RBCC Red Blood Cell Collection

FAS (APT1, FAS1, TNFRSF6) [Confidence: medium (present in either hRBCD or BSc_CH or PM22954596)]
Tumor necrosis factor receptor superfamily member 6 (Apo-1 antigen; Apoptosis-mediating surface antigen FAS; FASLG receptor; CD95; Flags: Precursor)

UniProt P25445
ID TNR6_HUMAN Reviewed; 335 AA.
AC P25445; A9UJX4; B6VNV4; Q14292; Q14293; Q14294; Q14295; Q16652;
read moreAC Q5T9P1; Q5T9P2; Q5T9P3; Q6SSE9;
DT 01-MAY-1992, integrated into UniProtKB/Swiss-Prot.
DT 01-MAY-1992, sequence version 1.
DT 22-JAN-2014, entry version 180.
DE RecName: Full=Tumor necrosis factor receptor superfamily member 6;
DE AltName: Full=Apo-1 antigen;
DE AltName: Full=Apoptosis-mediating surface antigen FAS;
DE AltName: Full=FASLG receptor;
DE AltName: CD_antigen=CD95;
DE Flags: Precursor;
GN Name=FAS; Synonyms=APT1, FAS1, TNFRSF6;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=1713127; DOI=10.1016/0092-8674(91)90614-5;
RA Itoh N., Yonehara S., Ishii A., Yonehara M., Mizushima S.,
RA Sameshima M., Hase A., Seto Y., Nagata S.;
RT "The polypeptide encoded by the cDNA for human cell surface antigen
RT Fas can mediate apoptosis.";
RL Cell 66:233-243(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PROTEIN SEQUENCE OF
RP 226-240; 269-291 AND 321-335.
RX PubMed=1375228;
RA Oehm A., Behrmann I., Falk W., Pawlita M., Maier G., Klas C.,
RA Li-Weber M., Richards S., Dhein J., Trauth B.C., Ponstingl H.,
RA Krammer P.H.;
RT "Purification and molecular cloning of the APO-1 cell surface antigen,
RT a member of the tumor necrosis factor/nerve growth factor receptor
RT superfamily. Sequence identity with the Fas antigen.";
RL J. Biol. Chem. 267:10709-10715(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 3; 4 AND 6), AND TISSUE
RP SPECIFICITY.
RX PubMed=7575433;
RA Liu C., Cheng J., Mountz J.D.;
RT "Differential expression of human Fas mRNA species upon peripheral
RT blood mononuclear cell activation.";
RL Biochem. J. 310:957-963(1995).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 2; 3 AND 6), AND FUNCTION.
RX PubMed=7533181;
RA Cascino I., Fiucci G., Papoff G., Ruberti G.;
RT "Three functional soluble forms of the human apoptosis-inducing Fas
RT molecule are produced by alternative splicing.";
RL J. Immunol. 154:2706-2713(1995).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 7).
RX PubMed=8598453;
RA Cascino I., Papoff G., De Maria R., Testi R., Ruberti G.;
RT "Fas/Apo-1 (CD95) receptor lacking the intracytoplasmic signaling
RT domain protects tumor cells from Fas-mediated apoptosis.";
RL J. Immunol. 156:13-17(1996).
RN [6]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 4 AND 5).
RX PubMed=8648105;
RA Papoff G., Cascino I., Eramo A., Starace G., Lynch D.H., Ruberti G.;
RT "An N-terminal domain shared by Fas/Apo-1 (CD95) soluble variants
RT prevents cell death in vitro.";
RL J. Immunol. 156:4622-4630(1996).
RN [7]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND VARIANT ALPS1A SER-262.
RX PubMed=17336828; DOI=10.1016/j.imbio.2006.12.003;
RA Del-Rey M.J., Manzanares J., Bosque A., Aguilo J.I., Gomez-Rial J.,
RA Roldan E., Serrano A., Anel A., Paz-Artal E., Allende L.M.;
RT "Autoimmune lymphoproliferative syndrome (ALPS) in a patient with a
RT new germline Fas gene mutation.";
RL Immunobiology 212:73-83(2007).
