Alternative titles; symbols
HGNC Approved Gene Symbol: LYN
Cytogenetic location: 8q12.1 Genomic coordinates (GRCh38): 8:55,879,835-56,014,169 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q12.1 | Autoinflammatory disease, systemic, with vasculitis | 620376 | Autosomal dominant | 3 |
The LYN gene encodes a member of the Src family of protein tyrosine kinases. It is a nonreceptor cytoplasmic protein that plays an important role in the regulation of innate and adaptive immune responses, as well as other cellular processes (summary by Harper et al., 2022 and Louvrier et al., 2023).
Using a v-yes DNA as the probe, Yamanashi et al. (1987) screened a human cDNA library made from placental RNA and derived DNA clones representing a novel genetic locus termed LYN. Nucleotide sequencing showed that LYN encodes a novel tyrosine kinase. Northern hybridization analysis showed that a 3.2-kb LYN mRNA was expressed in a variety of tissues of the human fetus. The pattern of expression was different from those of related genes such as YES (164880).
LYN is expressed in endothelial cells of small vessels, in liver sinusoidal endothelial cells, and in neutrophils, monocytes, and macrophages (summary by de Jesus et al., 2023).
Parravicini et al. (2002) noted that Lyn deficiency impairs some mast cell functions, but degranulation and cytokine production are intact. In Gab2 (606203)-deficient mice, on the other hand, degranulation and cytokine production are impaired. Using immunoblot analysis, they showed that although Lyn is essential for Syk (600085) activation and Lat (602354) phosphorylation after Fcer1 (see FCER1G; 147139) aggregation, neither Lyn nor Lat are necessary for Gab2 phosphorylation. RT-PCR and coimmunoprecipitation analyses demonstrated abundant Fyn (137025) expression in mast cells and an association with Gab2. In cells lacking Fyn, neither Gab2 nor Akt (164730) were phosphorylated. Functional analysis showed that Lyn -/- mast cells exhibited hyperdegranulation and enhanced PI3K (see 601232) activity and Akt phosphorylation, whereas in Fyn -/- mast cells the degranulation response was inhibited. The inhibition was associated with decreased binding of PI3K with Gab2. Parravicini et al. (2002) observed that the degranulation response was independent of Fcer1 stimulation in Fyn-deficient mast cells and that degranulation was dependent on PI3K in wildtype and mutant cell lines. The degranulation response was dependent on a rise in intracellular calcium that was inhibited in Lyn-deficient mast cells but intact in Fyn-deficient cells. Degranulation proceeded in Lyn -/- cells due to increased activation and constitutive phosphorylation of the calcium-independent protein kinase C delta isoform (PRKCD; 176977). Parravicini et al. (2002) concluded that Fyn- and Lyn-initiated pathways synergize in late events at the level of protein kinase C and calcium, respectively, to regulate mast cell degranulation.
Yoo et al. (2011) identified Lyn as a redox sensor that mediates initial neutrophil recruitment to wounds in zebrafish larvae. Lyn activation in neutrophils is dependent on wound-derived H2O2 after tissue injury, and inhibition of Lyn attenuates neutrophil wound recruitment. Inhibition of Src family kinase (SFK) also disrupted H2O2-mediated chemotaxis of primary human neutrophils. In vitro analysis identified a single cysteine residue, C466, as being responsible for direct oxidation-mediated activation of Lyn. Furthermore, transgenic tissue-specific reconstitution with wildtype Lyn and a cysteine mutant revealed that Lyn C466 is important for the neutrophil wound response and downstream signaling in vivo. Yoo et al. (2011) concluded that this was the first identification of a physiologic redox sensor that mediates leukocyte wound attraction in multicellular organisms.
By hybridization analysis of DNA from sorted chromosomes, Yamanashi et al. (1987) mapped the LYN gene to chromosome 8q13-qter.
