms of disease (Fang et al. 2008). In cell culture experiments, CD28 protein surface levels were found to be downregulated by HIV-1 accessory proteins Nef and Vpu (Pawlak et al. 2018). In severe cases of COVID-19 infection, immuno-dysregulation may lead to a decrease of CD28+ cytotoxic suppressor T cells (Tufan et al. 2020, review) PMID: 29329537; Pawlak et al.(2018) - CD28 is a transmembrane receptor expressed on the surface of T cells. It is essential for immune cell activation and proliferation of naïve and memory T cell. Cell culture experiments using CD4+ Sup-T1 cells or primary CD4+ T cells and infected with VSV-G pseudotyped NL4.3 viruses showed that the HIV-1 accessory proteins Nef and Vpu modify the immune response and increase viral persistence by decreasing the cell surface levels of CD28 (fig.1). PMID: 32299202; Tufan et al. (2020) Review. SARS-CoV-2 infection can lead to immune dysregulation through affecting the subset of T cells. In severe cases of COVID-19 infection, it was observed that the percentage of naïve helper T cells amplifies while the percentage of memory helper T cells and CD28+ cytotoxic suppressor T cells decreases. PMID: 17114476; Fang et al. (2008) - CD28 KO mice in a mousepox-resistant B6 background infected with ECTV showed a 40% mortality 7–14 days PI (Fig. 1A) and all remaining CD28KO mice developed mousepox (Fig. 1, B and C). All control wild-type B6 mice survived the infection without any symptoms of disease. CD28 KO mice that survived past 14 days PI gradually recovered from the disease and survived indefinitely. A comparison of CD8+ T cell responses to ECTV and VACV suggests that the main reason for the susceptibility of CD28 KO mice to mousepox is a reduced response at the early stages of infection. |
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| COVID-19 research v0.347 | DEFA1 | Alison Coffey commented on gene: DEFA1: Evidence Summary from Illumina curation team: DEFA1, or HNP1, is a member of the defensin family of host defense peptides, a group of microbicidal and cytotoxic peptides made by neutrophils. Defensins are known to have a role in innate immunity as a core host-protective component against bacterial, viral and fungal infections (Xu and Wuyaun, 2020). Defensins have direct antiviral activity in cell culture, with varied mechanisms for individual viruses. Defensins also have a potent immunomodulatory activity that can alter innate and adaptive immune responses to viral infection and are able to target multiple steps of host-virus interactions to reduce infectivity of both enveloped and non-enveloped viruses. Targets include viral envelopes, glycoproteins, and capsids or host cells. DEFA1 is well-recognized for its direct anti-HIV activity, it also restrains HIV-1 uptake by inhibiting Env-mediated viral fusion and downregulating host cell surface expression of CD4 and coreceptor CXCR4. Post-entry inhibition of enveloped viruses such as HIV-1 and influenza by DEFA1 is mediated through interfering with cell signaling pathways such as PKC that are required for viral replication (Xu and Wuyaun, 2020). An unpublished study by Kit and Kit (2020), demonstrated in silico that the affinity of human alpha-defensins 1, 2, 3 and 5 to SARS-CoV-2 spike protein is higher than that of the SARS-CoV-2 spike protein towards ACE2. The authors suggest that these alpha-defensins may serve as primary factors in protecting lung tissue from COVID-19 viral infection. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | CCR7 | Alison Coffey commented on gene: CCR7: Evidence Summary from Illumina curation team: The CCR7 gene encodes the C-C chemokine receptor 7, a chemokine receptor which is a member of the G protein-coupled receptor superfamily. CCR7 plays an important role in the homing of central memory and nave T cells to peripheral lymphoid organs. The binding of CCR7 ligands CCL19 and CCL21 during viral infection promotes activation and differentiation of CCR7 expressing cells, as well as changes in their migration properties to modulate the immune response (reviewed Yan et al. 2019). Some viral proteins target CCR7 and reduce its expression during viral infection (reviewed Yan et al. 2019), for example, the HIV-1 accessory protein, Vpu, interacts directly with CCR7 to cause its retention within the trans Golgi network of primary CD4+ T cells (Ramirez et al. 2014). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.347 | ATG5 | Alison Coffey commented on gene: ATG5: Evidence Summary from Illumina curation team: The ATG5 gene encodes a core autophagy protein which forms a complex with ATG12 and ATG16L that is important for autophagophore elongation. Autophagy plays a key antiviral role in various human infections by modulating different aspects of the immune response (Reviewed Tao et al. 2020; Ahmed et al.2018). ATG5 may play a role in cytokine regulation, in vitro, ATG5 depleted primary human blood macrophages produced lower levels of CXCL10 and IFNa when infected with influenza A virus (Law et al. 2007). ATG5 deficient mice also show reduced Ifn and Il22 secretion when infected with the single stranded RNA vesicular stomatitis virus (VSV) (Lee et al. 2007). Using a mouse model with a conditional depletion of ATG5 within dendritic cells, Lee et al. 2010 showed that ATG5 is required for antigen presentation by dendritic cells, as a result of reduced MHC-II antigen presentation, these mice, when intradermally injected with HSV-1, showed significantly lower IFNgamma production by CD4+ T cells. (Lee et al., 2010). The ATG5 complex is targeted by some viruses to enhance infection, for example, the foot and mouth disease virus (FMDV) targets the ATG5-ATG12 complex for degradation through its viral protein 3Cpro, similarly, depletion of ATG5 and ATG12 in vitro, by siRNA increased susceptibility to FMDV infection by reducing activation of the NF-?B and IRF3 pathways (Fan et al 2017). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.308 | SERINC3 |
Catherine Snow changed review comment from: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus". No current gene disease relationship in OMIM. The human immunodeficiency virus (HIV)-1 Nef protein and the unrelated murine leukemia virus (MLV) glycosylated Gag (glycoGag) protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 (614551) precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS. Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3 (607165), inhibited infectivity of human immunodeficiency virus (HIV)-1 (see 609423) and murine leukemia retrovirus (MLV) Sources: Literature; to: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus". No current gene disease relationship in OMIM. The human immunodeficiency virus (HIV)-1 Nef protein and the unrelated murine leukemia virus (MLV) glycosylated Gag (glycoGag) protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 (614551) precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS. Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3, inhibited infectivity of human immunodeficiency virus (HIV)-1 and murine leukemia retrovirus (MLV) Sources: Literature |
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| COVID-19 research v0.307 | SERINC3 |
Catherine Snow changed review comment from: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus". No current gene disease relationship in OMIM. The human immunodeficiency virus (HIV)-1 Nef protein and the unrelated murine leukemia virus (MLV) glycosylated Gag (glycoGag) protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 (614551) precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS. Sources: Literature; to: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus". No current gene disease relationship in OMIM. The human immunodeficiency virus (HIV)-1 Nef protein and the unrelated murine leukemia virus (MLV) glycosylated Gag (glycoGag) protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 (614551) precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS. Screening human cell lines and using CRISPR-Cas9 analysis, Rosa et al. (2015) found that SERINC5, and to a lesser extent SERINC3 (607165), inhibited infectivity of human immunodeficiency virus (HIV)-1 (see 609423) and murine leukemia retrovirus (MLV) Sources: Literature |
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| COVID-19 research v0.307 | SERINC3 |