RN [8]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5).
RC TISSUE=Peripheral blood lymphocyte;
RA Schaetzlein C.E., Poehlmann R., Philippsen P., Eibel H.;
RL Submitted (JUN-1995) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RA De La Calle-Martin O.;
RL Submitted (OCT-2008) to the EMBL/GenBank/DDBJ databases.
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS THR-16; ILE-122 AND
RP ILE-305.
RG NIEHS SNPs program;
RL Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases.
RN [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15164054; DOI=10.1038/nature02462;
RA Deloukas P., Earthrowl M.E., Grafham D.V., Rubenfield M., French L.,
RA Steward C.A., Sims S.K., Jones M.C., Searle S., Scott C., Howe K.,
RA Hunt S.E., Andrews T.D., Gilbert J.G.R., Swarbreck D., Ashurst J.L.,
RA Taylor A., Battles J., Bird C.P., Ainscough R., Almeida J.P.,
RA Ashwell R.I.S., Ambrose K.D., Babbage A.K., Bagguley C.L., Bailey J.,
RA Banerjee R., Bates K., Beasley H., Bray-Allen S., Brown A.J.,
RA Brown J.Y., Burford D.C., Burrill W., Burton J., Cahill P., Camire D.,
RA Carter N.P., Chapman J.C., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Corby N., Coulson A., Dhami P., Dutta I., Dunn M., Faulkner L.,
RA Frankish A., Frankland J.A., Garner P., Garnett J., Gribble S.,
RA Griffiths C., Grocock R., Gustafson E., Hammond S., Harley J.L.,
RA Hart E., Heath P.D., Ho T.P., Hopkins B., Horne J., Howden P.J.,
RA Huckle E., Hynds C., Johnson C., Johnson D., Kana A., Kay M.,
RA Kimberley A.M., Kershaw J.K., Kokkinaki M., Laird G.K., Lawlor S.,
RA Lee H.M., Leongamornlert D.A., Laird G., Lloyd C., Lloyd D.M.,
RA Loveland J., Lovell J., McLaren S., McLay K.E., McMurray A.,
RA Mashreghi-Mohammadi M., Matthews L., Milne S., Nickerson T.,
RA Nguyen M., Overton-Larty E., Palmer S.A., Pearce A.V., Peck A.I.,
RA Pelan S., Phillimore B., Porter K., Rice C.M., Rogosin A., Ross M.T.,
RA Sarafidou T., Sehra H.K., Shownkeen R., Skuce C.D., Smith M.,
RA Standring L., Sycamore N., Tester J., Thorpe A., Torcasso W.,
RA Tracey A., Tromans A., Tsolas J., Wall M., Walsh J., Wang H.,
RA Weinstock K., West A.P., Willey D.L., Whitehead S.L., Wilming L.,
RA Wray P.W., Young L., Chen Y., Lovering R.C., Moschonas N.K.,
RA Siebert R., Fechtel K., Bentley D., Durbin R.M., Hubbard T.,
RA Doucette-Stamm L., Beck S., Smith D.R., Rogers J.;
RT "The DNA sequence and comparative analysis of human chromosome 10.";
RL Nature 429:375-381(2004).
RN [13]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [14]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Urinary bladder;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [15]
RP INTERACTION WITH RIPK1.
RX PubMed=7538908; DOI=10.1016/0092-8674(95)90072-1;
RA Stanger B.Z., Leder P., Lee T.-H., Kim E., Seed B.;
RT "RIP: a novel protein containing a death domain that interacts with
RT Fas/APO-1 (CD95) in yeast and causes cell death.";
RL Cell 81:513-523(1995).
RN [16]
RP INTERACTION WITH FEM1B.
RX PubMed=10542291; DOI=10.1074/jbc.274.45.32461;
RA Chan S.-L., Tan K.-O., Zhang L., Yee K.S.Y., Ronca F., Chan M.-Y.,
RA Yu V.C.;
RT "F1Aalpha, a death receptor-binding protein homologous to the
RT Caenorhabditis elegans sex-determining protein, FEM-1, is a caspase
RT substrate that mediates apoptosis.";
RL J. Biol. Chem. 274:32461-32468(1999).
