Alternative titles; symbols
HGNC Approved Gene Symbol: SEMA7A
Cytogenetic location: 15q24.1 Genomic coordinates (GRCh38): 15:74,409,289-74,433,958 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 15q24.1 | ?Cholestasis, progressive familial intrahepatic, 11 | 619874 | Autosomal recessive | 3 |
| [Blood group, John-Milton-Hagen system] | 614745 | 3 |
SEMA7A is an 80-kD membrane-bound semaphorin that associates with cell surfaces via a glycosylphosphatidylinositol (GPI) linkage. It is preferentially expressed on activated lymphocytes and erythrocytes. SEMA7A carries the John Milton Hagen (JMH) blood group antigens (see 614745) (summary by Yamada et al., 1999).
By PCR using primers designed from alcelaphine herpesvirus-1 (AHV) sema, followed by 5-prime and 3-prime RACE, Lange et al. (1998) cloned full-length SEMA7A, which they designated SEMAL, from a placenta cDNA library. The deduced 666-amino acid protein has a calculated molecular mass of about 75 kD, and the unglycosylated protein has a calculated molecular mass of about 70 kD following signal peptide cleavage. SEMA7A contains a 44-amino acid N-terminal signal sequence, a semaphorin domain of about 500 amino acids, an immunoglobulin-like motif, and a C-terminal hydrophobic domain that lacks a significant intracellular tail. The semaphorin domain has several conserved cysteine residues and an RGD motif. SEMA7A also contains 5 N-glycosylation sites and several myristoylation sites. Northern blot analysis detected a 3.2-kb transcript expressed predominantly in spleen, thymus, testis, and ovary. Little or no expression was detected in prostate, small intestine, colon, and peripheral blood leukocytes. RNA dot blot analysis detected expression in placenta, spleen, and gonadal tissue, but not in neuronal or muscular tissue.
By searching an EST database using AHV sema as probe, Xu et al. (1998) identified SEMA7A, which they designated SEMAK1. SEMA7A shares about 50% amino acid identity with AHV sema and less than 30% identity with other semaphorins. Northern blot analysis of adult mouse tissues detected a 4.4-kb Sema7a transcript expressed at high levels in brain, spinal cord, lung, and testis. In situ hybridization detected weak but dynamic expression of Sema7a in spinal cord, cerebellum, and cortex during embryonic development. In adult mice, Sema7a was expressed in several brain structures and cell layers.
By PCR using primers based on the N-terminal amino acid sequence of SEMA7A, followed by screening a leukemic T-cell line cDNA library and a placenta cDNA library, Yamada et al. (1999) cloned SEMA7A, which they called CDW108. Northern blot analysis detected a 3.5-kb transcript expressed at highest levels in placenta, testis, and spleen, with low levels in brain and thymus. Yamada et al. (1999) detected 5 differentially glycosylated forms of SEMA7A by SDS-PAGE of a transfected esophageal cancer cell line. The largest protein had an apparent molecular mass of about 80 kD. Treatment with peptide-N-glycosidase revealed a deglycosylated protein with an apparent molecular mass of about 65 kD.
Sato and Takahashi (1998) cloned mouse Sema7a. They noted that the immunoglobulin-like domain of the deduced 664-amino acid protein is of the C2 type. Human and mouse SEMA7A share 89.5% identity. Northern blot analysis of rat tissues detected highest expression in the nervous system, and expression in the cerebellum and brain stem increased during development. Moderate expression was detected in thymus and spleen.
Lange et al. (1998) determined that the SEMA7A gene contains at least 13 exons and spans about 9 kb.
Seltsam et al. (2007) stated that the SEMA7A gene contains 14 exons.
By FISH, Lange et al. (1998) mapped the SEMA7A gene to chromosome 15q22.2-q23. Using radiation hybrid analysis, Yamada et al. (1999) mapped the SEMA7A gene to chromosome 15q23-q24.
Gross (2017) mapped the SEMA7A gene to chromosome 15q24.1 based on an alignment of the SEMA7A sequence (GenBank AF071542) with the genomic sequence (GRCh38).
Lange et al. (1998) mapped the mouse Sema7a gene to chromosome 9A3.3-B.
Xu et al. (1998) demonstrated that SEMA7A is a GPI-anchored membrane protein. SEMA7A was expressed on the cell surface of transfected COS-7 cells, and treatment with phospholipase C (see 600220) released the protein from the cell surface. A soluble mutant of SEMA7A bound to macrophage and mast cell lines, but it did not bind to COS-7 cells expressing neuropilin-1 (602069) or neuropilin-2 (602070), receptors for several secreted semaphorins. Xu et al. (1998) concluded that these macrophage and mast cell lines contain a specific receptor for SEMA7A.
