Alternative titles; symbols
HGNC Approved Gene Symbol: CORO1A
SNOMEDCT: 1229942009;
Cytogenetic location: 16p11.2 Genomic coordinates (GRCh38) : 16:30,183,602-30,189,076 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p11.2 | Immunodeficiency 8 | 615401 | Autosomal recessive | 3 |
The CORO1A gene encodes an actin-regulating protein that is expressed mainly in hematopoietic cells (summary by Shiow et al., 2008).
By micropeptide sequence analysis of a 57-kD protein that copurified with a phospholipase C protein (see PLCD1; 602142), followed by probing a T cell line, Suzuki et al. (1995) obtained a cDNA encoding CORO1A, which they called p57. The deduced 461-amino acid CORO1A protein shares 40% amino acid identity with coronin, an actin-binding protein of Dictyostelium discoideum. Sequence analysis predicted that CORO1A contains a WD (trp/asp) repeat and a leucine zipper motif. Immunoblot analysis revealed cross-reactivity of human, calf, and mouse CORO1A, and Coro1a was clearly expressed in mouse brain, thymus, spleen, bone marrow, and lymph node, with weak expression in lung and gut, and no expression in liver, kidney, stomach, and skeletal muscle. Using a cosedimentation assay, Suzuki et al. (1995) determined that CORO1A is an actin-binding protein.
Mycobacteria are pathogens that successfully exploit cellular mechanisms to survive within macrophage phagosomes. Instead of being destroyed in this normally hostile environment, mycobacteria, which include the causative organisms of tuberculosis and leprosy, evade host defenses and use host cellular components to thrive within macrophages. Phagosomes containing living but not dead mycobacteria resist fusion to endosomal and lysosomal organelles, presumably allowing mycobacteria to escape macrophage bactericidal mechanisms. The mycobacterial phagosome lacks late-stage but not early-stage markers of the endocytic pathway. For example, the mycobacterial phagosome selectively excludes the proton-ATPase (see ATP6F; 603717) responsible for acidification along the pathway. To identify factors that contribute to the intraphagosomal survival of mycobacteria, Ferrari et al. (1999) used organelle electrophoresis to separate early phagosomes from late phagosomes (containing living and dead mycobacteria, respectively), isoelectric-focusing (IEF)/SDS-PAGE analysis, and micropeptide sequence analysis. They identified a mouse protein matching the digestion profile of human CORO1A peptides, and by screening a mouse macrophage cDNA library with a human CORO1A cDNA, they obtained a cDNA encoding the 461-amino acid mouse Coro1a protein, which they called Taco (tryptophane aspartate-containing coat protein). Sequence analysis predicted that the Coro1a protein contains a coiled-coil region within the 32 C-terminal amino acids, 5 WD repeats, and no signal sequence. Immunoblot analysis detected Coro1a expression in spleen, lymph nodes, thymus, and brain, with weak expression in lung and no expression in heart, kidney, and muscle. Confocal immunofluorescence microscopy of uninfected macrophages demonstrated that Coro1a localizes with tubulin (see TUBB; 191130) but not actin in the cell cortex. Immediately after infection, Coro1a localized around mycobacterial phagosomes as well as cortex before localizing predominantly to the phagosomal membrane for prolonged periods of time. The phagosomal localization was only transient in macrophages exposed to heat-killed mycobacteria. Tubulin, on the other hand, localized transiently to live mycobacterial phagosomes and persistently only to dead mycobacterial phagosomes. Immunoblot analysis showed that Coro1a is absent in liver macrophages (Kupffer cells), which also rapidly destroy mycobacteria. Based on the interaction between Coro1a and tubulin, Ferrari et al. (1999) speculated that the WD repeats in CORO1A may act as microtubule-binding domains. Given the apparent involvement of tubulin in phagosome-lysosome fusion, they suggested that mycobacteria retain CORO1A on the phagosomal membrane to prevent the recruitment of lysosomes.
