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Other entities represented in this entry:
HGNC Approved Gene Symbol: SP110
Cytogenetic location: 2q37.1 Genomic coordinates (GRCh38) : 2:230,165,186-230,225,636 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q37.1 | {Mycobacterium tuberculosis, susceptibility to} | 607948 | 3 | |
| Hepatic venoocclusive disease with immunodeficiency | 235550 | Autosomal recessive | 3 |
Exposure to interferons (IFNs; see, for example, 147570) leads to a modulation in the levels of many cellular proteins (see 604456) that mediate the pleiotropic effects of IFNs. Using a rabbit polyclonal antibody against PKR p68 (PRKR; 176871), Kadereit et al. (1993) isolated from interferon-induced Daudi cells crossreacting but otherwise unrelated cDNAs encoding IFI41 and IFI75. IFI75 cDNA hybridized in Northern blots with 2-kb mRNA from IFN-induced cells. IFI41 cDNA hybridized in Northern blots with 2-kb mRNA from IFN-induced cells and with 0.5-kb mRNA from both induced and control cells. Sequence analysis revealed that IFI41 and IFI75 are very hydrophilic 248- and 371-amino acid polypeptides, respectively, are rich in basic residues, and have several potential phosphorylation sites. The 2 proteins contain an identical 204-amino acid stretch and have protamine- and histone-like nuclear targeting sequences. Expression in the rabbit reticulocyte lysate system directed the synthesis of a 52-kD IFI75 protein, higher than the calculated molecular mass of 42 kD. IFI75 expression in Sf9 cells in the baculovirus system resulted in a phosphorylated 65- to 67-kD protein that is associated with the nuclear pellet after NP40 detergent extraction. IFI41 had a molecular mass of 30 kD. In contrast to IFI75, IFI41 was toxic for Sf9 cells in the baculovirus system.
Welsh et al. (1999) demonstrated that IFI41 is localized to the nucleolus in mammalian cells. IFI75 is localized primarily in the periphery of the nucleolus but is also found throughout the nucleoplasm in mammalian cells. Treatment with interferon resulted in a translocation of IFI41 to the periphery of the nucleolus. The authors suggested that IFI41 and IFI75, in association with nucleolin, with which they colocalize, play a role in ribosome biogenesis.
SP110 is associated with the PML (see 102578) nuclear body, a macromolecular complex within the nucleus that is deployed to areas of active host or viral DNA replication, transcription, and repair. In addition to the regulation of gene transcription, the PML nuclear body is involved in other cellular processes such as apoptosis, cell cycle control, and the immune response. The findings of Roscioli et al. (2006) were consistent with an important role of SP110 in the immune response without being essential for PML nuclear body formation. The study indicated that SP110 has an important role in immunoprotective mechanisms against infectious organisms in humans.
Pan et al. (2005) identified a gene, which they designated intracellular pathogen resistance-1 (Ipr1), within Sst1 (super-susceptibility to tuberculosis-1) in the mouse. The Ipr1 gene is upregulated in the Sst1-resistant macrophages after activation and infection, but it is not expressed in the Sst1-susceptible macrophages. Expression of the Ipr1 transgene in the Sst1-susceptible macrophages limits the multiplication not only of M. tuberculosis but also of Listeria monocytogenes and switches a cell death pathway of the infected macrophages from necrosis to apoptosis. Pan et al. (2005) concluded that the Ipr1 gene product might have a previously undocumented function in integrating signals generated by intracellular pathogens with mechanisms controlling innate immunity, cell death, and pathogenesis. SP110 is the closest homolog of the Ipr1 protein in humans. Both Ipr1 and the human SP110 proteins contain motifs that are involved in protein-protein interactions (Sp100 domain), chromatin binding (SAND domain), nuclear localization signal, and the nuclear receptor-binding (NRB) motif LXXLL.
Roscioli et al. (2006) identified the SP110 gene within a minimal critical region for hepatic venoocclusive disease with immunodeficiency (VODI; 235550) on chromosome 2q37.1.