Stumpf (2023) mapped the LYN gene to chromosome 8q12.1 based on an alignment of the LYN sequence (GenBank BC126456) with the genomic sequence (GRCh38).
In a 3-year-old boy with systemic autoinflammatory disease with vasculitis (SAIDV; 620376), de Jesus et al. (2016) identified a de novo heterozygous nonsense mutation in the LYN gene (Y508X; 165120.0001). The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. The mutation was predicted to result in a truncated protein lacking the phosphorylation site (Y508) that inactivates the LYN kinase. Patient B lymphocytes showed constitutive phosphorylation of LYN.
In 3 unrelated boys with SAIDV, including the patient reported by de Jesus et al. (2016), de Jesus et al. (2023) identified 3 different de novo heterozygous mutations in the LYN gene (Y508X, 165120.0001, Y508F, 165120.0002, and Q507X, 165120.0003). All occurred at the C-terminal end of the protein and disrupted residue Y508, an important regulatory region that renders LYN inactive when phosphorylated. In vitro studies in HEK293 cells transfected with the mutations showed constitutive phosphorylation of the kinase-activating tyrosine Y397 and absent phosphorylation of the inhibitory tyrosine Y508. Mutant LYN caused increased phosphorylation of several kinase targets. Increased phosphorylation of LYN kinase substrates was also observed in B cells from P1. Serologic assays showed an enhanced inflammatory response with biomarkers of neutrophil, endothelial cell, and macrophage activation. Skin and liver sinusoidal endothelial cells from P1 showed increased expression of ICAM1 (147840), and neutrophils had increased expression of beta2-integrins (see, e.g., ITGB2, 600065), which increased neutrophil adhesion and vascular transendothelial migration. Similar findings were observed in induced patient-derived endothelial cells. The findings suggested a pivotal role for LYN gain-of-function mutations in endothelial dysregulation, which is a driver of vasculitis and liver fibrosis.
In a 4-year-old girl with SAIDV, Louvrier et al. (2023) identified a de novo heterozygous missense mutation in the LYN gene (Y508H; 165120.0004). The mutation was absent from the gnomAD database. In vitro functional expression studies in transfected HEK293 cells showed that 3 variants involving tyr508 (Y508H, Y508F, and Y508X) were not phosphorylated at residue 508 but were constitutively phosphorylated at tyr397, thus maintaining LYN in its active state. All 3 mutants activated the NFKB (see 164011) signaling pathway, whereas wildtype LYN did not. The findings were consistent with a gain-of-function effect.
Hibbs et al. (1995) demonstrated that mice homozygous for a disruption of the Lyn locus display abnormalities associated with the B-lymphocyte lineage and in mast cell function. Despite reduced numbers of recirculating B lymphocytes, the homozygous deficient mice are immunoglobulin M hyperglobulinemic. Lyn-deficient mice show IgM hyperglobulinemia. Immune responses to T-independent and T-dependent antigens were affected. The deficient mice failed to mediate an allergic response to IgE cross-linking, indicating that activation of Lyn plays an indispensable role in signaling by the high-affinity IgE receptor (FCER). Homozygous deficient mice had circulating autoreactive antibodies, and many showed severe glomerulonephritis caused by the deposition of IgG immune complexes in the kidney, a pathology reminiscent of systemic lupus erythematosus. Hibbs et al. (1995) stated that, collectively, these results implicated LYN as having an indispensable role in immunoglobulin-mediated signaling, particularly in establishing B cell tolerance.
Harder et al. (2001) generated mice with a gain-of-function Lyn mutation (Y508F, see 165120.0002), which they referred to as 'up,' analogous to the Y527F activating mutation in the mouse Src gene (190090) (Webster et al., 1995). Even aging mice with the Lyn up/up phenotype did not display hematologic malignancies, unlike Lyn -/- mice, which developed splenomegaly, increased myeloid progenitors, and monocyte/macrophage tumors. Biochemical analysis revealed that Lyn is essential in establishing ITIM (immunoreceptor tyrosine-based inhibitory motif)-dependent signaling and for the activation of specific protein tyrosine phosphatases within myeloid cells, which may underlie the susceptibility of Lyn -/- mice to tumorigenesis.
