* 164350

2-PRIME,5-PRIME-OLIGOADENYLATE SYNTHETASE 1; OAS1


Alternative titles; symbols

2-PRIME,5-PRIME-OLIGOISOADENYLATE SYNTHETASE; OIAS
2-PRIME,5-PRIME-A SYNTHETASE


HGNC Approved Gene Symbol: OAS1

Cytogenetic location: 12q24.13     Genomic coordinates (GRCh38): 12:112,906,962-112,933,219 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
12q24.13 Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinemia 618042 AD 3

TEXT

Description

The 2-prime,5-prime oligoadenylate synthetases (OASs), such as OAS1, are interferon-induced proteins characterized by their capacity to catalyze the synthesis of 2-prime,5-prime oligomers of adenosine (2-5As). 2-5As bind to and activate RNase L (RNASEL; 180435), which degrades viral and cellular RNAs, leading to inhibition of cellular protein synthesis and impairment of viral replication. In addition to a possible role in mediating resistance to virus infection, the 2-5A system has been implicated in the control of cell growth, differentiation, and apoptosis (summary by Hovnanian et al., 1998).


Cloning and Expression

Using a hybridization-translation assay, Merlin et al. (1983) identified a partial OAS1 cDNA. Northern blot analysis revealed that OAS1 was expressed as 1.6-, 1.8-, and 3.6-kb interferon-induced mRNAs in an SV80-transformed fibroblast cell line. By screening a library derived from interferon-treated human amniotic cells with an oligonucleotide based on the partial cDNA sequence, Wathelet et al. (1986) isolated an OAS1 cDNA corresponding to the 1.6-kb mRNA. The predicted protein contained 364 amino acids. In vitro translation of this OAS1 cDNA yielded a 39-kD protein. Injection of OAS1 mRNA into Xenopus oocytes resulted in production of active OAS. Benech et al. (1985) determined that cell-specific differential splicing gives rise to the 1.6- and 1.8-kb OAS1 mRNAs. The 1.8-kb mRNA encodes a second, longer, OAS1 isoform. The 2 isoforms share the same N-terminal 346 amino acids. Sequence analysis indicated that the longer OAS1 protein contains approximately 400 amino acids and has a deduced molecular mass of 46 kD.


Gene Structure

Benech et al. (1985) determined that the OAS1 gene contains 8 exons. the 1.6- and 1.8-kb transcripts are encoded by 7 and 8 exons, respectively. The 3.6-kb mRNA appears to be an incompletely spliced precursor of the 1.8-kb transcript.


Mapping

Williams et al. (1986) assigned the low molecular weight 2-5A synthetase gene to chromosome 12 using rodent-human somatic cell hybrids and filter hybridization analysis of cell hybrid DNA. Assignment to chromosome 12 was confirmed by Wathelet et al. (1988).

By fluorescence in situ hybridization and by inclusion within mapped clones, Hovnanian et al. (1998) determined that the OAS1, OAS2 (603350), and OAS3 (603351) genes are clustered with a 130-kb region on 12q24.2. The genes are transcribed in the same direction and are arranged in the order cen--5-prime--OAS1--OAS3--OAS2--3-prime--tel. They reported that the OAS1, OAS2, and OAS3 proteins contain 1, 2, and 3 conserved OAS domains or units, respectively, and proposed that the clustering of these genes reflects their evolutionary relationship possibly through the duplication of the conserved OAS functional domain.

Rutherford et al. (1991) found that there are 2 OAS1-related genes in mouse that are located within an approximately 40-kb region. Hovnanian et al. (1998) suggested that a duplication of the OAS functional domain might also have occurred in mouse.


Gene Function

Using a human lung cell line, Lin et al. (2009) showed that RNASEL played an antiviral role against Dengue virus (see 614371). Of the 10 OAS isoforms generated by alternative splicing of the 4 human OAS genes, only the p42 and p46 isoforms of OAS1 and the p100 isoform of OAS3 blocked Dengue virus replication by inducing RNASEL activity in infected cells.

Thavachelvam et al. (2015) previously showed that exogenous recombinant porcine Oas1 was taken up by cells and reduced viral replication both in cell culture and in vivo independently of Rnasel. Thavachelvam et al. (2015) found that recombinant porcine Oas1 was rapidly internalized and that heparin could block uptake of Oas1 and Oas1 antiviral activity. In addition, they demonstrated that Oas1 targeted an early step of the viral replication cycle.


Molecular Genetics

Susceptibility to Viral Infection

OAS genes are critical components of the innate immune response to viruses. The enzyme encoded by the OAS genes uses adenosine triphosphate in 2-prime-specific nucleotidyl transfer reactions to synthesize 2-prime,5-prime-oligoadenylates, which activate latent ribonuclease, resulting in degradation of viral RNA and inhibition of virus replication. Bonnevie-Nielsen et al. (2005) reported that new analysis of data from an earlier study of human 2-prime,5-prime AS response to yellow fever vaccine (Bonnevie-Nielsen et al., 1989) revealed a highly significant correlation between basal enzyme activity and virus-stimulated activity measured 7 days after vaccination. Bonnevie-Nielsen et al. (2005) asked whether constitutive activity is genetically determined and, if so, by what variants. Analysis of 83 families containing 2 parents and 2 children demonstrated significant correlations between basal activity in parent-child pairs (p less than 0.0001) and sib pairs (p = 0.0044), but not spousal pairs, suggesting strong genetic control of basal activity. They next analyzed association between basal activity and 15 markers across the OAS gene cluster. Significant association was detected at multiple markers, the strongest being at an A/G single-nucleotide polymorphism (SNP) at the exon 7 splice acceptor site (AG or AA) of the OAS1 gene (164350.0001). At this unusual polymorphism, allele G had a higher gene frequency in persons with high enzyme activity than in those with low enzyme activity. Enzyme activity varied in a dose-dependent manner across the GG, GA, and AA genotypes. Allele G generated the p46 enzyme isoform (Ghosh et al., 2001), whereas allele A ablated the splice site and generated a dual-function antiviral/proapoptotic p48 isoform and a novel p52 isoform. This genetic polymorphism makes OAS1 an excellent candidate for a human gene that influences host susceptibility to viral infection.