Tanigawa et al. (2009) found that CORO1A suppressed Toll-like receptor (TLR) signaling following expression in a human monocytic cell line. TLR2 (603028)-mediated activation of the innate immune response resulted in suppression of CORO1A expression. However, in cells infected with Mycobacterium leprae, the causative agent of leprosy (see 609888), TLR2-mediated CORO1A suppression was inhibited, as was NFKB (see 164011) activation. Tanigawa et al. (2009) proposed that the balance between TLR2-mediated signaling and CORO1A expression is key in determining the fate of M. leprae after infection.
In a girl with immunodeficiency-8 (IMD8; 615401), Shiow et al. (2009) identified compound heterozygosity for a truncating mutation in the CORO1A gene (605000.0001) and a de novo heterozygous 600-kb deletion of chromosome 16p11.2 (611913) encompassing 24 genes, including CORO1A. Thus, she had a homozygous absence of the CORO1A gene, with absent expression of the protein in her lymphocytes. She presented with early-onset recurrent infections and post-vaccination varicella at age 13 months. Immunologic workup showed decreased numbers of lymphocytes, poor T-cell function with decreased proliferative response and lack of helper T-cell function for antibody isotype switching, and low immunoglobulins. B and NK cells were present, and her thymus was present. Shiow et al. (2008) demonstrated that Coro1a is mutated in a mouse model with peripheral T-cell deficiency (Ptcd), providing further evidence for pathogenicity.
Moshous et al. (2013) reported 3 sibs, born of consanguineous Moroccan parents, with infantile-onset recurrent infections and an aggressive Epstein-Barr virus (EVS)-induced B-cell lymphoproliferative disorder associated with a homozygous missense mutation in the CORO1A gene (V134M; 605000.0002). The mutation, which was found using homozygosity mapping and exome sequencing, segregated with the disorder in the family and was not found in the dbSNP or the Exome Variant Server database. Patient lymphocytes showed normal levels of mutant mRNA, but significantly decreased amounts of the mutant protein, suggesting that the mutation causes decreased CORO1A stability. Two of the sibs died in infancy, whereas the remaining sib was successfully treated and in remission at age 11.5 years, but had some cognitive and behavioral abnormalities, including attention deficit and hyperactivity. Overall, the findings were consistent with an immunodeficiency characterized by a defect in naive T cells and a defect in expansion of oligoclonal T cells associated with increased susceptibility to EBV infection. Impaired survival of mature T cells in turn likely affected lymphocyte homeostasis, repertoire selection, and lineage commitment. Moshous et al. (2013) noted that the immunodeficiency phenotype in their patients was less severe than that reported by Shiow et al. (2009), suggesting that the missense mutant protein may have retained some residual function.
In 2 sibs with IMD8, one of whom died at age 16 years, Stray-Pedersen et al. (2014) identified compound heterozygous truncating mutations in the CORO1A gene (605000.0001 and 605000.0003). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Western blot analysis showed absence of the CORO1A protein in the surviving affected brother. Both sibs presented at age 7 years with a mucocutaneous immunodeficiency of HPV and molluscum; 1 had mycobacterial leprosy. Immunologic work-up over the course of the disease in both patients showed absence of CD4+ T cells, decreased memory B cells, and decreased NK cells.
Foger et al. (2006) generated coronin-1-null mice and found that coronin-1 exerted an inhibitory effect on cellular steady-state F-actin formation via an Arp2/3 (604221)-dependent mechanism. Whereas coronin-1 was required for chemokine-mediated migration, it was dispensable for T-cell antigen receptor functions in T cells. Moreover, Foger et al. (2006) found that actin dynamics, through a mitochondrial pathway, was linked to lymphocyte homeostasis.
Haraldsson et al. (2008) identified a gln262-to-ter mutation in the Coro1a gene within the lupus (SLE; 152700)-related Lmb3 quantitative trait locus on mouse chromosome 7. The mutation resulted in T cells with diminished capacity to migrate, survive, be activated, and undergo Ca(2+) flux. Transfer of mutant Coro1a T cells suppressed development of autoimmunity in recipient mice. Haraldsson et al. (2008) concluded that CORO1A is required for development of SLE.