Pasterkamp et al. (2003) showed that semaphorin 7A, a membrane-anchored member of the semaphorin family of guidance proteins known for its immunomodulatory effects, can also mediate neuronal functions. Pasterkamp et al. (2003) showed that unlike many other semaphorins, which act as repulsive guidance cues, SEMA7A enhances central and peripheral axon growth and is required for proper axon tract formation during embryonic development. Unexpectedly, SEMA7A enhancement of axon outgrowth requires integrin receptors and activation of MAPK signaling pathways. Pasterkamp et al. (2003) concluded that their findings defined a theretofore unknown biologic function for semaphorins, identified an unexpected role for integrins and integrin-dependent intracellular signaling in mediating semaphorin responses, and provided a framework for understanding and interfering with SEMA7A function in both immune and nervous systems. Pasterkamp et al. (2003) showed that SEMA7A-mediated axon growth is plexin C1 (604259)-independent.
Suzuki et al. (2007) demonstrated that SEMA7A, which is expressed on activated T cells, stimulates cytokine production in monocytes and macrophages through alpha-1-beta-1 integrin (192968, 135630) (also known as very late antigen-1) as a component of the immunologic synapse, and is critical for the effector phase of the inflammatory immune response. Sema7A-null mice are defective in cell-mediated immune responses such as contact hypersensitivity and experimental autoimmune encephalomyelitis. Although antigen-specific and cytokine-producing effector T cells could develop and migrate into antigen-challenged sites in Sema7a-null mice, Sema7a-null T cells failed to induce contact hypersensitivity even when directly injected into the antigen-challenged sites. Thus, Suzuki et al. (2007) concluded that the interaction between SEMA7A and alpha-1-beta-1 integrin is crucial at the site of inflammation.
Uesaka et al. (2014) identified semaphorins, a family of versatile cell recognition molecules, as retrograde signals for elimination of redundant climbing fiber to Purkinje cell synapses in developing mouse cerebellum. Knockdown of Sema3a (603961), a secreted semaphorin, in Purkinje cells or its receptor in climbing fibers accelerated synapse elimination during postnatal day 8 (P8) to P18. Conversely, knockdown of Sema7a, a membrane-anchored semaphorin, in Purkinje cells or either of its 2 receptors in climbing fibers impaired synapse elimination after P15. The effect of Sema7a involves signaling by metabotropic glutamate receptor-1 (GRM1; 604473), a canonical pathway for climbing fiber synapse elimination. Uesaka et al. (2014) concluded that their findings defined how semaphorins retrogradely regulate multiple processes of synapse elimination.
Lee et al. (2017) showed that bitter and sweet taste receptor cells provide instructive signals to bitter and sweet target neurons via different guidance molecules, SEMA3A and SEMA7A, respectively. Lee et al. (2017) demonstrated that targeted expression of SEMA3A or SEMA7A in different classes of taste receptor cells produces peripheral taste systems with miswired sweet or bitter cells. They engineered mice with bitter neurons that responded to sweet tastants, sweet neurons that responded to bitter, or sweet neurons that responded to sour stimuli. Lee et al. (2017) concluded that their results uncovered the basic logic of the wiring of the taste system at the periphery, and illustrated how a labeled-line sensory circuit preserves signaling integrity despite rapid and stochastic turnover of receptor cells.
By RT-PCR analysis of human peripheral blood mononuclear cells, Korner et al. (2021) showed that SEMA7A expression was higher in antiinflammatory M2 macrophages than in proinflammatory M1 macrophages. Further analysis suggested that SEMA7A shifted cells from the M1 to the M2 phenotype. SEMA7A reduced M1 macrophage chemotaxis and chemokinesis and enhanced macrophage phagocytosis by interacting with integrin receptors. Analysis with mouse residential peritoneal Sema7a -/- macrophages revealed that changes in macrophage phenotype profiles were associated with alterations in cellular energy metabolism, as Sema7a regulated immunometabolism in macrophages. Protein microarray analysis showed that Sema7a activated the Mtor (601231) and Akt1 (164730) phosphorylation signaling pathways to induce metabolic reprogramming of mouse macrophages. In support of the in vitro findings, Sema7a -/- mice displayed impaired resolution features and worse survival compared with wildtype upon induction of peritonitis by zymosan A. Furthermore, plasma SEMA7A was associated with clinical outcome in critically ill children with abdominal compartment syndrome. A peptide consisting of 19 amino acids of the SL4CD region of mouse Sema7a showed potential therapeutic efficacy in acute inflammation, as administration of the peptide fostered resolution of acute inflammation and promoted tissue repair/regeneration in the zymosan A-induced mouse peritonitis model.