Because of the 2 to 10% primary failure rate of measles vaccination and the importance of innate immunity to prevent or reduce viral replication and spread until the adaptive immune response to eliminate the virus, Haralambieva et al. (2011) performed a comprehensive candidate gene association study in a racially diverse cohort of 745 healthy schoolchildren in Minnesota who had had 2 doses of measles vaccine. Variants within DDX58 (609631) were associated with measles-specific antibody variations in Caucasians. Four DDX58 polymorphisms in high linkage disequilibrium were also associated with variations in measles-specific IFNG (147570) and IL2 (147680) secretion in Caucasians. ADAR (146920) variants also had a role in regulating measles-specific IFNG responses in Caucasians. Two intronic OAS1 SNPs, including rs10774671, were associated with increased neutralizing antibody levels in African Americans. Haralambieva et al. (2011) concluded that multiple innate immunity genes and genetic variants are likely involved in modulating the adaptive immune response to live attenuated measles vaccine in Caucasians and African Americans.

Bigham et al. (2011) tested 360 common haplotype-tagging and/or functional SNPs in 86 genes encoding immune function regulators in 422 individuals with symptomatic West Nile virus (WNV; see 610379) infections and 331 WNV-infected individuals without symptoms. After correcting for multiple tests, they found that SNPs in IRF3 (603734) and MX1 (147150) were associated with symptomatic WNV infection and that a single SNP in OAS1, rs34137742, was associated with increased risk of WNV encephalitis and paralysis. Bigham et al. (2011) concluded that genetic variation in the interferon response pathway is associated with risk for symptomatic WNV infection and WNV disease progression.

By genotyping 501 WNV-infected Caucasians, Lim et al. (2009) showed that the frequency of the hypofunctional A allele of SNP rs10774671 of OAS1 was increased in both symptomatic and asymptomatic WNV seroconverters. Highest WNV accumulation occurred in tonsil tissue from donors homozygous for the hypofunctional A allele. Lim et al. (2009) concluded that OAS1 activity may influence the probability of initial WNV infection, but not the severity or symptomatic nature of the infection after WNV exposure.

By performing cis-expression quantitative trait locus (eQTL) analysis focusing on differentially expressed type I IFN-inducible transcripts in Sjogren syndrome (SS; 270150) patients, Li et al. (2017) identified multiple eQTLs associated with OAS1 transcript levels peaking at rs10774671. Metaanalysis of 2 independent cohorts confirmed an association of SS susceptibility with rs10774671. The risk allele shifted splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. These 3 alternative transcripts lacked translational response to type I IFN stimulation. Li et al. (2017) concluded that OAS1 is a risk locus for SS and may be associated with defective viral clearance due to altered IFN responses.

In large-scale cohorts of over 20,000 individuals of European descent, Zhou et al. (2021) found an association between increased circulating levels of OAS1 protein and protection from COVID-19 in a noninfectious state. The increased OAS1 levels protected against 3 measured outcomes: infection, hospitalization, and overall disease severity. The protection was likely due to increased levels of the p46 isoform, which is associated with the ancestral G allele of rs10774671, and has been shown to be more active in certain viral infections. OAS1 protein levels were drawn from a cohort of 399 individuals who tested positive for SARS-CoV-2 and 105 individuals who were negative for SARS-CoV-2. These results confirmed that increased OAS1 levels in noninfectious samples were associated with reduced odds of adverse COVID outcomes. However, during active infection with SARS-CoV-2, increased OAS1 levels were associated with increased odds of adverse COVID-19 outcomes. The findings suggested that increased OAS1 levels in a noninfectious state are associated with better outcomes and that during infection, OAS1 levels are increased, which may lead to poorer outcomes.

Immunodeficiency 100 with Pulmonary Alveolar Proteinosis and Hypogammaglobulinemia

In 5 Japanese patients, including 3 sibs, with immunodeficiency-100 with pulmonary alveolar proteinosis and hypogammaglobulinemia (IMD100; 618042), Cho et al. (2018) identified 3 different de novo heterozygous missense variants in the OAS1 gene (164350.0003-164350.0005). The variant in the first family was found by whole-exome sequencing; variants in the second 2 unrelated patients were found by direct sequencing. The unaffected mother in the first family was found to be a low-level mosaic for the variant. Molecular modeling indicated that the variants may affect important functional domains of the protein. However, functional studies of the variants and studies of patient cells were not performed. Cho et al. (2018) speculated that these de novo heterozygous OAS1 variants, which are presumably gain-of-function variants, may be associated with an exaggerated immune reaction in alveolar macrophages in response to viral infections, thus leading to their dysfunction and consequent impaired catabolism of lung surfactant.

In 6 unrelated patients with IMD100, Magg et al. (2021) identified de novo heterozygous gain-of-function missense mutations in the OAS1 gene (164350.0003-164350.0006). One of the patients was Japanese and had previously been reported by Cho et al. (2018); the other patients were of European or Hispanic origin. In vitro functional expression studies of patient cells showed impaired B-cell and T-cell proliferation and differentiation. This was associated with increased apoptosis of monocytes and B cells, but not apoptosis of T cells. The T-cell defect was attributed to defective costimulation of OAS1 B cells and monocytes. Studies of recombinant mutant proteins showed that they caused inappropriate 2-5A synthesis independent of dsRNA. Interferon-induced expression of the mutants increased RNase L-mediated cleavage of cellular RNA, leading to transcriptome alteration, translational arrest, and dysfunction and apoptosis of monocytes, iPSC-derived macrophages, and B cells. Macrophages with the mutations showed impaired adhesion and clustering, scavenger receptor expression, and phagocytosis in an RNase L-dependent manner that correlated with downregulated concomitant gene sets. RNase L inhibition with curcumin modulated the defects in vitro, and hematopoietic stem cell transplant in humans was curative. The authors suggested that hypogammaglobulinemia may cause susceptibility to infection, whereas monocyte and tissue macrophage dysfunction may cause the accumulation of proinflammatory damage-associated molecular patterns. The findings were consistent with a gain-of-function effect.


Evolution

Carey et al. (2019) reported that OAS1 loss-of-function variants are frequent in primates. They developed a yeast assay for OAS1/RNase L activity to test OAS1 proteins from genes cloned from different species. The gorilla Oas1 variant with an arg130-to-cys (R130C) substitution caused attenuated activity that could be reversed by correcting the sequence. The C130 allele was present in about one-third of gorillas tested. Oas1 loss-of-function alleles were also identified in various New World monkeys, and tamarins showed a complete loss of Oas1 activity. Carey et al. (2019) concluded that, in some species, the cost of activating the OAS1/RNase L pathway reduces fitness more than the positive effects of pathogen protection.