Hasegawa et al. (2001) generated mice deficient in both Cd19 (107265) and Lyn. Cd19 deficiency suppressed the hyperresponsive phenotype of Lyn -/- B cells and autoimmunity characterized by serum autoantibodies and immune complex-mediated glomerulonephritis in Lyn -/- mice. Cd19/Lyn -/- mice had additional reduction of primitive, predominantly IgM-secreting B1 lymphocytes. Cd19 deficiency inhibited activation of Src family protein tyrosine kinase-dependent signaling pathways and delayed enhanced intracellular calcium responses following B-cell antigen receptor ligation in Lyn -/- B cells. Hasegawa et al. (2001) concluded that Cd19 expression is required for the development of autoimmunity in Lyn -/- mice.
SYK controls pre-B cell development but does not affect NFKB (164011) induction. Saijo et al. (2003) showed that mice triple-deficient in the Src family protein tyrosine kinases (SFKs) Blk (191305), Fyn, and Lyn, but not single-deficient or Syk-deficient mice, had impaired Nfkb induction and B-cell development. The impairment of Nfkb induction could be overcome by protein kinase C-lambda (see 176982) activation. Saijo et al. (2003) suggested that there are 2 separate pathways in pre-B cell receptor signaling, one SFK-dependent and the other SYK-dependent, that contribute critically to pre-B cell development.
Hibbs et al. (2002) found that mice with a targeted gain-of-function Lyn allele (Y508F) ('up/up') had altered B-cell signaling. There were reduced numbers of B lymphocytes and downregulated surface IgM and costimulatory molecules. B cells also showed constitutive phosphorylation of both positive and negative regulators of B-cell receptor signaling. Lyn(up/up) mice developed autoreactive antibodies and lethal autoimmune glomerulonephritis, suggesting a breakdown in tolerance.
In a 3-year-old Caucasian boy (patient 1) with systemic autoinflammatory disease with vasculitis (SAIDV; 620376), de Jesus et al. (2016) identified a de novo heterozygous c.1524C-G transversion in the LYN gene, resulting in a tyr508-to-ter (Y508X) substitution with removal of the 5 terminal amino acids and loss of the phosphorylation site that inactivates the LYN kinase. The mutation was found by whole-exome sequencing and confirmed by Sanger sequencing. Patient B cells showed constitutive phosphorylation of LYN. There was a decrease in immature B cells in blood and bone marrow, and B-cell activation was reduced upon IgM stimulation compared to controls. The patient had cutaneous vasculitis and systemic features, including liver fibrosis.
De Jesus et al. (2023) restudied this patient (P1) and noted that the mutation resulted from a c.1524C-G transversion (c.1524C-G, NM_002350). In vitro studies in HEK293 cells transfected with the Y508X mutation showed constitutive phosphorylation of the kinase-activating tyrosine Y397 and absent phosphorylation of the inhibitory tyrosine Y508. Mutant LYN also caused phosphorylation and activation of downstream signaling molecules involved in inflammation. Flow cytometry of anti-IgM stimulated B cells from the patient showed increased phosphorylation of LYN kinase substrates.
Louvrier et al. (2023) noted that the Y508X mutation is located in the last exon of LYN and thus escapes nonsense-mediated mRNA decay.
