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|Coordinate||161,787,138 bp (GRCm38)|
|Base Change||T ⇒ G (forward strand)|
|Gene Name||Fas ligand (TNF superfamily, member 6)|
|Synonym(s)||APT1LG1, CD178, CD95L, Fas-L, Tnfsf6|
|Chromosomal Location||161,780,689-161,788,495 bp (-)|
FUNCTION: [Summary is not available for the mouse gene. This summary is for the human ortholog.] This gene is a member of the tumor necrosis factor superfamily. The primary function of the encoded transmembrane protein is the induction of apoptosis triggered by binding to FAS. The FAS/FASLG signaling pathway is essential for immune system regulation, including activation-induced cell death (AICD) of T cells and cytotoxic T lymphocyte induced cell death. It has also been implicated in the progression of several cancers. Defects in this gene may be related to some cases of systemic lupus erythematosus (SLE). Alternatively spliced transcript variants have been described. [provided by RefSeq, Nov 2014]
PHENOTYPE: Mice homozygous for a spontaneous allele, knock-out allele, or allele producting only the soluble isoform exhibit premature death due to the development of systemic lupus erythematosus, autoimmune glomerulonephritis, hepatomegaly, lymphadenopathy, and hypergammaglobulinaemia. [provided by MGI curators]
|Amino Acid Change||Serine changed to Arginine|
|Institutional Source||Beutler Lab|
|Gene Model||predicted gene model for protein(s): [ENSMUSP00000000834] [ENSMUSP00000141422]|
AA Change: S119R
|Predicted Effect||probably benign
PolyPhen 2 Score 0.001 (Sensitivity: 0.99; Specificity: 0.15)
|Predicted Effect||probably benign|
|Alleles Listed at MGI|
|Mode of Inheritance||Autosomal Recessive|
|Last Updated||2016-05-13 3:09 PM by Anne Murray|
|Record Created||2015-06-30 9:04 PM by Kuan-Wen Wang|
The riogrande2 phenotype was identified among N-ethyl-N-nitrosourea (ENU)-mutagenized G3 mice of the pedigree R2167, some of which showed exhibited diminished T-dependent antibody response to recombinant Semliki Forest virus (rSFV)-encoded β-galactosidase (rSFV-β-gal; Figure 1).
|Nature of Mutation|
Whole exome HiSeq sequencing of the G1 grandsire identified 65 mutations. The diminished T-dependent antibody response to rSFV-β-gal was linked by continuous variable mapping to a mutation in Fasl: an A to C transversion at base pair 161,787,138 (v38) on chromosome 1, or base pair 8,401 in the GenBank genomic region NC_000067. Linkage was found with a recessive model of inheritance (P = 2.666 x 10-6), wherein 1 variant homozygote departed phenotypically from 4 homozygous reference mice and 9 heterozygous mice (Figure 2).
The mutation corresponds to residue 565 in the mRNA sequence NM_010177 within exon 2 of 4 total exons.
The mutated nucleotide is indicated in red. The mutation results in a serine (S) to arginine (R) substitution at position 119 (S119R) in the FasL protein, and is strongly predicted by PolyPhen-2 to be benign (score = 0.001) (1).
Fasl encodes Fas ligand (FasL; alternatively, CD95L, TNFSF6, or CD178), a type II membrane protein and member of the tumor necrosis factor (TNF; see the record for Dome) family [reviewed in (2;3)]. The 279 amino acid mouse FasL consists of an intracellular domain (ICD; amino acids 1-78), a transmembrane domain (amino acids 79-100), and an extracellular TNF homology domain (THD; amino acids 101-279) that contains the Fas (see the record for cherry) receptor-binding site [Figure 3; (4); reviewed in (2)]. A proline-rich domain (PRD) and polyproline domain within the ICD (amino acids 4-69 and 45-51, respectively) facilitate the binding of Src homology 3 (SH3) or WW domain-containing proteins (e.g., Fyn, Nck, SNX9, SNX18, SNX33, and CD2BP1) to FasL [(5); reviewed in (2;3)].