ALLELIC VARIANTS ( 6 Selected Examples):

.0001 OAS1 POLYMORPHISM

OAS1, IVS6, G-A, -1 (rs10774671)
  
RCV000015021

The G-to-A splice polymorphism rs10774671 in the OAS1 gene induces alternative splicing that creates the p46 and p42 isoforms. Most individuals of European origin carry the alternative A allele. The ancestral G allele is the major allele in African populations, and became fixed in the Neanderthal genome. The G allele increases production of the p46 OAS1 isoform, which is more active than p42 in certain viral infections. This polymorphism is in linkage disequilibrium with another polymorphism, rs4767027, which is also associated with higher OAS1 levels (summary by Zhou et al., 2021).

Bonnevie-Nielsen et al. (2005) found an unusual splice acceptor site polymorphism of the OAS1 gene associated with high constitutive activity of the OAS enzyme. Enzyme activity varied in a dose-dependent manner across the GG, GA, and AA genotypes, with the allele G having the higher frequency in persons with high enzyme activity. Because constitutive enzyme activity of 2-prime,5-prime AS had been shown to correlate with strength of response to viral infections (Bonnevie-Nielsen et al., 1989), Bonnevie-Nielsen et al. (2005) suggested that OAS1 is a strong candidate for determining susceptibility or resistance to viral infections.

Susceptibility to SARS-CoV-2

In large-scale cohorts of over 20,000 individuals of European descent, Zhou et al. (2021) found an association between increased circulating levels of OAS1 protein and protection from COVID-19 in a noninfectious state. The increased OAS1 levels protected against 3 measured outcomes: infection, hospitalization, and overall disease severity. The protection was likely due to increased levels of the p46 isoform, which is associated with the ancestral G allele of rs10774671, and has been shown to be more active in certain viral infections.

In detailed in vitro cellular studies, Wickenhagen et al. (2021) determined that a prenylated form of OAS1 isoform p46 is necessary to initiate a block to SARS-CoV-2. Prenylation of the C terminus of OAS1 targeted it to perinuclear structures rich in viral dsRNA, whereas nonprenylated OAS1 was diffusely localized and unable to initiate a detectable block to SARS-CoV-2 replication. The antiviral activity of OAS1 was effective only in the presence of RNase L (RNASEL; 180435). OAS1 was able to sense conserved dsRNA structures in the SARS-CoV-2 5-prime untranslated region; this antiviral activity was highly specific for SARS-CoV-2 and not other viruses tested. The authors noted that the p46 isoform can be expressed only by the G allele of rs10774671; thus, only individuals with at least one G allele are able to express the OAS1 isoform necessary to initiate a block to SARS-CoV-2. Transcriptome analysis of 499 hospitalized COVID-19 patients from the UK showed that absence of the prenylated form of OAS1 was associated with more severe disease. Individuals lacking the p46 transcript (212 patients, 42.5%) were more likely to have severe disease (95 patients, 44.8%) compared to those expressing the p46 transcript (287 patients, 57.5%), of whom 34.1% (98 patients) had severe disease (OR 1.57, p = 0.016).

Possible Association With Type I Diabetes Mellitus

In a case-sib control study, Field et al. (2005) found that the minor allele (G) of the intron 6 OAS1 SNP (rs10774671) was associated with type 1 diabetes (T1D; see 222100). Tessier et al. (2006) confirmed this T1D association in 784 nuclear families (2 parents and at least 1 affected offspring) by the transmission disequilibrium test (TDT; G:A = 386:329, p = 0.033). However, because of linkage disequilibrium within OAS1 and with the other 2 OAS genes, functional attribution of the association to this SNP could not be assumed. To help answer this question, they also genotyped 2 nonsynonymous SNPs in OAS1 exons 3 and 7. All 3 SNPs showed significant transmission distortion. Tessier et al. (2006) described this variant as an A-to-G substitution and gave the frequency of the minor allele (G) as 0.373. They confirmed the T1D association with the splicing variant but concluded that it cannot be attributed (solely) to the splicing variant; they considered the ser162-to-gly substitution (164350.0002) in OAS1 exon 3 as more likely a functional variant.

Hamosh (2018) found this variant (c.1039-1G-A) in 182,659 of 274,116 alleles and in 62,631 homozygotes in the combined populations of the gnomAD database, for an allele frequency of 0.6664 (July 3, 2018).


.0002 RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

OAS1, SER162GLY
  
RCV000015022...

This variant, formerly titled DIABETES MELLITUS, TYPE 1, SUSCEPTIBILITY TO, has been reclassified based on a review of the gnomAD database by Hamosh (2018).

Tessier et al. (2006) confirmed the association of type 1 diabetes (222100) with a splicing alteration in OAS1 (164350.0001) but concluded that the closely linked ser162-to-gly (S162G; rs3741981) mutation is more likely responsible for the association. Tessier et al. (2006) described this variant as a C-to-T substitution and gave the frequency of the minor allele (C) as 0.373.

Hamosh (2018) found this variant (GLY162SER) in 155,412 of 275,902 alleles and in 46,108 homozygotes in the combined populations of the gnomAD database, for an allele frequency of 0.5633 (July 3, 2018).


.0003 IMMUNODEFICIENCY 100 WITH PULMONARY ALVEOLAR PROTEINOSIS AND HYPOGAMMAGLOBULINEMIA

OAS1, ALA76VAL
  
RCV000660868

In 3 Japanese sibs, born of unrelated parents (family A), with immunodeficiency-100 with pulmonary alveolar proteinosis and hypogammaglobulinemia (IMD100; 618042), Cho et al. (2018) identified a de novo heterozygous c.227C-T transition (c.227C-T, NM_016816.3) in the OAS1 gene, resulting in an ala76-to-val (A76V) substitution at a conserved residue between the metal binding sites (asp75 and asp77). The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Sequencing Project or ExAC databases, or in an in-house database of 153 exomes. The unaffected mother was found to be mosaic for the variant (3.81%). Molecular modeling indicated that ala76 is involved in a hydrophobic core that would define the active site structure in the RNA-bound form, suggesting that the A76V variant may affect enzymatic activity. Functional studies of the variant and studies of patient cells were not performed.