Hepatic Venoocclusive Disease with Immunodeficiency
Hepatic venoocclusive disease with immunodeficiency (VODI; 235550) is an autosomal recessive primary immunodeficiency associated with hepatic vascular occlusion and fibrosis. Roscioli et al. (2006) performed homozygosity mapping in 4 affected individuals with VODI and their parents, mapping the disorder to 2q36.3-q37.1. Fine-mapping studies identified a conserved haplotype of 3 short tandem repeat (STR) markers spanning a genomic interval of 1.422 Mb that contained the SP110 gene. Screening of the coding exons of SP110 for mutations by DNA sequencing identified a homozygous single-base deletion, 642delC (604457.0001), in exon 5 in affected individuals from 4 families. In a fifth family no living affected individuals were available, but the consanguineous parents and unaffected children were shown to share a heterozygous single-base deletion, 40delC (604457.0002), in exon 2 on a different haplotype background from the other 4 families. That mutation was homozygous in archival material from the deceased member of family 5. Neither mutation was found in 50 unrelated Lebanese controls and no mutation was found in the coding regions of SP110 in 89 isolated cases of common variable immunodeficiency (240500) of European or Middle Eastern origin.
Associations Pending Confirmation
See 604457.0003 and 604457.0004 for discussion of a possible association between susceptibility to Mycobacterium tuberculosis and variation in the SP110 gene.
In 4 families of Lebanese extraction, Roscioli et al. (2006) demonstrated that individuals with hepatic venoocclusive disease with immunodeficiency syndrome (VODI; 235550) carried a homozygous single-base deletion of 642delC (Pro214ProfsTer15) in exon 5 of the SP110 gene.
In a family of Lebanese extraction, Roscioli et al. (2006) demonstrated that a child who died from hepatic venoocclusive disease with immunodeficiency (VODI; 235550) was homozygous for a 1-bp deletion, 40delC (Gln14SerfsTer25), in exon 2 of the SP110 gene.
This variant, formerly titled MYCOBACTERIUM TUBERCULOSIS, SUSCEPTIBILITY TO (see 607948), has been reclassified based on the findings of Thye et al. (2006) and Szeszko et al. (2007).
Tosh et al. (2006) noted that The mouse Ipr1 gene, a homolog of SP110, had been shown to have a major role in the outcome of tuberculosis infection (see 607948). Tosh et al. (2006) examined 27 SNPs in the SP110 gene in 219 Gambian families and identified 3 that were associated with tuberculosis, including C/T in exon 11 (rs3948464), a nonsynonymous change in which the C allele encodes ser425 and the T allele encodes leu425. The most common allele (C) was transmitted more often than expected to affected offspring. The other 2 SNPs were a T/C change in intron 6 (604457.0004) and an A/G change in intron 10. Examination of an additional 99 Guinean and 102 Guinea-Bissau families independently replicated the associations for the SNPs in exon 11 and intron 6. None of the 3 SNPs affected known functional domains of SP110, although the intronic SNPs may have roles in alternative splicing. All 3 associated SNPs in Gambian families were in strong linkage disequilibrium and were found to lie within a 31-kb block of low haplotype diversity.
Thye et al. (2006) observed no significant differences in the frequencies of 21 SP110 variants, including leu425 to ser, between 2,004 sputum-positive, HIV-negative Ghanaian tuberculosis patients and 1,231 exposed, healthy personal contacts and 1,135 community controls. They concluded that an association of SP110 variants and distinct phenotypes of human M. tuberculosis infection is doubtful.
Szeszko et al. (2007) genotyped 29 SNPs in SP110, including 7 causing amino acid changes, and 15 ancestry-informative markers as genomic controls in nearly 2,000 HIV-seronegative, M. tuberculosis culture-positive Russians and a similar number of controls. They found no evidence for association of SP11O SNPs, including leu425 to ser, with susceptibility to adult pulmonary tuberculosis. Szeszko et al. (2007) proposed that the effect of SP110 polymorphisms in outbred human populations may be smaller than the effect of Ipr1 in inbred mice and emphasized the importance of whole-genome scans to identify genes and causal variants predisposing to tuberculosis in human populations.
This variant, formerly titled MYCOBACTERIUM TUBERCULOSIS, SUSCEPTIBILITY TO (see 607948), has been reclassified based on the findings of Thye et al. (2006) and Szeszko et al. (2007).
Tosh et al. (2006) examined 27 SNPs in the SP110 gene in 219 Gambian families and identified 3 that were associated with tuberculosis, including T/C in intron 6 (rs2114592). The most common allele (T) was transmitted more often than expected to affected offspring. Examination of an additional 99 Guinean and 102 Guinea-Bissau families independently replicated the association. The SNP did not affect a known functional domain of SP110.