FasL occurs in both a membrane-bound (mFasL) and soluble form (sFasL) as a result of proteolytic processing of FasL. A disintegrin and metallopeptidase domain 10 (ADAM10; for information about ADAM family member, Adam17, please see the record wavedX) cleaves FasL between Lys127 and Gln128. Following cleavage by ADAM10, FasL is further processed by signal peptide peptidase-like 2a (SPPL2a; amino acids 79-80). Metalloproteinase-3 (MMP3) and MMP7 (see the record cartoon for information about MMP family member Mmp14) have also been linked to the cleavage of FasL between Lys127 and Gln128 in some cells (e.g., glandular epithelial cells) (6).
The riogrande2 mutation results in a serine to arginine substitution at position 119 (S119R) within the THD domain.
Please see the record riogrande for more information about Fasl.
The FasL/Fas receptor system has several functions: (i) acting as a pro-apoptotic factor, (ii) facilitating the removal of target cells by NK and cytotoxic T lymphocytes (CTLs), (iii) maintaining immune-privileged sites, (iv) preventing autoimmunity, (v) regulating resting T cell activation by acting as a non-apoptotic costimulatory ligand/receptor, (vi) acting as a proinflammatory signal, (vii) acting as a proliferative/promigratory signal, and (viii) assisting in tumor cell survival [reviewed in (2;7)]. Loss of Fasl expression results in leukocytosis, splenomegaly, enlarged peripheral lymph nodes, and premature death by 4-5 months (8-10). Mutations in FASL are linked to autoimmune lymphoproliferative syndrome, type IB (ALPS; OMIM: #601859) (11). In ALPS, patients exhibit nonmalignant lymphadenopathy with splenomegaly (12). ALPS is an autosomal dominant disorder of FasL-induced apoptosis, resulting in the accumulation of autoreactive lymphocytes and the production of autoantibodies (13). Patients with ALPS may also exhibit includes Coombs-positive hemolytic anemia, chronic immune thrombocytopenic purpura, and neutropenia (12).
In both B and T cell development, apoptosis is essential to maintain immune cell homeostasis. Immature cells that fail to undergo proper V(D)J rearrangement and subsequently fail to express surface antigen receptors (BCR or TCR) undergo apoptosis. Fas/FasL-induced apoptosis is essential for the deletion of autoreactive thymocytes and immature B cells in the bone marrow [(14;15); reviewed in (16)]. Homozygous Fasl ΔIntra mice, a knockin model that expresses a FasL protein that lacks the ICD but expresses a functional, truncated mFasL, exhibited elevated plasma cells and increased generation of germinal center B cells, leading to increased titers of NP-specific IgM antibodies in the serum after immunization with 3-hydroxy 4-nitrophenylacetyl chicken gamma globulin (NP-CGG) (17). T-independent immunization of homozygous Fasl ΔIntra mice with NP-Ficoll resulted in increased plasma cell number as well as NP-specific IgM titers (17). In addition, the Fasl-/- and Fasldel mice exhibited increased IgG and IgM levels compared to wild-type levels (8;10). The riogrande2 mice exhibit reduced T-dependent IgG responses to rSFV, indicating that the activation of B and/or T cells in the riogrande2 mice may be negatively affected by the Fasl mutation.
riogrande2(F):5'- GTCAAAAGCTCCTCAGGGTTTC -3'
riogrande2(R):5'- CCTCTCTGAGTTGTCAAGGGTG -3'
riogrande2_seq(F):5'- CCTCAGGGTTTCATGCCTAGG -3'
riogrande2_seq(R):5'- CGCTGCTTCATGTTTAGTGATTCAAG -3'
1. Adzhubei, I. A., Schmidt, S., Peshkin, L., Ramensky, V. E., Gerasimova, A., Bork, P., Kondrashov, A. S., and Sunyaev, S. R. (2010) A Method and Server for Predicting Damaging Missense Mutations. Nat Methods. 7, 248-249.
2. Lettau, M., Paulsen, M., Schmidt, H., and Janssen, O. (2011) Insights into the Molecular Regulation of FasL (CD178) Biology. Eur J Cell Biol. 90, 456-466.
3. Ehrenschwender, M., and Wajant, H. (2009) The Role of FasL and Fas in Health and Disease. Adv Exp Med Biol. 647, 64-93.