Catherine Snow gene: SERINC3 was added gene: SERINC3 was added to COVID-19 research. Sources: Literature Mode of inheritance for gene: SERINC3 was set to Unknown Review for gene: SERINC3 was set to AMBER Added comment: Curation by Illumina clinical curators contributing to Covid-19 effort. Curation on all OMIM genes which hit the term "virus". No current gene disease relationship in OMIM. The human immunodeficiency virus (HIV)-1 Nef protein and the unrelated murine leukemia virus (MLV) glycosylated Gag (glycoGag) protein enhance HIV-1 infectivity. Usami et al. (2015) found that silencing both SERINC3 and SERINC5 (614551) precisely phenocopied the effects of Nef and glycoGag on HIV-1 infectivity. CD4-positive T cells lacking both SERINC3 and SERINC5 showed significantly increased susceptibility to Nef-deficient virions. SERINC3 and SERINC5 together restricted HIV-1 replication, and this restriction was evaded by Nef. Usami et al. (2015) proposed that inhibiting Nef-mediated downregulation of SERINC3 and SERINC5, which are normally highly expressed in HIV-1 target cells, has the potential to combat HIV/AIDS. Sources: Literature |
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| COVID-19 research v0.207 | SELPLG |
Sarah Leigh commented on gene: SELPLG: PMID: 30833724 identifies SELPLG (refered to as PSGL1 in the literature) as an HIV restriction factor, SELPLG is induced by interferon-γ in activated CD4+ T cells to inhibit HIV-1 reverse transcription and potently block viral infectivity by incorporating in progeny virions. Preprint https://doi.org/10.1101/2020.05.01.073387 report that virion incorporation of SELPLG on SARS-CoV and SARS-CoV-2 pseudovirions blocks S protein-mediated virus attachment and infection of target cells, Suggesting that SELPLG-imprinted non-infectious viral particles could serve as a live attenuated vaccine for SARS-CoV-2 infection. |
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| COVID-19 research v0.205 | CCR5 | Sarah Leigh edited their review of gene: CCR5: Added comment: Preprint https://doi.org/10.1101/2020.05.02.20084673 reports 10 terminally-ill, critical COVID-19 patients with profound elevation of plasma IL-6 and CCL5 (RANTES), decreased CD8+ T cell levels, and SARS-CoV-2 plasma viremia. Treatment with CCR5 blocking antibody leronlimab, results in complete CCR5 receptor occupancy on macrophage and T cells, rapid reduction of plasma IL-6, restoration of the CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia. From single-cell RNA-sequencing, this effect appears to be a result of reduced transcriptomic myeloid cell clusters expressing IL-6 and interferon-related genes.; Changed publications: https://doi.org/10.1101/2020.05.02.20084673 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.204 | IL6 | Sarah Leigh edited their review of gene: IL6: Added comment: Preprint https://doi.org/10.1101/2020.05.02.20084673 reports 10 terminally-ill, critical COVID-19 patients with profound elevation of plasma IL-6 and CCL5 (RANTES), decreased CD8+ T cell levels, and SARS-CoV-2 plasma viremia. Treatment with CCR5 blocking antibody leronlimab, results in complete CCR5 receptor occupancy on macrophage and T cells, rapid reduction of plasma IL-6, restoration of the CD4/CD8 ratio, and a significant decrease in SARS-CoV-2 plasma viremia. From single-cell RNA-sequencing, this effect appears to be a result of reduced transcriptomic myeloid cell clusters expressing IL-6 and interferon-related genes.; Changed publications: https://doi.org/10.1101/2020.05.02.20084673 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.195 | CD4 | Ivone Leong Classified gene: CD4 as Amber List (moderate evidence) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.195 | CD4 |
Ivone Leong Added comment: Comment on list classification: Promoted from Red to Amber based on expert review. "Single individual reported, functional data, emerging gene. Zornitza Stark (Australian Genomics), 1 May 2020" - review copied from Primary immunodeficiency (Version 2.155). |
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| COVID-19 research v0.195 | CD4 | Ivone Leong Gene: cd4 has been classified as Amber List (Moderate Evidence). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.194 | CD4 | Ivone Leong Phenotypes for gene: CD4 were changed from Selective CD4 cell deficiency to Selective CD4 cell deficiency; OKT4 epitope deficiency, 613949; Absence of CD4+ T cells; exuberant, relapsing, treatment-refractory warts | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.193 | CD4 | Ivone Leong Publications for gene: CD4 were set to 25611551 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.192 | CD4 | Ivone Leong Mode of inheritance for gene: CD4 was changed from Unknown to BIALLELIC, autosomal or pseudoautosomal | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.99 | CD4 | Rebecca Foulger Publications for gene: CD4 were set to | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.98 | CD4 | Rebecca Foulger commented on gene: CD4 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| COVID-19 research v0.81 | HLA-DRB1 |