Association with Bone Mineral Density
Koh et al. (2006) genotyped 5 polymorphisms of the SEMA7A gene in 560 postmenopausal Korean women and measured bone mineral density (BMD; see 601884) of the lumbar spine and proximal femur. The SEMA7A polymorphisms 15775C-G (rs2072649) and 22331A-G (rs741761) were associated with a low BMD of the femoral neck and lumbar spine (p = 0.02 and 0.04, respectively) in a recessive model. A haplotype based on the 5 SNPs, so-called ht4, was associated with risk of vertebral fracture (OR = 1.87 and 1.93, p = 0.03 and 0.02, in dominant and codominant models, respectively). Koh et al. (2006) suggested that variations in SEMA7A may play a role in decreased BMD and risk of vertebral fracture.
John Milton Hagen Blood Group System: JMH-Variant Phenotype
In 5 unrelated individuals with JMH-variant phenotype (see 614745) from 5 different countries, Seltsam et al. (2007) identified 4 missense mutations in the SEMA7A gene (607961.0001-607961.0004). These mutations were not detected in genomic DNA from 100 randomly selected individuals from Northern Germany. All 4 missense mutations occurred in the semaphorin domain of SEMA7A.
Progressive Familial Intrahepatic Cholestasis 11
In a female infant, born of unrelated Chinese Han parents, with progressive familial intrahepatic cholestasis-11 (PFIC11; 619874), Pan et al. (2021) identified a homozygous missense mutation in the SEMA7A gene (R148W; 607961.0006). The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Liver tissue from the patient was not available for study, but expression of the orthologous mutation in mice resulted in cholestatic liver disease associated with decreased levels of bile acid transporters (see ANIMAL MODEL).
Czopik et al. (2006) found that T cells from immunized Sema7a -/- mice had increased proliferative responses to antigen that were not attributable to Sema7a deficiency on macrophages or dendritic cells. Sema7a -/- mice were prone to die at the onset of experimental autoimmune encephalomyelitis (EAE) and had higher clinical EAE scores compared with wildtype littermates. Delayed-type hypersensitivity responses were also enhanced in Sema7a -/- mice. Czopik et al. (2006) concluded that SEMA7A plays an important T cell-intrinsic inhibitory role and is essential in limiting T cell-mediated autoimmunity.
Pan et al. (2021) found that mutant mice homozygous for the R145W mutation, which is orthologous to the human R148W mutation (607961.0006), developed elevated serum levels of liver enzymes ALT and AST and increased total bile acid associated with hydropic degeneration in hepatocytes. Liver tissue from mutant mice showed accumulation of bile acids and impaired hepatic excretion of bile acids compared to controls. The findings were consistent with cholestatic liver disease and recapitulated the human phenotype. Mutant mouse liver showed decreased protein levels of the canalicular bile acid transporters Bsep (ABCB11; 603201) and Mrp2 (ABCC2; 601107), although the mRNA levels of these genes were normal, suggesting post-translational regulation. This was associated with increased phosphorylation of protein kinase C (PRKCD, 176977 and PRKCE, 176975). Pan et al. (2021) concluded that the R145W mutation is likely a gain-of-function mutation that reduces Bsep and Mrp2 expression in hepatocytes by increasing PKC activity, which reduces canalicular expression of these protein in cholestatic hepatocytes.
In 2 unrelated individuals with JMH-negative phenotype (see 614745) from Germany and Canada, Seltsam et al. (2007) identified a 620G-A transition in exon 6 of the SEMA7A gene, resulting in an arg207-to-gln (R207Q) substitution in the semaphorin domain of the protein.
In a Japanese individual with JMH-negative phenotype (see 614745), Seltsam et al. (2007) identified a 619C-T transition in exon 6 of the SEMA7A gene, resulting in an arg207-to-trp (R207W) substitution in the semaphorin domain of the protein.
In an individual with JMH-negative phenotype (see 614745) from the U.S., Seltsam et al. (2007) identified a 1379G-A transition in exon 11 of the SEMA7A gene, resulting in an arg460-to-his (R460H) substitution in the semaphorin domain of the protein.