RN [17]
RP INTERACTION WITH FAIM2.
RX PubMed=10535980; DOI=10.1073/pnas.96.22.12667;
RA Somia N.V., Schmitt M.J., Vetter D.E., Van Antwerp D., Heinemann S.F.,
RA Verma I.M.;
RT "LFG: an anti-apoptotic gene that provides protection from fas-
RT mediated cell death.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:12667-12672(1999).
RN [18]
RP SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S).
RX PubMed=14759258; DOI=10.1186/gb-2004-5-2-r8;
RA Hillman R.T., Green R.E., Brenner S.E.;
RT "An unappreciated role for RNA surveillance.";
RL Genome Biol. 5:R8.1-R8.16(2004).
RN [19]
RP INTERACTION WITH BRE.
RX PubMed=15465831; DOI=10.1074/jbc.M408678200;
RA Li Q., Ching A.K.-K., Chan B.C.-L., Chow S.K.-Y., Lim P.-L.,
RA Ho T.C.-Y., Ip W.-K., Wong C.-K., Lam C.W.-K., Lee K.K.-H.,
RA Chan J.Y.-H., Chui Y.-L.;
RT "A death receptor-associated anti-apoptotic protein, BRE, inhibits
RT mitochondrial apoptotic pathway.";
RL J. Biol. Chem. 279:52106-52116(2004).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of
RT the kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [21]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-209, AND MASS
RP SPECTROMETRY.
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [22]
RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-118, AND MASS
RP SPECTROMETRY.
RC TISSUE=Liver;
RX PubMed=19159218; DOI=10.1021/pr8008012;
RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.;
RT "Glycoproteomics analysis of human liver tissue by combination of
RT multiple enzyme digestion and hydrazide chemistry.";
RL J. Proteome Res. 8:651-661(2009).
RN [23]
RP INTERACTION WITH FADD.
RX PubMed=21109225; DOI=10.1016/j.ajhg.2010.10.028;
RA Bolze A., Byun M., McDonald D., Morgan N.V., Abhyankar A.,
RA Premkumar L., Puel A., Bacon C.M., Rieux-Laucat F., Pang K.,
RA Britland A., Abel L., Cant A., Maher E.R., Riedl S.J., Hambleton S.,
RA Casanova J.L.;
RT "Whole-exome-sequencing-based discovery of human FADD deficiency.";
RL Am. J. Hum. Genet. 87:873-881(2010).
RN [24]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S.,
RA Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full
RT phosphorylation site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [25]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [26]
RP GLYCOSYLATION AT THR-28, STRUCTURE OF CARBOHYDRATES, AND MASS
RP SPECTROMETRY.
RX PubMed=22171320; DOI=10.1074/mcp.M111.013649;
RA Halim A., Nilsson J., Ruetschi U., Hesse C., Larson G.;
RT "Human urinary glycoproteomics; attachment site specific analysis of
RT N-and O-linked glycosylations by CID and ECD.";
RL Mol. Cell. Proteomics 0:0-0(2011).
RN [27]
RP STRUCTURE BY NMR OF 218-335.
RX PubMed=8967952; DOI=10.1038/384638a0;
RA Huang B., Eberstadt M., Olejniczak E.T., Meadows R.P., Fesik S.W.;
RT "NMR structure and mutagenesis of the Fas (APO-1/CD95) death domain.";
RL Nature 384:638-641(1996).
RN [28]
RP X-RAY CRYSTALLOGRAPHY (2.73 ANGSTROMS) OF 223-335 IN COMPLEX WITH
RP FADD, FUNCTION, SUBUNIT, SUBCELLULAR LOCATION, AND MUTAGENESIS OF
RP TYR-291 AND ILE-313.