In a 15-year-old boy (P2) with systemic autoinflammatory disease with vasculitis (SAIDV; 620376), de Jesus et al. (2023) identified a de novo heterozygous c.1523A-T transversion (c.1523A-T, NM_002350) in the LYN gene, resulting in a tyr508-to-phe (Y508F) substitution at a conserved residue Y508 that is a regulatory tyrosine. The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, was absent from public databases, including gnomAD. In vitro studies in HEK293 cells transfected with the mutation showed constitutive phosphorylation of the kinase-activating tyrosine Y397 and absent phosphorylation of the inhibitory tyrosine Y508. Mutant LYN also caused phosphorylation and activation of downstream signaling molecules involved in inflammation. The patient had cutaneous vasculitis and other systemic features, but no liver fibrosis.
In a 4-month-old boy (P3) with systemic autoinflammatory disease with vasculitis (SAIDV; 620376), de Jesus et al. (2023) identified a de novo heterozygous c.1519C-T transition (c.1519C-T, NM_002350) in the LYN gene, resulting in a gln507-to-ter (Q507X) substitution and a loss of 6 terminal residues, including the regulatory Y508. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not present in public databases, including gnomAD. In vitro studies in HEK293 cells transfected with the mutation showed constitutive phosphorylation of the kinase-activating tyrosine Y397 and absent phosphorylation of the inhibitory tyrosine Y508. Mutant LYN also caused phosphorylation and activation of downstream signaling molecules involved in inflammation. The patient had cutaneous vasculitis and liver fibrosis.
In a 4-year-old girl with systemic autoinflammatory disease with vasculitis (SAIDV; 620376), Louvrier et al. (2023) identified a de novo heterozygous c.1522T-C transition (c.1522T-C, NM_002350) in the LYN gene, resulting in a tyr508-to-his (Y508H) substitution at a conserved residue in the C-terminus known to be involved in the negative regulation of LYN. The mutation, which was found by next-generation sequencing and confirmed by Sanger sequencing, was absent from the gnomAD database. In vitro functional expression studies in transfected HEK293 cells showed that the tyr508 residue was not phosphorylated but that there was constitutive phosphorylation at tyr397, thus maintaining LYN in its active state. The mutant protein activated the NFKB (see 164011) signaling pathway. The findings were consistent with a gain-of-function effect.
de Jesus, A. A., Chen, G., Yang, D., Brdicka, T., Ruth, N. M., Bennin, D., Cebecauerova, D., Malcova, H., Freeman, H., Martin, N., Svojgr, K., Passo, M. H., and 42 others. Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome. Nature Commun. 14: 1502, 2023. [PubMed: 36932076] [Full Text: https://doi.org/10.1038/s41467-023-36941-y]
de Jesus, A. A., Montealegre, G. A., Freeman, H., Martin, N., Omoyinmi, E., Marrero, B., Calvo, K. R., Lee, C.-C. R., Brundidge, A. D., Kleiner, D., Hewitt, S., Chapelle, D. C., and 11 others. Mutations in the tyrosine-protein kinase Lyn cause an early-onset neutrophilic vasculitis syndrome. 2016 ACR/ARHP Annual Meeting Abstract Supplement. Arthritis Rheum. 68 Suppl. 10: 1-4550, 2016. Note: Abstract 2430. [PubMed: 27870508] [Full Text: https://doi.org/10.1002/art.39977]