Magg et al. (2021) identified a de novo heterozygous A76V mutation in the OAS1 gene in a girl of European descent with IMD100. In vitro functional expression studies showed that the variant resulted in a gain-of-function effect with IFN-induced RNase L (180435) pathway-mediated hyperinflammatory monocyte and B-cell dysfunction.


.0004 IMMUNODEFICIENCY 100 WITH PULMONARY ALVEOLAR PROTEINOSIS AND HYPOGAMMAGLOBULINEMIA

OAS1, CYS109TYR
  
RCV000660869...

In a Japanese girl (family B) with immunodeficiency-100 with pulmonary alveolar proteinosis and hypogammaglobulinemia (IMD100; 618042), originally reported by Tanaka-Kubota et al. (2018), Cho et al. (2018) identified a de novo heterozygous c.326G-A transition (c.326G-A, NM_016816.3) in the OAS1 gene, resulting in a cys109-to-tyr (C109Y) substitution at a conserved residue. The variant, which was found by direct sequencing of the OAS1 gene, was not found in the ExAC or Exome Sequencing Project databases. Molecular modeling suggested that the C109Y variant likely disrupts the hydrophobic core of the apo form of OAS1, which is important for regulation of enzymatic activity by dsRNA. Functional studies of the variant and studies of patient cells were not performed.

Magg et al. (2021) identified a de novo heterozygous C109Y mutation in the OAS1 gene in 3 unrelated patients of European descent with IMD100. In vitro functional expression studies showed that the variant resulted in a gain-of-function effect with IFN-induced RNase L (180435) pathway-mediated hyperinflammatory monocyte and B-cell dysfunction.


.0005 IMMUNODEFICIENCY 100 WITH PULMONARY ALVEOLAR PROTEINOSIS AND HYPOGAMMAGLOBULINEMIA

OAS1, LEU198VAL
  
RCV000660870

In a Japanese girl (family C) with immunodeficiency-100 with pulmonary alveolar proteinosis and hypogammaglobulinemia (IMD100; 618042), originally reported by Tanaka-Kubota et al. (2018), Cho et al. (2018) identified a de novo heterozygous c.592C-G transversion (c.592C-G, NM_016816.3) in the OAS1 gene, resulting in a leu198-to-val (L198V) substitution at a conserved residue. The variant, which was found by direct sequencing of the OAS1 gene, was not found in the ExAC or Exome Sequencing Project databases. Molecular modeling suggested that the L198V variant may impair ATP binding and enzymatic activity. Functional studies of the variant and studies of patient cells were not performed.

Magg et al. (2021) restudied this individual as patient 5 and demonstrated that the L198V variant resulted in a gain-of-function effect with IFN-induced RNase L (180435) pathway-mediated hyperinflammatory monocyte and B-cell dysfunction.


.0006 IMMUNODEFICIENCY 100 WITH PULMONARY ALVEOLAR PROTEINOSIS AND HYPOGAMMAGLOBULINEMIA

OAS1, VAL121GLY
  
RCV002248449

In a girl of Latino descent (patient 4) with immunodeficiency-100 with pulmonary alveolar proteinosis and hypogammaglobulinemia (IMD100; 618042), Magg et al. (2021) identified a de novo heterozygous c.362T-G transversion (c.362T-G, NM_002534.3) in the OAS1 gene, resulting in a val121-to-gly (V121G) substitution. In vitro functional expression studies showed that the variant resulted in a gain-of-function effect with IFN-induced RNase L (180435) pathway-mediated hyperinflammatory monocyte and B-cell dysfunction.


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  21. Wathelet, M. G., Szpirer, J., Nols, C. B., Clauss, I. M., De Wit, L., Islam, M. Q., Levan, G., Horisberger, M. A., Content, J., Szpirer, C., Huez, G. A. Cloning and chromosomal location of human genes inducible by type I interferon. Somat. Cell Molec. Genet. 14: 415-426, 1988. [PubMed: 3175763, related citations] [Full Text]

  22. Wathelet, M., Moutschen, S., Cravador, A., DeWit, L., Defilippi, P., Huez, G., Content, J. Full-length sequence and expression of the 42 kDa 2-5A synthetase induced by human interferon. FEBS Lett. 196: 113-120, 1986. [PubMed: 3753689, related citations] [Full Text]

  23. Wickenhagen, A., Sugrue, E., Lytras, S., Kuchi, S., Noerenberg, M., Turnbull, M. L., Loney, C., Herder, V., Allan, J., Jarmson, I., Cameron-Ruiz, N., Varjak, M., and 37 others. A prenylated dsRNA sensor protects against severe COVID-19. Science 374: eabj3624, 2021. [PubMed: 34581622, images, related citations] [Full Text]

  24. Williams, B. R. G., Saunders, M. E., Willard, H. F. Interferon-regulated human 2-5A synthetase gene maps to chromosome 12. Somat. Cell Molec. Genet. 12: 403-408, 1986. [PubMed: 2426799, related citations] [Full Text]

  25. Zhou, S., Butler-Laporte, G., Nakanishi, T., Morrison, D. R., Afilalo, J., Afilalo, M., Laurent, L., Pietzner, M., Kerrison, N., Zhao, K., Brunet-Ratnasingham, E., Henry, D., and 29 others. A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity. Nature Med. 27: 659-667, 2021. [PubMed: 33633408, related citations] [Full Text]


Alan F. Scott - updated : 07/07/2022
Cassandra L. Kniffin - updated : 05/11/2022
Cassandra L. Kniffin - updated : 06/29/2018
Paul J. Converse - updated : 08/15/2017
Paul J. Converse - updated : 05/03/2016
Paul J. Converse - updated : 9/11/2015
Paul J. Converse - updated : 7/3/2012
Victor A. McKusick - updated : 3/9/2006
Victor A. McKusick - updated : 3/11/2005
Rebekah S. Rasooly - updated : 12/9/1998
Creation Date:
Victor A. McKusick : 6/2/1986
carol : 09/21/2022
mgross : 07/07/2022
alopez : 05/16/2022
ckniffin : 05/11/2022
carol : 05/17/2019
alopez : 07/05/2018
ckniffin : 07/03/2018
ckniffin : 06/29/2018
carol : 08/16/2017
mgross : 08/15/2017
mgross : 05/03/2016
mgross : 9/11/2015
mgross : 7/20/2012
mgross : 7/20/2012
terry : 7/3/2012
mgross : 6/22/2012
carol : 12/29/2011
joanna : 8/18/2010
alopez : 3/15/2006
alopez : 3/14/2006
terry : 3/9/2006
tkritzer : 5/10/2005
alopez : 3/16/2005
terry : 3/11/2005
kayiaros : 7/13/1999
alopez : 12/9/1998
alopez : 10/27/1998
supermim : 3/16/1992
carol : 10/23/1991
supermim : 3/20/1990
ddp : 10/27/1989
root : 7/5/1989
marie : 3/25/1988