RX PubMed=19118384; DOI=10.1038/nature07606;
RA Scott F.L., Stec B., Pop C., Dobaczewska M.K., Lee J.J., Monosov E.,
RA Robinson H., Salvesen G.S., Schwarzenbacher R., Riedl S.J.;
RT "The Fas-FADD death domain complex structure unravels signalling by
RT receptor clustering.";
RL Nature 457:1019-1022(2009).
RN [29]
RP VARIANT ALPS1A PRO-241.
RX PubMed=7540117; DOI=10.1016/0092-8674(95)90013-6;
RA Fisher G.H., Rosenberg F.J., Straus S.E., Dale J.K., Middleton L.A.,
RA Lin A.Y., Strober W., Lenardo M.J., Puck J.M.;
RT "Dominant interfering Fas gene mutations impair apoptosis in a human
RT autoimmune lymphoproliferative syndrome.";
RL Cell 81:935-946(1995).
RN [30]
RP VARIANT ALPS1A TYR-260.
RX PubMed=8929361; DOI=10.1056/NEJM199611283352204;
RA Drappa J., Vaishnaw A.K., Sullivan K.E., Chu J.-L., Elkon K.B.;
RT "Fas gene mutations in the Canale-Smith syndrome, an inherited
RT lymphoproliferative disorder associated with autoimmunity.";
RL N. Engl. J. Med. 335:1643-1649(1996).
RN [31]
RP VARIANTS ALPS1A TRP-121 AND CYS-232.
RX PubMed=9028321;
RA Bettinardi A., Brugnoni D., Quiros-Roldan E., Malagoli A.,
RA La Grutta S., Correra A., Notarangelo L.D.;
RT "Missense mutations in the Fas gene resulting in autoimmune
RT lymphoproliferative syndrome: a molecular and immunological
RT analysis.";
RL Blood 89:902-909(1997).
RN [32]
RP VARIANTS ALPS1A ASP-257 AND SER-310.
RX PubMed=9028957;
RA Sneller M.C., Wang J., Dale J.K., Strober W., Middelton L.A., Choi Y.,
RA Fleisher T.A., Lim M.S., Jaffe E.S., Puck J.M., Lenardo M.J.,
RA Straus S.E.;
RT "Clinical, immunologic, and genetic features of an autoimmune
RT lymphoproliferative syndrome associated with abnormal lymphocyte
RT apoptosis.";
RL Blood 89:1341-1348(1997).
RN [33]
RP VARIANT ALPS1A ALA-28.
RX PubMed=9322534;
RA Pensati L., Costanzo A., Ianni A., Accapezzato D., Iorio R.,
RA Natoli G., Nisini R., Almerighi C., Balsano C., Vajro P., Vegnente A.,
RA Levrero M.;
RT "Fas/Apo1 mutations and autoimmune lymphoproliferative syndrome in a
RT patient with type 2 autoimmune hepatitis.";
RL Gastroenterology 113:1384-1389(1997).
RN [34]
RP VARIANTS NON-HODGKIN LYMPHOMA THR-25; PHE-180; LEU-183; ILE-198;
RP VAL-260; LYS-264; LYS-272; PHE-278 AND ASN-299.
RX PubMed=9787134;
RA Groenbaek K., Straten P.T., Ralfkiaer E., Ahrenkiel V., Andersen M.K.,
RA Hansen N.E., Zeuthen J., Hou-Jensen K., Guldberg P.;
RT "Somatic Fas mutations in non-Hodgkin's lymphoma: association with
RT extranodal disease and autoimmunity.";
RL Blood 92:3018-3024(1998).
RN [35]
RP VARIANT ALPS1A VAL-260.
RX PubMed=9821419; DOI=10.1016/S0022-3476(98)70102-7;
RA Infante A.J., Britton H.A., DeNapoli T., Middelton L.A., Lenardo M.J.,
RA Jackson C.E., Wang J., Fleisher T., Straus S.E., Puck J.M.;
RT "The clinical spectrum in a large kindred with autoimmune
RT lymphoproliferative syndrome caused by a Fas mutation that impairs
RT lymphocyte apoptosis.";
RL J. Pediatr. 133:629-633(1998).