Harder, K. W., Parsons, L. M., Armes, J., Evans, N., Kountouri, N., Clark, R., Quillici, C., Grail, D., Hodgson, G. S., Dunn, A. R., Hibbs, M. L. Gain- and loss-of-function Lyn mutant mice define a critical inhibitory role for Lyn in the myeloid lineage. Immunity 15: 603-615, 2001. [PubMed: 11672542] [Full Text: https://doi.org/10.1016/s1074-7613(01)00208-4]
Harper, R., Yu, Q., Liu, Y., Yang, D., Zou, J., Beers, J., de Jesus Rasheed, A. A., Goldbach-Mansky, R., Boehm, M., Chen, G. Human induced pluripotent stem cells generated from a patient with a heterozygous mutation in the Lyn kinase gene. Stem Cell Res. 64: 102933, 2022. Note: Erratum: Stem Cell Res. 69: 103059 only, 2023. [PubMed: 36215934] [Full Text: https://doi.org/10.1016/j.scr.2022.102933]
Hasegawa, M., Fujimoto, M., Poe, J. C., Steeber, D. A., Lowell, C. A., Tedder, T. F. A CD19-dependent signaling pathway regulates autoimmunity in Lyn-deficient mice. J. Immun. 167: 2469-2478, 2001. [PubMed: 11509585] [Full Text: https://doi.org/10.4049/jimmunol.167.5.2469]
Hibbs, M. L., Harder, K. W., Armes, J., Kountouri, N., Quilici, C., Casagranda, F., Dunn, A. R., Tarlinton, D. M. Sustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity. J. Exp. Med. 196: 1593-1604, 2002. [PubMed: 12486102] [Full Text: https://doi.org/10.1084/jem.20020515]
Hibbs, M. L., Tarlinton, D. M., Armes, J., Grail, D., Hodgson, G., Maglitto, R., Stacker, S. A., Dunn, A. R. Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease. Cell 83: 301-311, 1995. [PubMed: 7585947] [Full Text: https://doi.org/10.1016/0092-8674(95)90171-x]
Louvrier, C., El Khouri, E., Grall Lerosey, M., Quartier, P., Guerrot, A.-M., Bader Meunier, B., Chican, J., Mohammad, M., Assrawi, E., Daskalopoulou, A., Arenas Garcia, A., Copin, B., Piterboth, W., Dastot Le Moal, F., Karabina, S. A., Amselem, S., Giurgea, I. De novo gain-of-function variations in LYN associated with an early-onset systemic autoinflammatory disorder. Arthritis Rheum. 75: 468-474, 2023. [PubMed: 36122175] [Full Text: https://doi.org/10.1002/art.42354]
Parravicini, V., Gadina, M., Kovarova, M., Odom, S., Gonzalez-Espinosa, C., Furumoto, Y., Saitoh, S., Samelson, L. E., O'Shea, J. J., Rivera, J. Fyn kinase initiates complementary signals required for IgE-dependent mast cell degranulation. Nature Immun. 3: 741-748, 2002. [PubMed: 12089510] [Full Text: https://doi.org/10.1038/ni817]
Saijo, K., Schmedt, C., Su, I., Karasuyama, H., Lowell, C. A., Reth, M., Adachi, T., Patke, A., Santana, A., Tarakhovsky, A. Essential role of Src-family protein tyrosine kinases in NF-kappa-B activation during B cell development. Nature Immun. 4: 274-279, 2003. [PubMed: 12563261] [Full Text: https://doi.org/10.1038/ni893]
Stumpf, A. M. Personal Communication. Baltimore, Md. 05/16/2023.
Webster, M. A., Cardiff, R. D., Muller, W. J. Induction of mammary epithelial hyperplasias and mammary tumors in transgenic mice expressing a murine mammary tumor virus/activated c-src fusion gene. Proc. Nat. Acad. Sci. 92: 7849-7853, 1995. [PubMed: 7544006] [Full Text: https://doi.org/10.1073/pnas.92.17.7849]
Yamanashi, Y., Fukushige, S.-I., Semba, K., Sukegawa, J., Miyajima, N., Matsubara, K.-I., Yamamoto, T., Toyoshima, K. The yes-related cellular gene lyn encodes a possible tyrosine kinase similar to p56(lck). Molec. Cell. Biol. 7: 237-243, 1987. [PubMed: 3561390] [Full Text: https://doi.org/10.1128/mcb.7.1.237-243.1987]
Yoo, S. K., Starnes, T. W., Deng, Q., Huttenlocher, A. Lyn is a redox sensor that mediates leukocyte wound attraction in vivo. Nature 480: 109-112, 2011. [PubMed: 22101434] [Full Text: https://doi.org/10.1038/nature10632]