* 164350

2-PRIME,5-PRIME-OLIGOADENYLATE SYNTHETASE 1; OAS1


Alternative titles; symbols

2-PRIME,5-PRIME-OLIGOISOADENYLATE SYNTHETASE; OIAS
2-PRIME,5-PRIME-A SYNTHETASE


HGNC Approved Gene Symbol: OAS1

Cytogenetic location: 12q24.13     Genomic coordinates (GRCh38): 12:112,906,962-112,933,219 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
12q24.13 Immunodeficiency 100 with pulmonary alveolar proteinosis and hypogammaglobulinemia 618042 Autosomal dominant 3

TEXT

Description

The 2-prime,5-prime oligoadenylate synthetases (OASs), such as OAS1, are interferon-induced proteins characterized by their capacity to catalyze the synthesis of 2-prime,5-prime oligomers of adenosine (2-5As). 2-5As bind to and activate RNase L (RNASEL; 180435), which degrades viral and cellular RNAs, leading to inhibition of cellular protein synthesis and impairment of viral replication. In addition to a possible role in mediating resistance to virus infection, the 2-5A system has been implicated in the control of cell growth, differentiation, and apoptosis (summary by Hovnanian et al., 1998).


Cloning and Expression

Using a hybridization-translation assay, Merlin et al. (1983) identified a partial OAS1 cDNA. Northern blot analysis revealed that OAS1 was expressed as 1.6-, 1.8-, and 3.6-kb interferon-induced mRNAs in an SV80-transformed fibroblast cell line. By screening a library derived from interferon-treated human amniotic cells with an oligonucleotide based on the partial cDNA sequence, Wathelet et al. (1986) isolated an OAS1 cDNA corresponding to the 1.6-kb mRNA. The predicted protein contained 364 amino acids. In vitro translation of this OAS1 cDNA yielded a 39-kD protein. Injection of OAS1 mRNA into Xenopus oocytes resulted in production of active OAS. Benech et al. (1985) determined that cell-specific differential splicing gives rise to the 1.6- and 1.8-kb OAS1 mRNAs. The 1.8-kb mRNA encodes a second, longer, OAS1 isoform. The 2 isoforms share the same N-terminal 346 amino acids. Sequence analysis indicated that the longer OAS1 protein contains approximately 400 amino acids and has a deduced molecular mass of 46 kD.


Gene Structure

Benech et al. (1985) determined that the OAS1 gene contains 8 exons. the 1.6- and 1.8-kb transcripts are encoded by 7 and 8 exons, respectively. The 3.6-kb mRNA appears to be an incompletely spliced precursor of the 1.8-kb transcript.


Mapping

Williams et al. (1986) assigned the low molecular weight 2-5A synthetase gene to chromosome 12 using rodent-human somatic cell hybrids and filter hybridization analysis of cell hybrid DNA. Assignment to chromosome 12 was confirmed by Wathelet et al. (1988).

By fluorescence in situ hybridization and by inclusion within mapped clones, Hovnanian et al. (1998) determined that the OAS1, OAS2 (603350), and OAS3 (603351) genes are clustered with a 130-kb region on 12q24.2. The genes are transcribed in the same direction and are arranged in the order cen--5-prime--OAS1--OAS3--OAS2--3-prime--tel. They reported that the OAS1, OAS2, and OAS3 proteins contain 1, 2, and 3 conserved OAS domains or units, respectively, and proposed that the clustering of these genes reflects their evolutionary relationship possibly through the duplication of the conserved OAS functional domain.

Rutherford et al. (1991) found that there are 2 OAS1-related genes in mouse that are located within an approximately 40-kb region. Hovnanian et al. (1998) suggested that a duplication of the OAS functional domain might also have occurred in mouse.


Gene Function

Using a human lung cell line, Lin et al. (2009) showed that RNASEL played an antiviral role against Dengue virus (see 614371). Of the 10 OAS isoforms generated by alternative splicing of the 4 human OAS genes, only the p42 and p46 isoforms of OAS1 and the p100 isoform of OAS3 blocked Dengue virus replication by inducing RNASEL activity in infected cells.

Thavachelvam et al. (2015) previously showed that exogenous recombinant porcine Oas1 was taken up by cells and reduced viral replication both in cell culture and in vivo independently of Rnasel. Thavachelvam et al. (2015) found that recombinant porcine Oas1 was rapidly internalized and that heparin could block uptake of Oas1 and Oas1 antiviral activity. In addition, they demonstrated that Oas1 targeted an early step of the viral replication cycle.


Molecular Genetics

Susceptibility to Viral Infection

OAS genes are critical components of the innate immune response to viruses. The enzyme encoded by the OAS genes uses adenosine triphosphate in 2-prime-specific nucleotidyl transfer reactions to synthesize 2-prime,5-prime-oligoadenylates, which activate latent ribonuclease, resulting in degradation of viral RNA and inhibition of virus replication. Bonnevie-Nielsen et al. (2005) reported that new analysis of data from an earlier study of human 2-prime,5-prime AS response to yellow fever vaccine (Bonnevie-Nielsen et al., 1989) revealed a highly significant correlation between basal enzyme activity and virus-stimulated activity measured 7 days after vaccination. Bonnevie-Nielsen et al. (2005) asked whether constitutive activity is genetically determined and, if so, by what variants. Analysis of 83 families containing 2 parents and 2 children demonstrated significant correlations between basal activity in parent-child pairs (p less than 0.0001) and sib pairs (p = 0.0044), but not spousal pairs, suggesting strong genetic control of basal activity. They next analyzed association between basal activity and 15 markers across the OAS gene cluster. Significant association was detected at multiple markers, the strongest being at an A/G single-nucleotide polymorphism (SNP) at the exon 7 splice acceptor site (AG or AA) of the OAS1 gene (164350.0001). At this unusual polymorphism, allele G had a higher gene frequency in persons with high enzyme activity than in those with low enzyme activity. Enzyme activity varied in a dose-dependent manner across the GG, GA, and AA genotypes. Allele G generated the p46 enzyme isoform (Ghosh et al., 2001), whereas allele A ablated the splice site and generated a dual-function antiviral/proapoptotic p48 isoform and a novel p52 isoform. This genetic polymorphism makes OAS1 an excellent candidate for a human gene that influences host susceptibility to viral infection.

