Alternative titles; symbols
HGNC Approved Gene Symbol: SPPL2A
Cytogenetic location: 15q21.2 Genomic coordinates (GRCh38): 15:50,702,266-50,765,706 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q21.2 | Immunodeficiency 86, mycobacteriosis | 619549 | Autosomal recessive | 3 |
The SPPL2A gene encodes an intramembrane protease essential for degradation of the N-terminal fragment of the CD74 (142790) protein, which is the invariant chain of the MHC class II complex that plays a central role in the function of antigen-presenting cells in the immune system (summary by Gradtke et al., 2021).
By searching sequence databases for homologs of Dictyostelium discoideum Impas, which shares homology with presenilin (104311), followed by PCR of lymphocyte and hippocampus cDNA libraries, Grigorenko et al. (2002) cloned IMP3. The deduced protein contains 520 amino acids. Like other IMP proteins, IMP3 contains an N-terminal protease-associated (PA) domain, several transmembrane regions, a hydrophilic loop, conservative sequences around the first and second aspartate residues, and an invariant PAL motif near the C terminus.
TMEM106B (613413) is a type II single-pass transmembrane protein residing primarily within the limiting membrane of late endosomes and lysosomes. Brady et al. (2014) found that TMEM106B underwent intramembrane proteolysis. The lysosomal luminal C-terminal domain of TMEM106B was removed by lysosomal cysteine proteinases to generate a stable N-terminal fragment that included the transmembrane region and cytosolic N terminus. Subsequently, lysosomal membrane proteinase SPLL2A cleaved the N-terminal fragment at 2 places within the transmembrane segment to yield an unstable intracellular domain.
By genomic sequence analysis, Grigorenko et al. (2002) mapped the IMP3 gene to chromosome 15.
Stumpf (2021) mapped the SPPL2A gene to chromosome 15q21.2 based on an alignment of the SPPL2A sequence (GenBank BC025740) with the genomic sequence (GRCh38).
In 3 patients from 2 unrelated consanguineous families with immunodeficiency-86 (IMD86; 619549) manifest as increased susceptibility to mycobacterial infection after BCG vaccination, Kong et al. (2018) identified homozygous splice site mutations in the SPPL2A gene (608238.0001 and 608238.0002). The mutations, which were found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the families. The variants were not present in the gnomAD database. Patient HLA class II antigen-presenting cells (APCs) had increased levels of CD74 N-terminal fragments (NTF) compared to controls, consistent with decreased SPPL2A function. Expression of wildtype SPPL2A rescued the CD74 NTF accumulation. The cDC2 subset of conventional dendritic cells accumulated the highest levels of CD74 NTF of the patient leukocytes. The authors suggested that CD74 NTF-mediated toxicity probably triggers an unfolded protein response. Studies of patient cells showed low numbers and impaired development of progenitor dendritic cells as well as deficient mycobacterium-specific IFNG (147570) production by memory CD4+ T cells (Th1*). CD4+ helper T cells developed normally, and the patients did not have B-cell deficiency, in contrast to Sppl2a-null mice (see ANIMAL MODEL).
Kong et al. (2018) found that Sppl2a-null mice had increased susceptibility to mycobacterial infection after BCG administration compared to wildtype mice. Mutant mice had decreased numbers of cDC2 cells, a smaller sized IFNG+ CD4+ and CD8+ T cell fraction, and decreased production of IFNG by splenocytes compared to wildtype. They also had profound B cell deficiency due to CD74 NTF accumulation. Although the CD4+ T cell response to mycobacteria and B cell survival in mice differs from humans, the experiments showed that mouse Sppl2a is required for optimal IFNG production by T cells after mycobacterial infection.
Gradtke et al. (2021) confirmed depletion of conventional DC2 dendritic cells (cDC2) in lymphatic tissues of Sppl2a-null mice. Detailed studies of bone marrow-derived dendritic cells exposed to mycobacteria showed enhanced secretion of IL1B (147720), where production of IL10 (124092) and IFNB (147640) were reduced. There were also some alterations in stimulation of pattern recognition receptors. The findings suggested that SPPL2A disturbs immunologic responses in a CD74-dependent way, shifting the balance from anti- to proinflammatory cytokines in antimycobacterial responses.