RN [36]
RP VARIANTS ALPS1A LYS-241 AND GLN-250.
RX PubMed=10090885; DOI=10.1086/302333;
RA Jackson C.E., Fischer R.E., Hsu A.P., Anderson S.M., Choi Y., Wang J.,
RA Dale J.K., Fleisher T.A., Middelton L.A., Sneller M.C., Lenardo M.J.,
RA Straus S.E., Puck J.M.;
RT "Autoimmune lymphoproliferative syndrome with defective Fas: genotype
RT influences penetrance.";
RL Am. J. Hum. Genet. 64:1002-1014(1999).
RN [37]
RP VARIANTS ALPS1A LEU-249; PRO-250; ASP-253; SER-253; ARG-259; LYS-270
RP AND LYS-272.
RX PubMed=10515860;
RA Rieux-Laucat F., Blachere S., Danielan S., De Villartay J.P.,
RA Oleastro M., Solary E., Bader-Meunier B., Arkwright P., Pondare C.,
RA Bernaudin F., Chapel H., Nielsen S., Berrah M., Fischer A.,
RA Le Deist F.;
RT "Lymphoproliferative syndrome with autoimmunity: A possible genetic
RT basis for dominant expression of the clinical manifestations.";
RL Blood 94:2575-2582(1999).
RN [38]
RP VARIANT ALPS1A GLY-272.
RX PubMed=10340403; DOI=10.1016/S0301-472X(99)00033-8;
RA Peters A.M., Kohfink B., Martin H., Griesinger F., Wormann B.,
RA Gahr M., Roesler J.;
RT "Defective apoptosis due to a point mutation in the death domain of
RT CD95 associated with autoimmune lymphoproliferative syndrome, T-cell
RT lymphoma, and Hodgkin's disease.";
RL Exp. Hematol. 27:868-874(1999).
RN [39]
RP VARIANTS ALPS1A ARG-82; PRO-250; GLY-260 AND ILE-270.
RX PubMed=9927496; DOI=10.1172/JCI5121;
RA Vaishnaw A.K., Orlinick J.R., Chu J.-L., Krammer P.H., Chao M.V.,
RA Elkon K.B.;
RT "The molecular basis for apoptotic defects in patients with CD95
RT (Fas/Apo-1) mutations.";
RL J. Clin. Invest. 103:355-363(1999).
RN [40]
RP VARIANTS SQUAMOUS CELL CARCINOMA SER-118; ARG-178 AND ASP-255.
RX PubMed=10620127; DOI=10.1046/j.1523-1747.2000.00819.x;
RA Lee S.H., Shin M.S., Kim H.S., Park W.S., Kim S.Y., Jang J.J.,
RA Rhim K.J., Jang J., Lee H.K., Park J.Y., Oh R.R., Han S.Y., Lee J.H.,
RA Lee J.Y., Yoo N.J.;
RT "Somatic mutations of Fas (Apo-1/CD95) gene in cutaneous squamous cell
RT carcinoma arising from a burn scar.";
RL J. Invest. Dermatol. 114:122-126(2000).
RN [41]
RP VARIANTS ALPS1A PRO-241; VAL-260; ILE-270 AND GLY-272.
RX PubMed=11418480; DOI=10.1182/blood.V98.1.194;
RA Straus S.E., Jaffe E.S., Puck J.M., Dale J.K., Elkon K.B.,
RA Roesen-Wolff A., Peters A.M.J., Sneller M.C., Hallahan C.W., Wang J.,
RA Fischer R.E., Jackson C.M., Lin A.Y., Baeumler C., Siegert E.,
RA Marx A., Vaishnaw A.K., Grodzicky T., Fleisher T.A., Lenardo M.J.;
RT "The development of lymphomas in families with autoimmune
RT lymphoproliferative syndrome with germline Fas mutations and defective
RT lymphocyte apoptosis.";
RL Blood 98:194-200(2001).