Abdelazeem Elhabyan gene: HLA-DRB1 was added gene: HLA-DRB1 was added to Viral susceptibility. Sources: Literature Mode of inheritance for gene: HLA-DRB1 was set to Unknown Publications for gene: HLA-DRB1 were set to PMID: 19445991,26456283,19597844,10823757, Penetrance for gene: HLA-DRB1 were set to unknown Mode of pathogenicity for gene: HLA-DRB1 was set to Other Review for gene: HLA-DRB1 was set to GREEN Added comment: Association of human leukocyte antigen class II alleles with severe acute respiratory syndrome in the Vietnamese population PMID: 19445991, HLA-DRB1*12 was more frequently shown in SARS patients than in controls (corrected p = 0.042). HLA-DRB1*1202, the predominant allele in the Vietnamese population showed the strongest association with SARS in a dominant model (corrected p = 0.0065 and 0.0052, depending on the controls to be compared). Our results and accumulated data on HLA in the Asian populations would help in the understanding of associations with emerging infectious diseases. Amino Acid Variation in HLA Class II Proteins Is a Major Determinant of Humoral Response to Common Viruses PMID: 26456283 The magnitude of the human antibody response to viral antigens is highly variable. To explore the human genetic contribution to this variability, we performed genome-wide association studies of the immunoglobulin G response to 14 pathogenic viruses in 2,363 immunocompetent adults. Significant associations were observed in the major histocompatibility complex region on chromosome 6 for influenza A virus, Epstein-Barr virus, JC polyomavirus, and Merkel cell polyomavirus. Using local imputation and fine mapping, we identified specific amino acid residues in human leucocyte antigen (HLA) class II proteins as the most probable causal variants underlying these association signals. Common HLA-DRβ1 haplotypes showed virus-specific patterns of humoral-response regulation Clear and Independent Associations of Several HLA-DRB1 Alleles With Differential Antibody Responses to Hepatitis B Vaccination in Youth PMID: 19597844 To confirm and refine associations of human leukocyte antigen (HLA) genotypes with variable antibody (Ab) responses to hepatitis B vaccination, we have analyzed 255 HIV-1 seropositive (HIV(+)) youth and 80 HIV-1 seronegatives (HIV(-)) enrolled into prospective studies. In univariate analyses that focused on HLA-DRB1, -DQA1, and -DQB1 alleles and haplotypes, the DRB1*03 allele group and DRB1*0701 were negatively associated with the responder phenotype (serum Ab concentration > or = 10 mIU/mL) (P = 0.026 and 0.043, respectively). Collectively, DRB1*03 and DRB1*0701 were found in 42 (53.8%) out of 78 non-responders (serum Ab <10 mIU/mL), 65 (40.6%) out of 160 medium responders (serum Ab 10-1,000 mIU/mL), and 27 (27.8%) out of 97 high responders (serum Ab >1,000 mIU/mL) (P < 0.001 for trend). Meanwhile, DRB1*08 was positively associated with the responder phenotype (P = 0.010), mostly due to DRB1*0804 (P = 0.008). Influence of HLA Supertypes on Susceptibility and Resistance to Human Immunodeficiency Virus Type 1 Infection PMID: 10823757 To determine whether HLA polymorphism influences HIV-1 susceptibility, a longitudinal cohort of highly HIV-1-exposed female sex workers based in Nairobi, Kenya, was prospectively analyzed. Decreased HIV-1 infection risk was strongly associated with possession of a cluster of closely related HLA alleles (A2/6802 supertype; incidence rate ratio [IRR], 0.45; 95% confidence interval [CI], 0.27-0.72; P=.0003). The alleles in this supertype are known in some cases to present the same peptide epitopes for T cell recognition. In addition, resistance to HIV-1 infection was independently associated with HLA DRB1*01 (IRR, 0.22; 95% CI, 0.06-0.60; P=.0003), which suggests that anti-HIV-1 class II restricted CD4 effector mechanisms may play an important role in protecting against viral challenge Sources: Literature |