4. Suda, T., Takahashi, T., Golstein, P., and Nagata, S. (1993) Molecular Cloning and Expression of the Fas Ligand, a Novel Member of the Tumor Necrosis Factor Family. Cell. 75, 1169-1178.
5. Ghadimi, M. P., Sanzenbacher, R., Thiede, B., Wenzel, J., Jing, Q., Plomann, M., Borkhardt, A., Kabelitz, D., and Janssen, O. (2002) Identification of Interaction Partners of the Cytosolic Polyproline Region of CD95 Ligand (CD178). FEBS Lett. 519, 50-58.
6. Tanaka, M., Itai, T., Adachi, M., and Nagata, S. (1998) Downregulation of Fas Ligand by Shedding. Nat Med. 4, 31-36.
7. Walczak, H. (2013) Death Receptor-Ligand Systems in Cancer, Cell Death, and Inflammation. Cold Spring Harb Perspect Biol. 5, a008698.
8. Karray, S., Kress, C., Cuvellier, S., Hue-Beauvais, C., Damotte, D., Babinet, C., and Levi-Strauss, M. (2004) Complete Loss of Fas Ligand Gene Causes Massive Lymphoproliferation and Early Death, Indicating a Residual Activity of Gld Allele. J Immunol. 172, 2118-2125.
9. Roths, J. B., Murphy, E. D., and Eicher, E. M. (1984) A New Mutation, Gld, that Produces Lymphoproliferation and Autoimmunity in C3H/HeJ Mice. J Exp Med. 159, 1-20.
10. Wang, C. C., Zeng, Q., Hwang, L. A., Guo, K., Li, J., Liew, H. C., and Hong, W. (2006) Mouse Lymphomas Caused by an Intron-Splicing Donor Site Deletion of the FasL Gene. Biochem Biophys Res Commun. 349, 50-58.
11. Del-Rey, M., Ruiz-Contreras, J., Bosque, A., Calleja, S., Gomez-Rial, J., Roldan, E., Morales, P., Serrano, A., Anel, A., Paz-Artal, E., and Allende, L. M. (2006) A Homozygous Fas Ligand Gene Mutation in a Patient Causes a New Type of Autoimmune Lymphoproliferative Syndrome. Blood. 108, 1306-1312.
12. Randhawa, S. R., Chahine, B. G., Lowery-Nordberg, M., Cotelingam, J. D., and Casillas, A. M. (2010) Underexpression and Overexpression of Fas and Fas Ligand: A Double-Edged Sword. Ann Allergy Asthma Immunol. 104, 286-292.
13. Canale, V. C., and Smith, C. H. (1967) Chronic Lymphadenopathy Simulating Malignant Lymphoma. J Pediatr. 70, 891-899.
14. Rubio, C. F., Kench, J., Russell, D. M., Yawger, R., and Nemazee, D. (1996) Analysis of Central B Cell Tolerance in Autoimmune-Prone MRL/lpr Mice Bearing Autoantibody Transgenes. J Immunol. 157, 65-71.
15. Singer, G. G., and Abbas, A. K. (1994) The Fas Antigen is Involved in Peripheral but Not Thymic Deletion of T Lymphocytes in T Cell Receptor Transgenic Mice. Immunity. 1, 365-371.
16. Strasser, A., Jost, P. J., and Nagata, S. (2009) The Many Roles of FAS Receptor Signaling in the Immune System. Immunity. 30, 180-192.
17. Luckerath, K., Kirkin, V., Melzer, I. M., Thalheimer, F. B., Siele, D., Milani, W., Adler, T., Aguilar-Pimentel, A., Horsch, M., Michel, G., Beckers, J., Busch, D. H., Ollert, M., Gailus-Durner, V., Fuchs, H., Hrabe de Angelis, M., Staal, F. J., Rajalingam, K., Hueber, A. O., Strobl, L. J., Zimber-Strobl, U., and Zornig, M. (2011) Immune Modulation by Fas Ligand Reverse Signaling: Lymphocyte Proliferation is Attenuated by the Intracellular Fas Ligand Domain. Blood. 117, 519-529.
|Science Writers||Anne Murray|
|Authors||Kuan-Wen Wang, Jin Huk Choi, Bruce Beutler|
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