RN [42]
RP CHARACTERIZATION OF VARIANTS ALPS1A CYS-232; GLN-250; ASP-257;
RP TYR-260; VAL-260; LYS-270 AND LYS-272, AND MUTAGENESIS OF ARG-250;
RP GLU-261; GLN-283 AND LYS-287.
RX PubMed=20935634; DOI=10.1038/nsmb.1920;
RA Wang L., Yang J.K., Kabaleeswaran V., Rice A.J., Cruz A.C., Park A.Y.,
RA Yin Q., Damko E., Jang S.B., Raunser S., Robinson C.V., Siegel R.M.,
RA Walz T., Wu H.;
RT "The Fas-FADD death domain complex structure reveals the basis of DISC
RT assembly and disease mutations.";
RL Nat. Struct. Mol. Biol. 17:1324-1329(2010).
CC -!- FUNCTION: Receptor for TNFSF6/FASLG. The adapter molecule FADD
CC recruits caspase-8 to the activated receptor. The resulting death-
CC inducing signaling complex (DISC) performs caspase-8 proteolytic
CC activation which initiates the subsequent cascade of caspases
CC (aspartate-specific cysteine proteases) mediating apoptosis. FAS-
CC mediated apoptosis may have a role in the induction of peripheral
CC tolerance, in the antigen-stimulated suicide of mature T-cells, or
CC both. The secreted isoforms 2 to 6 block apoptosis (in vitro).
CC -!- SUBUNIT: Binds DAXX. Interacts with HIPK3. Part of a complex
CC containing HIPK3 and FADD (By similarity). Binds RIPK1 and FAIM2.
CC Interacts with BRE and FEM1B. Interacts with FADD.
CC -!- INTERACTION:
CC Self; NbExp=3; IntAct=EBI-494743, EBI-494743;
CC P62158:CALM3; NbExp=4; IntAct=EBI-494743, EBI-397435;
CC Q14790:CASP8; NbExp=14; IntAct=EBI-494743, EBI-78060;
CC Q03135:CAV1; NbExp=3; IntAct=EBI-494743, EBI-603614;
CC Q9UER7:DAXX; NbExp=2; IntAct=EBI-494743, EBI-77321;
CC Q13158:FADD; NbExp=32; IntAct=EBI-494743, EBI-494804;
CC P48023:FASLG; NbExp=3; IntAct=EBI-494743, EBI-495538;
CC P12815:Pdcd6 (xeno); NbExp=2; IntAct=EBI-494743, EBI-309164;
CC P29590:PML; NbExp=4; IntAct=EBI-494743, EBI-295890;
CC Q15156:PML-RAR; NbExp=6; IntAct=EBI-494743, EBI-867256;
CC Q12923:PTPN13; NbExp=3; IntAct=EBI-494743, EBI-355227;
CC P12931:SRC; NbExp=2; IntAct=EBI-494743, EBI-621482;
CC -!- SUBCELLULAR LOCATION: Isoform 1: Cell membrane; Single-pass type I
CC membrane protein.
CC -!- SUBCELLULAR LOCATION: Isoform 2: Secreted.
CC -!- SUBCELLULAR LOCATION: Isoform 3: Secreted.
CC -!- SUBCELLULAR LOCATION: Isoform 4: Secreted.
CC -!- SUBCELLULAR LOCATION: Isoform 5: Secreted.