Because of the 2 to 10% primary failure rate of measles vaccination and the importance of innate immunity to prevent or reduce viral replication and spread until the adaptive immune response to eliminate the virus, Haralambieva et al. (2011) performed a comprehensive candidate gene association study in a racially diverse cohort of 745 healthy schoolchildren in Minnesota who had had 2 doses of measles vaccine. Variants within DDX58 (609631) were associated with measles-specific antibody variations in Caucasians. Four DDX58 polymorphisms in high linkage disequilibrium were also associated with variations in measles-specific IFNG (147570) and IL2 (147680) secretion in Caucasians. ADAR (146920) variants also had a role in regulating measles-specific IFNG responses in Caucasians. Two intronic OAS1 SNPs, including rs10774671, were associated with increased neutralizing antibody levels in African Americans. Haralambieva et al. (2011) concluded that multiple innate immunity genes and genetic variants are likely involved in modulating the adaptive immune response to live attenuated measles vaccine in Caucasians and African Americans.

Bigham et al. (2011) tested 360 common haplotype-tagging and/or functional SNPs in 86 genes encoding immune function regulators in 422 individuals with symptomatic West Nile virus (WNV; see 610379) infections and 331 WNV-infected individuals without symptoms. After correcting for multiple tests, they found that SNPs in IRF3 (603734) and MX1 (147150) were associated with symptomatic WNV infection and that a single SNP in OAS1, rs34137742, was associated with increased risk of WNV encephalitis and paralysis. Bigham et al. (2011) concluded that genetic variation in the interferon response pathway is associated with risk for symptomatic WNV infection and WNV disease progression.

By genotyping 501 WNV-infected Caucasians, Lim et al. (2009) showed that the frequency of the hypofunctional A allele of SNP rs10774671 of OAS1 was increased in both symptomatic and asymptomatic WNV seroconverters. Highest WNV accumulation occurred in tonsil tissue from donors homozygous for the hypofunctional A allele. Lim et al. (2009) concluded that OAS1 activity may influence the probability of initial WNV infection, but not the severity or symptomatic nature of the infection after WNV exposure.

By performing cis-expression quantitative trait locus (eQTL) analysis focusing on differentially expressed type I IFN-inducible transcripts in Sjogren syndrome (SS; 270150) patients, Li et al. (2017) identified multiple eQTLs associated with OAS1 transcript levels peaking at rs10774671. Metaanalysis of 2 independent cohorts confirmed an association of SS susceptibility with rs10774671. The risk allele shifted splicing of OAS1 from production of the p46 isoform to multiple alternative transcripts, including p42, p48, and p44. These 3 alternative transcripts lacked translational response to type I IFN stimulation. Li et al. (2017) concluded that OAS1 is a risk locus for SS and may be associated with defective viral clearance due to altered IFN responses.

In large-scale cohorts of over 20,000 individuals of European descent, Zhou et al. (2021) found an association between increased circulating levels of OAS1 protein and protection from COVID-19 in a noninfectious state. The increased OAS1 levels protected against 3 measured outcomes: infection, hospitalization, and overall disease severity. The protection was likely due to increased levels of the p46 isoform, which is associated with the ancestral G allele of rs10774671, and has been shown to be more active in certain viral infections. OAS1 protein levels were drawn from a cohort of 399 individuals who tested positive for SARS-CoV-2 and 105 individuals who were negative for SARS-CoV-2. These results confirmed that increased OAS1 levels in noninfectious samples were associated with reduced odds of adverse COVID outcomes. However, during active infection with SARS-CoV-2, increased OAS1 levels were associated with increased odds of adverse COVID-19 outcomes. The findings suggested that increased OAS1 levels in a noninfectious state are associated with better outcomes and that during infection, OAS1 levels are increased, which may lead to poorer outcomes.

Immunodeficiency 100 with Pulmonary Alveolar Proteinosis and Hypogammaglobulinemia

In 5 Japanese patients, including 3 sibs, with immunodeficiency-100 with pulmonary alveolar proteinosis and hypogammaglobulinemia (IMD100; 618042), Cho et al. (2018) identified 3 different de novo heterozygous missense variants in the OAS1 gene (164350.0003-164350.0005). The variant in the first family was found by whole-exome sequencing; variants in the second 2 unrelated patients were found by direct sequencing. The unaffected mother in the first family was found to be a low-level mosaic for the variant. Molecular modeling indicated that the variants may affect important functional domains of the protein. However, functional studies of the variants and studies of patient cells were not performed. Cho et al. (2018) speculated that these de novo heterozygous OAS1 variants, which are presumably gain-of-function variants, may be associated with an exaggerated immune reaction in alveolar macrophages in response to viral infections, thus leading to their dysfunction and consequent impaired catabolism of lung surfactant.

In 6 unrelated patients with IMD100, Magg et al. (2021) identified de novo heterozygous gain-of-function missense mutations in the OAS1 gene (164350.0003-164350.0006). One of the patients was Japanese and had previously been reported by Cho et al. (2018); the other patients were of European or Hispanic origin. In vitro functional expression studies of patient cells showed impaired B-cell and T-cell proliferation and differentiation. This was associated with increased apoptosis of monocytes and B cells, but not apoptosis of T cells. The T-cell defect was attributed to defective costimulation of OAS1 B cells and monocytes. Studies of recombinant mutant proteins showed that they caused inappropriate 2-5A synthesis independent of dsRNA. Interferon-induced expression of the mutants increased RNase L-mediated cleavage of cellular RNA, leading to transcriptome alteration, translational arrest, and dysfunction and apoptosis of monocytes, iPSC-derived macrophages, and B cells. Macrophages with the mutations showed impaired adhesion and clustering, scavenger receptor expression, and phagocytosis in an RNase L-dependent manner that correlated with downregulated concomitant gene sets. RNase L inhibition with curcumin modulated the defects in vitro, and hematopoietic stem cell transplant in humans was curative. The authors suggested that hypogammaglobulinemia may cause susceptibility to infection, whereas monocyte and tissue macrophage dysfunction may cause the accumulation of proinflammatory damage-associated molecular patterns. The findings were consistent with a gain-of-function effect.