In a Polish individual with JMH-negative phenotype (see 614745), Seltsam et al. (2007) identified a 1381C-T transition in exon 11 of the SEMA7A gene, resulting in an arg461-to-cys (R461C) substitution in the semaphorin domain of the protein.
In 4 young Native American women with JMH-negative phenotype (see 614745) from a reservation northwest of Quebec City, Canada, Richard et al. (2011) identified a 1040G-T transversion in exon 9 of the SEMA7A gene, resulting in an arg347-to-leu (R347L) substitution in the semaphorin domain. At least 2 of the women were JHM-positive and their alloantibody was compatible with most JHM-negative red blood cells tested; the other 2 women were not tested. Soluble forms of wildtype and R347L variant SEMA7A proteins were produced in vitro and demonstrated a specific alloantibody reaction with wildtype recombinant SEMA7A, but not with the R347L variant form.
In a female infant, born of unrelated Chinese Han parents, with progressive familial intrahepatic cholestasis-11 (PFIC11; 619874), Pan et al. (2021) identified a homozygous c.442C-T transition in exon 4 of the SEMA7A gene, resulting in an arg148-to-trp (R148W) substitution at a conserved residue in the SEMA domain. The mutation, which was found by whole-genome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Liver tissue from the patient was not available for analysis. Mutant mice homozygous for the orthologous mutation (R145W) developed elevated serum levels of liver enzymes ALT and AST and increased total bile acid associated with hydropic degeneration in hepatocytes. Liver tissue from mutant mice showed accumulation of bile acids and impaired hepatic excretion of bile acids compared to controls. There were also decreased protein levels of the canalicular bile acid transporters Bsep (ABCB11; 603201) and Mrp2 (ABCC2; 601107), although the mRNA levels of these genes were normal, suggesting post-translational regulation. These findings were consistent with cholestatic liver disease and recapitulated the human phenotype. Genetic analysis in the proband also identified a homozygous missense mutation in the SLC10A1 gene (S267F; 182396.0002) that may have contributed to the phenotype in the patient, although expression of the homozygous SLC10A1 mutation in mice did not lead to liver injury or hypercholanemia in mice, suggesting that the primary cause of the disease is the SEMA7A mutation.
Czopik, A. K., Bynoe, M. S., Palm, N., Raine, C. S., Medzhitov, R. Semaphorin 7A is a negative regulator of T cell responses. Immunity 24: 591-600, 2006. [PubMed: 16713976] [Full Text: https://doi.org/10.1016/j.immuni.2006.03.013]
Gross, M. B. Personal Communication. Baltimore, Md. 9/13/2017.
Koh, J.-M., Oh, B., Lee, J. Y., Lee, J.-K., Kimm, K., Kim, G. S., Park, B. L., Cheong, H. S., Shin, H. D., Hong, J. M., Kim, T.-H., Park, E. K., Kim, S.-Y. Association study of semaphorin 7a (sema7a) polymorphisms with bone mineral density and fracture risk in postmenopausal Korean women. J. Hum. Genet. 51: 112-117, 2006. [PubMed: 16372136] [Full Text: https://doi.org/10.1007/s10038-005-0331-z]
Korner, A., Bernard, A., Fitzgerald, J. C., Alarcon-Barrera, J., Kostidis, S., Kaussen, T., Giera, M., Mirakaj, V. Sema7A is crucial for resolution of severe inflammation. Proc. Nat. Acad. Sci. 118: e2017527118, 2021. [PubMed: 33637648] [Full Text: https://doi.org/10.1073/pnas.2017527118]
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Pan, Q., Luo, G., Qu, J., Chen, S., Zhang, X., Zhao, N., Ding, J., Yang, H., Li, M., Li, L., Cheng, Y., Li, X., and 11 others. A homozygous R148W mutation in Semaphorin 7A causes progressive familial intrahepatic cholestasis. EMBO Molec. Med. 13: e14563, 2021. [PubMed: 34585848] [Full Text: https://doi.org/10.15252/emmm.202114563]
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Uesaka, N., Uchigashima, M., Mikuni, T., Nakazawa, T., Nakao, H., Hirai, H., Aiba, A., Watanabe, M., Kano, M. Retrograde semaphorin signaling regulates synapse elimination in the developing mouse brain. Science 344: 1020-1023, 2014. [PubMed: 24831527] [Full Text: https://doi.org/10.1126/science.1252514]
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