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| COVID-19 research v0.36 | CD4 |
Ellen McDonagh gene: CD4 was added gene: CD4 was added to Viral susceptibility. Sources: Expert Review Red,ESID Registry 20171117 Mode of inheritance for gene: CD4 was set to Unknown Phenotypes for gene: CD4 were set to Selective CD4 cell deficiency |
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| COVID-19 research v0.36 | CD40LG |
Ellen McDonagh gene: CD40LG was added gene: CD40LG was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: CD40LG was set to X-LINKED: hemizygous mutation in males, biallelic mutations in females Publications for gene: CD40LG were set to 7678782; 7586644; 11875495; 20301576; 7882172; 17146684; 8094231; 7679206; 7679801 Phenotypes for gene: CD40LG were set to Hyper-IGM immunodeficiency, X-linked; HIGM; Hyper-IGM syndrome; Hyper-IgM syndrome type 1; Neutropenia, thrombocytopenia, hemolytic anemia, opportunistic infections, biliary tract and liver disease, Cryptosporidium infections; XHIM; Immunodeficiency, X-linked, with hyper-IgM; Immunodeficiencies affecting cellular and humoral immunity; Hyper-IgM syndrome due to CD40 ligand deficiency; Hyper-IgM syndrome due to CD40L deficiency; IHIS; HIGM1; IMD3; CSR defects and Hyper IgM (HIGM) syndromes; Immunodeficiency 3; CD40 ligand deficiency |
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| COVID-19 research v0.36 | ERCC2 |
Ellen McDonagh gene: ERCC2 was added gene: ERCC2 was added to Viral susceptibility. Sources: Victorian Clinical Genetics Services,North West GLH,Other,NHS GMS,London North GLH,Expert Review Red Mode of inheritance for gene: ERCC2 was set to Unknown Publications for gene: ERCC2 were set to 11737070 Phenotypes for gene: ERCC2 were set to Combined immunodeficiency (CID) in a child affected by trichothiodystrophy (TTD); CD4 + lymphopenia |
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| COVID-19 research v0.36 | CD46 |
Ellen McDonagh gene: CD46 was added gene: CD46 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: CD46 was set to BOTH monoallelic and biallelic, autosomal or pseudoautosomal Publications for gene: CD46 were set to 16621965; 14566051; 14615110 Phenotypes for gene: CD46 were set to Hemolytic uremic syndrome, atypical, susceptibility to, 2, 612922; atypical HUS; Membrane Cofactor Protein (CD46) deficiency; Complement Deficiencies; Atypical hemolytic-uremic syndrome, infections, preeclampsia |
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| COVID-19 research v0.36 | PTPRC |
Ellen McDonagh gene: PTPRC was added gene: PTPRC was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,Victorian Clinical Genetics Services,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,SCID v1.6,IUIS Classification February 2018 Mode of inheritance for gene: PTPRC was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PTPRC were set to 11145714; 10700239; 22689986 Phenotypes for gene: PTPRC were set to Nl g/d T cells; {Hepatitic C virus, susceptibility to}, 609532; CD45 deficiency; Immunodeficiencies affecting cellular and humoral immunity; T-B+ SCID; Omenn syndrome; Severe combined immunodeficiency, T cell-negative, B-cell/natural killer-cell positive; Severe combined immunodeficiency (SCID) |
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| COVID-19 research v0.36 | CD40 |
Ellen McDonagh gene: CD40 was added gene: CD40 was added to Viral susceptibility. Sources: Expert Review Green,ESID Registry 20171117,North West GLH,GRID V2.0,NHS GMS,GOSH PID v.8.0,London North GLH,IUIS Classification February 2018 Mode of inheritance for gene: CD40 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: CD40 were set to 17502893; 20301287; 12584544; 11675497 Phenotypes for gene: CD40 were set to Immunodeficiency with hyper-IgM, type 3; Hyper-IgM syndrome due to CD40 deficiency; non-X-linked hyper IgM syndrome; Immunodeficiencies affecting cellular and humoral immunity; HIGM3; CD40 deficiency; Neutropenia, opportunistic infections, gastrointestinal and biliary tract and liver disease, Cryptosporidium infections; CSR defects and Hyper IgM (HIGM) syndromes |
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