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COVID-19 research v1.16 CIB1 Sarah Leigh changed review comment from: CIB1 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: CIB1 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: From OMIM: Susceptibility to epidermodysplasia verruciformis-3 is conferred by homozygous variation in the CIB1 gene. Epidermodysplasia verruciformis-3 is characterized by onset in childhood or early adulthood of persistent disseminated flat warts and pityriasis versicolor-like lesions of the skin that are induced by cutaneous human papillomaviruses (HPVs) of the beta genus. Some patients develop nonmelanoma skin cancer, particularly on areas of the body exposed to the sun. Patients are otherwise healthy and normally resistant to other microorganisms, including other viruses and skintropic pathogens, and even all other cutaneous and mucosal HPVs. Gene:disease relationship with autosomal recessive epidermodysplasia verruciformis curated using the ClinGen framework for gene curation. The CIB1 gene is located on chromosome 15 at 15q26.1 and encodes calcium and integrin binding 1. This protein forms a complex with the products of the TMC6 (EVER1) and TMC8 (EVER2) genes. The CIB1/EVER1/EVER2 complex acts to restrict transcription of human papillomaviruses. The CIB1 gene was first reported in relation to autosomal recessive epidermodysplasia verruciformis in 2018 (PMID: 300068544). Five unique homozygous variants in this gene were reported in at least five probands including two frameshift, one stop-gained, one stop-lost, and one canonical splice variant. The evidence supporting the GDR includes segregation data - linkage analysis across three unrelated families of differing geographic origin resulted in a LOD score of 16.7. This gene-disease relationship is also supported by expression data and a shared biochemical function with additional genes that are also associated with the disease (PMID: 300068544). In summary, the GDR between CIB1 and autosomal recessive epidermodysplasia verruciformis is classified as strong using the ClinGen framework.
COVID-19 research v0.348 MIR155 Rebecca Foulger commented on gene: MIR155: Evidence Summary from Illumina curation team (Alison Coffey and Julie Taylor): MIR155 (also referred to as BIC) is an endogenous noncoding RNA involved in regulation of the immune response, in particular T-cell differentiation, and in regulation of innate immunity (PMID: 32233818; 217121651;1746328969;20852130). This miRNA has been associated with various virus infections (PMID: 32233818;28139244;23686237;26072128). miR-155-5p expression has been shown to be induced in mice infected with influenza A virus (PMID: 32308197 - in this study, lung injury by ARDS was attenuated by deletion of miR-155, making this miRNA a potential therapeutic target in the context of COVID-19). Through single cell and bulk RNA profiling of SARS-CoV-2 and SARS-CoV infections in three human cell lines (H1299, Caco-2 and Calu-3 cells), Emanuel et al. (2020) (bioRxiv preprint doi: https://doi.org/10.1101/2020.05.05.079194) demonstrated strong expression of the immunity and inflammation-associated microRNA miRNA-155 upon viral infection with both viruses. Both viruses triggered a 16-fold upregulation of one form of miR-155 and a 3-fold upregulation of another.

A role for MIR155 in viral susceptibility for a range of viruses and the immune response has also been demonstrated in a series of mouse models:

PMID 23601686: In Mir155 -/- mice, Dudda et al. (2013) observed severely reduced accumulation of Cd8-positive T cells during acute and chronic viral infections with impaired control of viral replication. Lack of Mir155 led to an accumulation of Socs1 resulting in defective cytokine signaling through Stat5. Dudda et al. also concluded that MIR155 and its target, SOCS1, are key regulators of CD8-positive T cells.

PMID 23275599: Lind et al. (2013) found that mice lacking Mir155 had impaired Cd8 positive T-cell responses to infections with lymphocytic choriomeningitis virus and the intracellular bacteria Listeria monocytogenes and concluded that MIR155 is required for acute CD8-positive T-cell responses and proposed that targeting MIR155 may be useful in modulating immune responses.