Shiow et al. (2008) determined that the 'peripheral T-cell deficiency' (Ptcd) trait in mice, which is characterized by defective egress of mature thymocytes from the thymus, is due to an E26K point mutation in the Coro1a gene. Ptcd T cells had an intrinsic migration defect, impaired lymphoid tissue trafficking, and irregularly shaped protrusions, suggestive of an abnormal actin cytoskeleton. In addition, mutant Coro1a was mislocalized from the leading edge of migrating T cells. Biochemical studies showed that the pathogenic E26K mutant protein enhanced Coro1a inhibition of the actin regulator Arp2/3, consistent with a gain of function. A parallel ENU-mutagenesis screen identified another mutant mouse model, 'Koyaanisqatsi' (Koy), with circulating T-cell lymphopenia due to a hypomorphic mutation in the Coro1a gene. The findings implicated a role for Coro1a in T-cell egress from the thymus and lymph nodes, which plays a larger role in immunity.
In a girl with immunodeficiency-8 (IMD8; 615401), Shiow et al. (2009) identified a heterozygous 2-bp deletion in exon 3 of the CORO1A gene (c.248_249delCT), resulting in a frameshift and premature termination (Pro83ArgfsTer10), which was inherited from her unaffected father. In addition, she had attention deficit-hyperactivity disorder and mild cognitive impairment associated with a de novo heterozygous 600-kb deletion of chromosome 16p11.2 (611913) encompassing 24 genes, including CORO1A. Thus, she had a homozygous absence of the CORO1A gene, with no expression of the protein in her lymphocytes. She presented with early-onset recurrent infections and postvaccination varicella at age 13 months. Immunologic workup showed decreased numbers of lymphocytes, poor T-cell function with decreased proliferative response and lack of helper T-cell function for antibody isotype switching, and low immunoglobulins. B and NK cells were present. Her thymus was present. Hematopoietic stem cell transplantation was successful. Shiow et al. (2008) demonstrated that Coro1a is mutated in a mouse model with peripheral T-cell deficiency (Ptcd), providing further evidence for pathogenicity.
In 2 sibs, born of unrelated parents, with IMD8, Stray-Pedersen et al. (2014) identified compound heterozygous mutations in the CORO1A gene: a 2-bp deletion (c.248_249delCT), which they determined was located in exon 4, and a 1-bp deletion (c.1077delC; 605000.0003) in exon 11, resulting in a frameshift and premature termination. The mutations, which were found by whole-exome sequencing, confirmed by Sanger sequencing, and filtered against the dbSNP and Exome Sequencing Project databases as well as in-house exomes, segregated with the disorder in the family. Western blot analysis of 1 patient showed absent CORO1A protein.
In 3 sibs, born of consanguineous parents of Moroccan ancestry, with immunodeficiency-8 (IMD8; 615401), Moshous et al. (2013) identified a homozygous c.717G-A transition in exon 4 of the CORO1A gene, resulting in a val134-to-met (V134M) substitution at a highly conserved residue in the beta-propeller domain. The mutation, which was found by homozygosity mapping and exome sequencing, segregated with the disorder in the family and was not found in the dbSNP or the Exome Variant Server database. Patient lymphocytes showed normal levels of mutant mRNA, but significantly decreased amounts of the mutant protein, suggesting that the mutation causes decreased CORO1A stability. Cells from the heterozygous mother showed a moderate decrease in mutant protein expression. Patient T-cell blasts showed delayed activation of signaling molecules ERK1 (601795) and ERK2 (176948), but further functional studies could not be performed because of lack of material. The patients presented in infancy with recurrent infections and Epstein-Barr virus (EBV)-induced B-cell lymphoproliferative disorder, resulting in early death in 2 sibs. The remaining sib was successfully treated and was in remission at age 11.5 years, but had some cognitive and behavioral abnormalities, including attention deficit and hyperactivity.
For discussion of the 1-bp deletion in the CORO1A gene (c.1077delC) that was found in compound heterozygous state in 2 sibs with immunodeficiency-8 (IMD8; 615401) by Stray-Pedersen et al. (2014), see 605000.0001.