Evolution

Carey et al. (2019) reported that OAS1 loss-of-function variants are frequent in primates. They developed a yeast assay for OAS1/RNase L activity to test OAS1 proteins from genes cloned from different species. The gorilla Oas1 variant with an arg130-to-cys (R130C) substitution caused attenuated activity that could be reversed by correcting the sequence. The C130 allele was present in about one-third of gorillas tested. Oas1 loss-of-function alleles were also identified in various New World monkeys, and tamarins showed a complete loss of Oas1 activity. Carey et al. (2019) concluded that, in some species, the cost of activating the OAS1/RNase L pathway reduces fitness more than the positive effects of pathogen protection.


ALLELIC VARIANTS 6 Selected Examples):

.0001   OAS1 POLYMORPHISM

OAS1, IVS6, G-A, -1 ({dbSNP rs10774671})
SNP: rs10774671, gnomAD: rs10774671, ClinVar: RCV000015021

The G-to-A splice polymorphism rs10774671 in the OAS1 gene induces alternative splicing that creates the p46 and p42 isoforms. Most individuals of European origin carry the alternative A allele. The ancestral G allele is the major allele in African populations, and became fixed in the Neanderthal genome. The G allele increases production of the p46 OAS1 isoform, which is more active than p42 in certain viral infections. This polymorphism is in linkage disequilibrium with another polymorphism, rs4767027, which is also associated with higher OAS1 levels (summary by Zhou et al., 2021).

Bonnevie-Nielsen et al. (2005) found an unusual splice acceptor site polymorphism of the OAS1 gene associated with high constitutive activity of the OAS enzyme. Enzyme activity varied in a dose-dependent manner across the GG, GA, and AA genotypes, with the allele G having the higher frequency in persons with high enzyme activity. Because constitutive enzyme activity of 2-prime,5-prime AS had been shown to correlate with strength of response to viral infections (Bonnevie-Nielsen et al., 1989), Bonnevie-Nielsen et al. (2005) suggested that OAS1 is a strong candidate for determining susceptibility or resistance to viral infections.

Susceptibility to SARS-CoV-2

In large-scale cohorts of over 20,000 individuals of European descent, Zhou et al. (2021) found an association between increased circulating levels of OAS1 protein and protection from COVID-19 in a noninfectious state. The increased OAS1 levels protected against 3 measured outcomes: infection, hospitalization, and overall disease severity. The protection was likely due to increased levels of the p46 isoform, which is associated with the ancestral G allele of rs10774671, and has been shown to be more active in certain viral infections.

In detailed in vitro cellular studies, Wickenhagen et al. (2021) determined that a prenylated form of OAS1 isoform p46 is necessary to initiate a block to SARS-CoV-2. Prenylation of the C terminus of OAS1 targeted it to perinuclear structures rich in viral dsRNA, whereas nonprenylated OAS1 was diffusely localized and unable to initiate a detectable block to SARS-CoV-2 replication. The antiviral activity of OAS1 was effective only in the presence of RNase L (RNASEL; 180435). OAS1 was able to sense conserved dsRNA structures in the SARS-CoV-2 5-prime untranslated region; this antiviral activity was highly specific for SARS-CoV-2 and not other viruses tested. The authors noted that the p46 isoform can be expressed only by the G allele of rs10774671; thus, only individuals with at least one G allele are able to express the OAS1 isoform necessary to initiate a block to SARS-CoV-2. Transcriptome analysis of 499 hospitalized COVID-19 patients from the UK showed that absence of the prenylated form of OAS1 was associated with more severe disease. Individuals lacking the p46 transcript (212 patients, 42.5%) were more likely to have severe disease (95 patients, 44.8%) compared to those expressing the p46 transcript (287 patients, 57.5%), of whom 34.1% (98 patients) had severe disease (OR 1.57, p = 0.016).

Possible Association With Type I Diabetes Mellitus

In a case-sib control study, Field et al. (2005) found that the minor allele (G) of the intron 6 OAS1 SNP (rs10774671) was associated with type 1 diabetes (T1D; see 222100). Tessier et al. (2006) confirmed this T1D association in 784 nuclear families (2 parents and at least 1 affected offspring) by the transmission disequilibrium test (TDT; G:A = 386:329, p = 0.033). However, because of linkage disequilibrium within OAS1 and with the other 2 OAS genes, functional attribution of the association to this SNP could not be assumed. To help answer this question, they also genotyped 2 nonsynonymous SNPs in OAS1 exons 3 and 7. All 3 SNPs showed significant transmission distortion. Tessier et al. (2006) described this variant as an A-to-G substitution and gave the frequency of the minor allele (G) as 0.373. They confirmed the T1D association with the splicing variant but concluded that it cannot be attributed (solely) to the splicing variant; they considered the ser162-to-gly substitution (164350.0002) in OAS1 exon 3 as more likely a functional variant.

Hamosh (2018) found this variant (c.1039-1G-A) in 182,659 of 274,116 alleles and in 62,631 homozygotes in the combined populations of the gnomAD database, for an allele frequency of 0.6664 (July 3, 2018).


.0002   RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE

OAS1, SER162GLY
SNP: rs1131454, gnomAD: rs1131454, ClinVar: RCV000015022, RCV001513965, RCV003488339, RCV003974825

This variant, formerly titled DIABETES MELLITUS, TYPE 1, SUSCEPTIBILITY TO, has been reclassified based on a review of the gnomAD database by Hamosh (2018).

Tessier et al. (2006) confirmed the association of type 1 diabetes (222100) with a splicing alteration in OAS1 (164350.0001) but concluded that the closely linked ser162-to-gly (S162G; rs3741981) mutation is more likely responsible for the association. Tessier et al. (2006) described this variant as a C-to-T substitution and gave the frequency of the minor allele (C) as 0.373.

Hamosh (2018) found this variant (GLY162SER) in 155,412 of 275,902 alleles and in 46,108 homozygotes in the combined populations of the gnomAD database, for an allele frequency of 0.5633 (July 3, 2018).