PMID 24516198: Bhela et al. (2014) – 75 to 80% of MIR155 null mice infected ocularly with herpes simplex virus (HSV)-1 developed herpes simplex encephalitis with elevated viral titers in brain, but not in cornea. Immunohistochemical and flow cytometric analyses in Mir155-null mice showed diminished Cd8-positive T-cell numbers, functionality, and homing capacity. Adoptive transfer of HSV-1-immune Cd8-positive T cells to Mir155-null mice 24 hours after infection provided protection from HSE. The authors concluded that MIR155 deficiency results in enhanced susceptibility of the nervous system to HSV-1 infection.
COVID-19 research v0.347 KIAA0319L Alison Coffey commented on gene: KIAA0319L: Evidence Summary from Illumina curation team: KIAA0319L, also known as AAVR or AAVRL, encodes the KIAA0319 like protein, a type-I transmembrane protein which acts as an essential receptor for adeno-associated virus (AAV) and is involved in adeno-associated virus infection through endocytosis system (PMID 26814968: Pillay et al. 2016). Genetic ablation of AAVR renders a wide range of mammalian cell types highly resistant to AAV infection. Adeno-associated virus vectors are widely used in virus-based gene therapy because of their broad tissue tropism, non-pathogenic nature and low immunogenicity. PMID 26814968: Pillay et al. (2016) - used a haploid genetic screen to identify the type I transmembrane protein KIAA0319L as an essential receptor that mediates AAV entry and renamed this protein the AAV receptor (AAVR). The function of AAVR was confirmed by using CRISPRCas9 to knock out the receptor and by using anti-AAVR blocking antibodies; both treatments rendered cells highly resistant to AAV infection with several serotypes, including AAV2, which is the most commonly used serotype for gene therapy in clinical trials. Finally, Aavr knockout mice were more resistant to AAV-mediated gene therapy than mice that expressed AAVR. PMID 28679762: Pillay et al. (2017) - Further defines AAV-AAVR interactions, genetically and biochemically.
COVID-19 research v0.347 GNAQ Alison Coffey commented on gene: GNAQ: Evidence Summary from Illumina curation team: The GNAQ gene encodes the Gq protein alpha subunit and belongs to the Gq/11 subfamily of heterotrimeric G proteins. GNAQ is ubiquitously expressed in mammalian cells and couples a wide variety of receptors to channel proteins, enzymes, and other effector molecules. Wang et al. (2019) found that Gnaq expression was downregulated during viral infection and that Gnaq siRNA transfection of host cells protected against infection from vesicular stomatitis virus (VSV) and HSV type 1 infection. Viral replication was also reduced in Gnaq deficient macrophages in cell culture and Gnaq-deficient mice were more resistant than wildtype mice to VSV infection. Further cell culture experiments showed that Gnaq modulated its antiviral response through the canonical PLC-b/Ca2+ signalling (Wang et al. 2019). PMID: 31324725 Wang et al. (2019) - Wang et al. demonstrated that GNAQ negatively regulates the antiviral innate immune responses in a calcineurin-dependent manner. Viral infection downregulates GNAQ expression in cell culture. mRNA expression levels were measured upon infection with VSV in mouse PEMs, BMMs,the fibroblast line L929 and the macrophage mouse line RAW264.7. Fig1. GNAQ negatively regulates host defence against viruses. Gnaq-specific siRNA knockdown reduced VSV infection in PEMS, overexpression of GNAQ in HEK293 cells increased VSV infection (Fig 2). PEMS and BMMs from myeloid cellspecific Gnaq-deficient mice showed reduced replication of VSV and HSV1 compared to WT. VSV replication and titers in the liver, spleen, and lung of Gnaq-deficient mice were all significantly lower than wt litter mates. Gnaq deficiency increases host resistance to viral infection (Fig 3). IFN-b (both mRNA and protein) was significantly enhanced in Gnaq-knockdown PEMs, Poly I;C (mimicking RNA viral infection), VSV infection and HSV-1 infection enhanced IgnBeta production in Gnaq-knockdown PEMs. In cell lines and in vivo, GNAQ negatively regulates IFN-beta production (Fig 4). GNAQ modulates antiviral innate immune responses through canonical PLC-b/Ca2+ signalling. Chemical inhibitors of the pathway reduced cell resistance to infection (Fig 5).
COVID-19 research v0.316 MICA Sarah Leigh Deleted their comment
COVID-19 research v0.315 MICA Sarah Leigh commented on gene: MICA: One of the 25 top novel PID-associated genes in a large-cohort WGS analysis, using BeviMed assessment of enrichment for candidate disease-causing variants in individual genes (https://doi.org/10.1101/499988).
COVID-19 research v0.297 SCARB1 Eleanor Williams gene: SCARB1 was added
gene: SCARB1 was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: SCARB1 was set to Unknown
Added comment: Not associated with any relevant disease phenotype in OMIM. SCARB1 is also known as SRB1

PMID: 12356718 - Scarselli et al 2002 - Characterization of hepatitis C virus (HCV) envelope glycoprotein E2 binding after chemical or enzymic modification of the cell surface led to the identification of the scavenger receptor type B class I (SR-BI) as the E2 receptor on HepG2 cells.