CC -!- SUBCELLULAR LOCATION: Isoform 6: Secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=7;
CC Name=1;
CC IsoId=P25445-1; Sequence=Displayed;
CC Name=2; Synonyms=del2, D;
CC IsoId=P25445-2; Sequence=VSP_006481, VSP_006482;
CC Note=May be produced at very low levels due to a premature stop
CC codon in the mRNA, leading to nonsense-mediated mRNA decay;
CC Name=3; Synonyms=del3, E;
CC IsoId=P25445-3; Sequence=VSP_006483, VSP_006484;
CC Note=May be produced at very low levels due to a premature stop
CC codon in the mRNA, leading to nonsense-mediated mRNA decay;
CC Name=4; Synonyms=B;
CC IsoId=P25445-4; Sequence=VSP_006485, VSP_006486;
CC Note=May be produced at very low levels due to a premature stop
CC codon in the mRNA, leading to nonsense-mediated mRNA decay;
CC Name=5; Synonyms=C;
CC IsoId=P25445-5; Sequence=VSP_006487, VSP_006488;
CC Note=May be produced at very low levels due to a premature stop
CC codon in the mRNA, leading to nonsense-mediated mRNA decay;
CC Name=6; Synonyms=TMdel, A;
CC IsoId=P25445-6; Sequence=VSP_006489;
CC Name=7; Synonyms=FasExo8Del;
CC IsoId=P25445-7; Sequence=VSP_045235, VSP_045236;
CC Note=Dominant negative isoform, resistant to Fas-mediated
CC apoptosis;
CC -!- TISSUE SPECIFICITY: Isoform 1 and isoform 6 are expressed at equal
CC levels in resting peripheral blood mononuclear cells. After
CC activation there is an increase in isoform 1 and decrease in the
CC levels of isoform 6.
CC -!- DOMAIN: Contains a death domain involved in the binding of FADD,
CC and maybe to other cytosolic adapter proteins.
CC -!- PTM: N- and O-glycosylated. O-glycosylated with core 1 or possibly
CC core 8 glycans.
CC -!- DISEASE: Autoimmune lymphoproliferative syndrome 1A (ALPS1A)
CC [MIM:601859]: A disorder of apoptosis that manifests in early
CC childhood and results in the accumulation of autoreactive
CC lymphocytes. It is characterized by non-malignant lymphadenopathy
CC with hepatosplenomegaly, and autoimmune hemolytic anemia,
CC thrombocytopenia and neutropenia. Note=The disease is caused by
CC mutations affecting the gene represented in this entry.
CC -!- SIMILARITY: Contains 1 death domain.
CC -!- SIMILARITY: Contains 3 TNFR-Cys repeats.
CC -!- WEB RESOURCE: Name=Autoimmune Lymphoproliferative Syndrome
CC Database (ALPSbase); Note=Mutations in TNFRSF6 causing ALPS type
CC Ia;
CC URL="http://research.nhgri.nih.gov/ALPS/alpsIa_mut.shtml";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/FAS";
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/tnfrsf6/";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
CC -----------------------------------------------------------------------
DR EMBL; M67454; AAA63174.1; -; mRNA.
DR EMBL; X63717; CAA45250.1; -; mRNA.
DR EMBL; X83490; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; X83491; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; X83492; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; X83493; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; Z47993; CAA88031.1; -; mRNA.
DR EMBL; Z47994; CAA88032.1; -; mRNA.
DR EMBL; Z47995; CAA88033.1; -; mRNA.
DR EMBL; Z66556; -; NOT_ANNOTATED_CDS; mRNA.
DR EMBL; Z70519; CAA94430.1; -; mRNA.
DR EMBL; Z70520; CAA94431.1; -; mRNA.
DR EMBL; AY495076; AAS76663.1; -; mRNA.
DR EMBL; X89101; CAA61473.1; -; mRNA.
DR EMBL; FM246458; CAR92543.1; -; mRNA.
DR EMBL; AK290978; BAF83667.1; -; mRNA.
DR EMBL; AY450925; AAR08906.1; -; Genomic_DNA.
DR EMBL; AL157394; CAI13870.1; -; Genomic_DNA.
DR EMBL; AL157394; CAI13871.1; -; Genomic_DNA.
DR EMBL; AL157394; CAI13872.1; -; Genomic_DNA.
DR EMBL; CH471066; EAW50151.1; -; Genomic_DNA.
DR EMBL; BC012479; AAH12479.1; -; mRNA.
DR PIR; A40036; A40036.
DR PIR; I37383; I37383.
DR PIR; I37384; I37384.
DR PIR; S58662; S58662.
DR RefSeq; NP_000034.1; NM_000043.4.
DR RefSeq; NP_690610.1; NM_152871.2.
DR RefSeq; NP_690611.1; NM_152872.2.
DR UniGene; Hs.244139; -.