Ferrari, G., Langen, H., Naito, M., Pieters, J. A coat protein on phagosomes involved in the intracellular survival of mycobacteria. Cell 97: 435-447, 1999. [PubMed: 10338208] [Full Text: https://doi.org/10.1016/s0092-8674(00)80754-0]
Foger, N., Rangell, L., Danilenko, D. M., Chan, A. C. Requirement for coronin 1 in T lymphocyte trafficking and cellular homeostasis. Science 313: 839-842, 2006. [PubMed: 16902139] [Full Text: https://doi.org/10.1126/science.1130563]
Haraldsson, M. K., Louis-Dit-Sully, C. A., Lawson, B. R., Sternik, G., Santiago-Raber, M.-L., Gascoigne, N. R. J., Theofilopoulos, A. N., Kono, D. H. The lupus-related Lmb3 locus contains a disease-suppressing coronin-1A gene mutation. Immunity 28: 40-51, 2008. [PubMed: 18199416] [Full Text: https://doi.org/10.1016/j.immuni.2007.11.023]
Moshous, D., Martin, E., Carpentier, W., Lim, A., Callebaut, I., Canioni, D., Hauck, F., Majewski, J., Schwartzentruber, J., Nitschke, P., Sirvent, N., Frange, P., Picard, C., Blanche, S., Revy, P., Fischer, A., Latour, S., Jabado, N., de Villartay, J.-P. Whole-exome sequencing identifies coronin-1A deficiency in 3 siblings with immunodeficiency and EBV-associated B-cell lymphoproliferation. J. Allergy Clin. Immun. 131: 1594-1603, 2013. [PubMed: 23522482] [Full Text: https://doi.org/10.1016/j.jaci.2013.01.042]
Shiow, L. R., Paris, K., Akana, M. C., Cyster, J. G., Sorensen, R. U., Puck, J. M. Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a coronin-1A mutation and a chromosome 16p11.2 deletion. Clin. Immun. 131: 24-30, 2009. [PubMed: 19097825] [Full Text: https://doi.org/10.1016/j.clim.2008.11.002]
Shiow, L. R., Roadcap, D. W., Paris, K., Watson, S. R., Grigorova, I. L., Lebet, T., An, J., Xu, Y., Jenne, C. N., Foger, N., Sorensen, R. U., Goodnow, C. C., Bear, J. E., Puck, J. M., Cyster, J. G. The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency. Nature Immun. 9: 1307-1315, 2008. [PubMed: 18836449] [Full Text: https://doi.org/10.1038/ni.1662]
Stray-Pedersen, A., Jouanguy, E., Crequer, A., Bertuch, A. A., Brown, B. S., Jhangiani, S. N., Muzny, D. M., Gambin, T., Sorte, H., Sasa, G., Metry, D., Campbell, J., and 9 others. Compound heterozygous CORO1A mutations in siblings with a mucocutaneous-immunodeficiency syndrome of epidermodysplasia verruciformis-HPV, molluscum contagiosum and granulomatous tuberculoid leprosy. J. Clin. Immun. 34: 871-890, 2014. [PubMed: 25073507] [Full Text: https://doi.org/10.1007/s10875-014-0074-8]
Suzuki, K., Nishihata, J., Arai, Y., Honma, N., Yamamoto, K., Irimura, T., Toyoshima, S. Molecular cloning of a novel actin-binding protein, p57, with a WD repeat and leucine zipper motif. FEBS Lett. 364: 283-288, 1995. [PubMed: 7758584] [Full Text: https://doi.org/10.1016/0014-5793(95)00393-n]
Tanigawa, K., Suzuki, K., Kimura, H., Takeshita, F., Wu, H., Akama, T., Kawashima, A., Ishii, N. Tryptophan aspartate-containing coat protein (CORO1A) suppresses Toll-like receptor signalling in Mycobacterium leprae infection. Clin. Exp. Immun. 156: 495-501, 2009. [PubMed: 19438603] [Full Text: https://doi.org/10.1111/j.1365-2249.2009.03930.x]