.0003   IMMUNODEFICIENCY 100 WITH PULMONARY ALVEOLAR PROTEINOSIS AND HYPOGAMMAGLOBULINEMIA

OAS1, ALA76VAL
SNP: rs1555223118, ClinVar: RCV000660868

In 3 Japanese sibs, born of unrelated parents (family A), with immunodeficiency-100 with pulmonary alveolar proteinosis and hypogammaglobulinemia (IMD100; 618042), Cho et al. (2018) identified a de novo heterozygous c.227C-T transition (c.227C-T, NM_016816.3) in the OAS1 gene, resulting in an ala76-to-val (A76V) substitution at a conserved residue between the metal binding sites (asp75 and asp77). The variant, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the Exome Sequencing Project or ExAC databases, or in an in-house database of 153 exomes. The unaffected mother was found to be mosaic for the variant (3.81%). Molecular modeling indicated that ala76 is involved in a hydrophobic core that would define the active site structure in the RNA-bound form, suggesting that the A76V variant may affect enzymatic activity. Functional studies of the variant and studies of patient cells were not performed.

Magg et al. (2021) identified a de novo heterozygous A76V mutation in the OAS1 gene in a girl of European descent with IMD100. In vitro functional expression studies showed that the variant resulted in a gain-of-function effect with IFN-induced RNase L (180435) pathway-mediated hyperinflammatory monocyte and B-cell dysfunction.


.0004   IMMUNODEFICIENCY 100 WITH PULMONARY ALVEOLAR PROTEINOSIS AND HYPOGAMMAGLOBULINEMIA

OAS1, CYS109TYR
SNP: rs1555223154, ClinVar: RCV000660869, RCV002263925

In a Japanese girl (family B) with immunodeficiency-100 with pulmonary alveolar proteinosis and hypogammaglobulinemia (IMD100; 618042), originally reported by Tanaka-Kubota et al. (2018), Cho et al. (2018) identified a de novo heterozygous c.326G-A transition (c.326G-A, NM_016816.3) in the OAS1 gene, resulting in a cys109-to-tyr (C109Y) substitution at a conserved residue. The variant, which was found by direct sequencing of the OAS1 gene, was not found in the ExAC or Exome Sequencing Project databases. Molecular modeling suggested that the C109Y variant likely disrupts the hydrophobic core of the apo form of OAS1, which is important for regulation of enzymatic activity by dsRNA. Functional studies of the variant and studies of patient cells were not performed.

Magg et al. (2021) identified a de novo heterozygous C109Y mutation in the OAS1 gene in 3 unrelated patients of European descent with IMD100. In vitro functional expression studies showed that the variant resulted in a gain-of-function effect with IFN-induced RNase L (180435) pathway-mediated hyperinflammatory monocyte and B-cell dysfunction.


.0005   IMMUNODEFICIENCY 100 WITH PULMONARY ALVEOLAR PROTEINOSIS AND HYPOGAMMAGLOBULINEMIA

OAS1, LEU198VAL
SNP: rs1555223390, ClinVar: RCV000660870

In a Japanese girl (family C) with immunodeficiency-100 with pulmonary alveolar proteinosis and hypogammaglobulinemia (IMD100; 618042), originally reported by Tanaka-Kubota et al. (2018), Cho et al. (2018) identified a de novo heterozygous c.592C-G transversion (c.592C-G, NM_016816.3) in the OAS1 gene, resulting in a leu198-to-val (L198V) substitution at a conserved residue. The variant, which was found by direct sequencing of the OAS1 gene, was not found in the ExAC or Exome Sequencing Project databases. Molecular modeling suggested that the L198V variant may impair ATP binding and enzymatic activity. Functional studies of the variant and studies of patient cells were not performed.

Magg et al. (2021) restudied this individual as patient 5 and demonstrated that the L198V variant resulted in a gain-of-function effect with IFN-induced RNase L (180435) pathway-mediated hyperinflammatory monocyte and B-cell dysfunction.


.0006   IMMUNODEFICIENCY 100 WITH PULMONARY ALVEOLAR PROTEINOSIS AND HYPOGAMMAGLOBULINEMIA

OAS1, VAL121GLY
SNP: rs2136295939, ClinVar: RCV002248449

In a girl of Latino descent (patient 4) with immunodeficiency-100 with pulmonary alveolar proteinosis and hypogammaglobulinemia (IMD100; 618042), Magg et al. (2021) identified a de novo heterozygous c.362T-G transversion (c.362T-G, NM_002534.3) in the OAS1 gene, resulting in a val121-to-gly (V121G) substitution. In vitro functional expression studies showed that the variant resulted in a gain-of-function effect with IFN-induced RNase L (180435) pathway-mediated hyperinflammatory monocyte and B-cell dysfunction.


REFERENCES

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Contributors:
Alan F. Scott - updated : 07/07/2022
Cassandra L. Kniffin - updated : 05/11/2022
Cassandra L. Kniffin - updated : 06/29/2018
Paul J. Converse - updated : 08/15/2017
Paul J. Converse - updated : 05/03/2016
Paul J. Converse - updated : 9/11/2015
Paul J. Converse - updated : 7/3/2012
Victor A. McKusick - updated : 3/9/2006
Victor A. McKusick - updated : 3/11/2005
Rebekah S. Rasooly - updated : 12/9/1998

Creation Date:
Victor A. McKusick : 6/2/1986

Edit History:
carol : 09/21/2022
mgross : 07/07/2022
alopez : 05/16/2022
ckniffin : 05/11/2022
carol : 05/17/2019
alopez : 07/05/2018
ckniffin : 07/03/2018
ckniffin : 06/29/2018
carol : 08/16/2017
mgross : 08/15/2017
mgross : 05/03/2016
mgross : 9/11/2015
mgross : 7/20/2012
mgross : 7/20/2012
terry : 7/3/2012
mgross : 6/22/2012
carol : 12/29/2011
joanna : 8/18/2010
alopez : 3/15/2006
alopez : 3/14/2006
terry : 3/9/2006
tkritzer : 5/10/2005
alopez : 3/16/2005
terry : 3/11/2005
kayiaros : 7/13/1999
alopez : 12/9/1998
alopez : 10/27/1998
supermim : 3/16/1992
carol : 10/23/1991
supermim : 3/20/1990
ddp : 10/27/1989
root : 7/5/1989
marie : 3/25/1988