Thye et al. (2006) observed no significant differences in the frequencies of 21 SP110 variants, including leu425 to ser (604457.0003), between 2,004 sputum-positive, HIV-negative Ghanaian tuberculosis patients and 1,231 exposed, healthy personal contacts and 1,135 community controls. They concluded that an association of SP110 variants and distinct phenotypes of human M. tuberculosis infection is doubtful.
Szeszko et al. (2007) genotyped 29 SNPs in SP110, including 7 causing amino acid changes, and 15 ancestry-informative markers as genomic controls in nearly 2,000 HIV-seronegative, M. tuberculosis culture-positive Russians and a similar number of controls. They found no evidence for association of SP11O SNPs, including leu425 to ser, with susceptibility to adult pulmonary tuberculosis. Szeszko et al. (2007) proposed that the effect of SP110 polymorphisms in outbred human populations may be smaller than the effect of Ipr1 in inbred mice and emphasized the importance of whole-genome scans to identify genes and causal variants predisposing to tuberculosis in human populations.
Kadereit, S., Gewert, D. R., Galabru, J., Hovanessian, A. G., Meurs, E. F. Molecular cloning of two new interferon-induced, highly related nuclear phosphoproteins. J. Biol. Chem. 268: 24432-24441, 1993. [PubMed: 7693701]
Pan, H., Yan, B.-S., Rojas, M., Shebzukhov, Y. V., Zhou, H., Kobzik, L., Higgins, D. E., Daly, M. J., Bloom, B. R., Kramnik, I. Ipr1 gene mediates innate immunity to tuberculosis. Nature 434: 767-772, 2005. [PubMed: 15815631] [Full Text: https://doi.org/10.1038/nature03419]
Roscioli, T., Cliffe, S. T., Bloch, D. B., Bell, C. G., Mullan, G., Taylor, P. J., Sarris, M., Wang, J., Donald, J. A., Kirk, E. P., Ziegler, J. B., Salzer, U., McDonald, G. B., Wong, M., Lindemann, R., Buckley, M. F. Mutations in the gene encoding the PML nuclear body protein Sp110 are associated with immunodeficiency and hepatic veno-occlusive disease. Nature Genet. 38: 620-622, 2006. [PubMed: 16648851] [Full Text: https://doi.org/10.1038/ng1780]
Szeszko, J. S., Healy, B., Stevens, H., Balabanova, Y., Drobniewski, F., Todd, J. A., Nejentsev, S. Resequencing and association analysis of the SP110 gene in adult pulmonary tuberculosis. Hum. Genet. 121: 155-160, 2007. [PubMed: 17149599] [Full Text: https://doi.org/10.1007/s00439-006-0293-z]
Thye, T., Browne, E. N., Chinbuah, M. A., Gyapong, J., Osei, I., Owusu-Dabo, E., Niemann, S., Rusch-Gerdes, S., Horstmann, R. D., Meyer, C. G. No associations of human pulmonary tuberculosis with Sp110 variants. J. Med. Genet. 43: e32, 2006. Note: Electronic Article. [PubMed: 16816019] [Full Text: https://doi.org/10.1136/jmg.2005.037960]
Tosh, K., Campbell, S. J., Fielding, K., Sillah, J., Bah, B., Gustafson, P., Manneh, K., Lisse, I., Sirugo, G., Bennett, S., Aaby, P., McAdam, K. P. W. J., Bah-Sow, O., Lienhardt, C., Kramnik, I., Hill, A. V. S. Variants in the SP110 gene are associated with genetic susceptibility to tuberculosis in West Africa. Proc. Nat. Acad. Sci. 103: 10364-10368, 2006. [PubMed: 16803959] [Full Text: https://doi.org/10.1073/pnas.0603340103]
Welsh, G. I., Kadereit, S., Coccia, E. M., Hovanessian, A. G., Meurs, E. F. Colocalization within the nucleolus of two highly related IFN-induced human nuclear phosphoproteins with nucleolin. Exp. Cell Res. 250: 62-74, 1999. [PubMed: 10388521] [Full Text: https://doi.org/10.1006/excr.1999.4505]