PMID: 28827115 - Sadeghi et al 2017 - SCARB1 rs10846744 (CC) genotype (P=0.001) was strongly associated with sustained virological response

PMID: 28363797 - Westhaus et al 2018 - Non-synonymous variants: S112F and T175A have greatly reduced Hepatitus C virus (HCV) receptor function. When present on the cell surface, these variants are impaired in their ability to interact with HCV E2. Non-coding variants: The G allele in rs3782287 is associated with decreased viral load.

PMID: 29715527 - Naffari et al 2018 -looked at treatment responses in 395 treatment-naïve patients with chronic Hepatitus C Virus (CHC) genotype 1 treated with pegylated interferon-α and ribavirin. Rapid virologic response (RVR), complete early virologic response (cEVR) , and sustained virologic responseSVR were significantly associated with SCARB1 rs10846744 (CC).
Sources: Literature
COVID-19 research v0.273 MICA Rebecca Foulger Classified gene: MICA as Amber List (moderate evidence)
COVID-19 research v0.273 MICA Rebecca Foulger Added comment: Comment on list classification: MICA was identified through an OMIM search for potential viral susceptibility genes. Based on initial triage by Illumina (Tier 5 grouping) and additional curation, upgraded rating from Red to Amber: A number of publications report association between MICA variants and HBV‐related hepatocellular carcinoma. Additional papers investigate MICA polymorphisms and response to viral infections/recovery (e.g. PMIDs:28925058, 15029237).
COVID-19 research v0.273 MICA Rebecca Foulger Gene: mica has been classified as Amber List (Moderate Evidence).
COVID-19 research v0.272 MICA Rebecca Foulger Publications for gene: MICA were set to https://doi.org/10.1101/499988; 28925058; 31033131; 15029237
COVID-19 research v0.271 MICA Rebecca Foulger Publications for gene: MICA were set to https://doi.org/10.1101/499988; 28925058; 31033131
COVID-19 research v0.270 MICA Rebecca Foulger commented on gene: MICA: PMID:15029237. Karacki et al., 2004 investigated whether MICA polymorphisms are associated with HCV recovery. They compared the frequency of all known MICA polymorphisms in 2 large cohorts of people who recovered from either HCV or HBV infection and controls. Of the 27 unique MICA polymorphisms examined, only one was detected more often in persons who had cleared HCV infection, compared with controls: MICA*015. However <4% of all those examined with viral clearance were MICA*015 positive. They cannot exclude the possibility that MICA*015 is tightly linked to another allele that is responsible for the association.
COVID-19 research v0.270 MICA Rebecca Foulger changed review comment from: Publications on association between MICA variants and hepatitis B virus (HBV) infection and HBV‐related hepatocellular carcinoma (PMIDs:31419949, 29584564).; to: Several publications on association between MICA variants and hepatitis B virus (HBV) infection and HBV‐related hepatocellular carcinoma (PMIDs:31419949, 29584564,25270965).
COVID-19 research v0.270 MICA Rebecca Foulger commented on gene: MICA: Publications on association between MICA variants and hepatitis B virus (HBV) infection and HBV‐related hepatocellular carcinoma (PMIDs:31419949, 29584564).
COVID-19 research v0.270 MICA Rebecca Foulger Phenotypes for gene: MICA were changed from to primary immunodeficiency
COVID-19 research v0.269 MICA Rebecca Foulger Publications for gene: MICA were set to
COVID-19 research v0.268 MICA Rebecca Foulger commented on gene: MICA: PMID:28925058. Luo et al., 2017 examined MICA/MIBC gene polymorphisms and respiratory syncytial virus (RSV) infection in 135 paediatric patients with and without pneuomina after RSV infection. Allele MICA*002:01/A9 and haplotype MICA*002:01-MICB*005:02 were negatively associated with RSV respiratory tract infections.
COVID-19 research v0.268 MICA Rebecca Foulger commented on gene: MICA
COVID-19 research v0.260 MICA Sarah Leigh reviewed gene: MICA: Rating: RED; Mode of pathogenicity: ; Publications: https://doi.org/10.1101/499988; Phenotypes: primary immunodeficiency; Mode of inheritance: Unknown
COVID-19 research v0.250 MICA Sarah Leigh gene: MICA was added
gene: MICA was added to COVID-19 research. Sources: Literature
Mode of inheritance for gene: MICA was set to Unknown