In a pair of 8-year-old monozygotic twin sisters, born of consanguineous Moroccan parents, with immunodeficiency-86 (IMD86; 619549), Kong et al. (2018) identified a homozygous G-to-A transition (c.733+1G-A) in intron 6 of the SPPL2A gene, resulting in a splicing defect. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. The variant was not present in the gnomAD database. Analysis of patient cells showed that the mutation caused the complete skipping of exon 6 and decreased mRNA levels, consistent with nonsense-mediated mRNA decay due to premature termination. No truncated protein was detected, consistent with a loss of function. Patient cells showed increased levels of CD74 N-terminal fragments (NTF) compared to controls. This was consistent with decreased SPPL2A function. Expression of wildtype SPPL2A rescued the CD74 NTF accumulation. The patients presented in infancy with mycobacterial lymphadenopathy after BCG vaccination. They made a full recovery after treatment and did not have subsequent mycobacterial infections. The patients had previously been reported by Kong et al. (2013), who diagnosed the girls with SPG51 (613744) caused by a homozygous mutation in the AP4E1 gene (607244.0005). Thus, these patients had 2 unrelated genetic disorders.
In an 11-year-old boy, born of consanguineous Turkish parents, with immunodeficiency-86 (IMD86; 619549), Kong et al. (2018) identified a homozygous G-to-A transition (c.1328-1G-A) in intron 13 of the SPPL2A gene. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, segregated with the disorder in the family. The variant was not present in the gnomAD database. Analysis of patient cells showed that the mutation resulted in the skipping of exon 14 and decreased mRNA levels, consistent with nonsense-mediated mRNA decay. Western blot analysis of cells transfected with the mutation showed presence of a truncated protein in an overexpression system. No full-length protein was detected. Patient cells showed increased levels of CD74 N-terminal fragments (NTF) compared to controls. This was consistent with decreased SPPL2A function. The patient presented in infancy with mycobacterial lymphadenopathy after BCG vaccination. He made a full recovery after treatment and did not have subsequent mycobacterial infections.
Brady, O. A., Zhou, X., Hu, F. Regulated intramembrane proteolysis of the frontotemporal lobar degeneration risk factor, TMEM106B, by signal peptide peptidase-like 2a (SPPL2a). J. Biol. Chem. 289: 19670-19680, 2014. [PubMed: 24872421] [Full Text: https://doi.org/10.1074/jbc.M113.515700]
Gradtke, A.-C., Mentrup, T., Lehmann, C. H. K., Cabrera-Cabrera, F., Desel, C., Okakpu, D., Assmann, M., Dalpke, A., Schaible, U. E., Dudziak, D., Schroder, B. Deficiency of the intramembrane protease SPPL2a alters antimycobacterial cytokine responses of dendritic cells. J. Immun. 206: 164-180, 2021. [PubMed: 33239420] [Full Text: https://doi.org/10.4049/jimmunol.2000151]
Grigorenko, A. P., Moliaka, Y. K., Korovaitseva, G. I., Rogaev, E. I. Novel class of polytopic proteins with domains associated with putative protease activity. Biochemistry 67: 826-834, 2002. [PubMed: 12139484] [Full Text: https://doi.org/10.1023/a:1016365227942]
Kong, X.-F., Bousfiha, A., Rouissi, A., Itan, Y., Abhyankar, A., Bryant, V., Okada, S., Ailal, F., Bustamante, J., Casanova, J.-L., Hirst, J., Boisson-Dupuis, S. A novel homozygous p.R1105X mutation of the AP4E1 gene in twins with hereditary spastic paraplegia and mycobacterial disease. PLoS One 8: e58286, 2013. [PubMed: 23472171] [Full Text: https://doi.org/10.1371/journal.pone.0058286]
Kong, X.-F., Martinez-Barricarte, R., Kennedy, J., Mele, F., Lazarov, T., Deenick, E. K., Ma, C. S., Breton, G., Lucero, K. B., Langlais, D., Bousfiha, A., Aytekin, C., and 29 others. Disruption of an antimycobacterial circuit between dendritic and helper T cells in human SPPL2a deficiency. Nature Immun. 19: 973-985, 2018. [PubMed: 30127434] [Full Text: https://doi.org/10.1038/s41590-018-0178-z]
Stumpf, A. M. Personal Communication. Baltimore, Md. 10/06/2021.