DR PDB; 1BZI; Model; -; A=1-335.
DR PDB; 1DDF; NMR; -; A=218-335.
DR PDB; 3EWT; X-ray; 2.40 A; E=230-254.
DR PDB; 3EZQ; X-ray; 2.73 A; A/C/E/G/I/K/M/O=223-335.
DR PDB; 3THM; X-ray; 2.10 A; F=17-172.
DR PDB; 3TJE; X-ray; 1.93 A; F=17-172.
DR PDBsum; 1BZI; -.
DR PDBsum; 1DDF; -.
DR PDBsum; 3EWT; -.
DR PDBsum; 3EZQ; -.
DR PDBsum; 3THM; -.
DR PDBsum; 3TJE; -.
DR ProteinModelPortal; P25445; -.
DR SMR; P25445; 52-163, 218-335.
DR DIP; DIP-924N; -.
DR IntAct; P25445; 35.
DR MINT; MINT-146256; -.
DR GuidetoPHARMACOLOGY; 1875; -.
DR PhosphoSite; P25445; -.
DR DMDM; 119833; -.
DR PaxDb; P25445; -.
DR PRIDE; P25445; -.
DR DNASU; 355; -.
DR Ensembl; ENST00000355279; ENSP00000347426; ENSG00000026103.
DR Ensembl; ENST00000355740; ENSP00000347979; ENSG00000026103.
DR Ensembl; ENST00000357339; ENSP00000349896; ENSG00000026103.
DR Ensembl; ENST00000479522; ENSP00000424113; ENSG00000026103.
DR Ensembl; ENST00000484444; ENSP00000420975; ENSG00000026103.
DR Ensembl; ENST00000488877; ENSP00000425159; ENSG00000026103.
DR Ensembl; ENST00000492756; ENSP00000422453; ENSG00000026103.
DR Ensembl; ENST00000494410; ENSP00000423755; ENSG00000026103.
DR GeneID; 355; -.
DR KEGG; hsa:355; -.
DR UCSC; uc001kfr.3; human.
DR CTD; 355; -.
DR GeneCards; GC10P090741; -.
DR HGNC; HGNC:11920; FAS.
DR HPA; HPA027444; -.
DR MIM; 134637; gene.
DR MIM; 601859; phenotype.
DR neXtProt; NX_P25445; -.
DR Orphanet; 3261; Autoimmune lymphoproliferative syndrome.
DR Orphanet; 85408; Juvenile rheumatoid factor-negative polyarthritis.
DR Orphanet; 85410; Oligoarticular juvenile arthritis.
DR PharmGKB; PA36613; -.
DR eggNOG; NOG45364; -.
DR HOVERGEN; HBG004091; -.
DR KO; K04390; -.
DR OMA; KPNFFCN; -.
DR OrthoDB; EOG7DVDC8; -.
DR PhylomeDB; P25445; -.
DR Reactome; REACT_578; Apoptosis.
DR EvolutionaryTrace; P25445; -.
DR GeneWiki; Fas_receptor; -.
DR GenomeRNAi; 355; -.
DR NextBio; 1471; -.
DR PMAP-CutDB; P25445; -.
DR PRO; PR:P25445; -.
DR ArrayExpress; P25445; -.
DR Bgee; P25445; -.
DR CleanEx; HS_FAS; -.
DR Genevestigator; P25445; -.
DR GO; GO:0031265; C:CD95 death-inducing signaling complex; IDA:UniProtKB.
DR GO; GO:0009986; C:cell surface; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; NAS:UniProtKB.
DR GO; GO:0009897; C:external side of plasma membrane; IEA:Ensembl.
DR GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral to membrane; IEA:UniProtKB-KW.
DR GO; GO:0045121; C:membrane raft; IDA:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:HPA.
DR GO; GO:0004872; F:receptor activity; NAS:UniProtKB.
DR GO; GO:0004871; F:signal transducer activity; TAS:ProtInc.
DR GO; GO:0004888; F:transmembrane signaling receptor activity; IEA:InterPro.
DR GO; GO:0006919; P:activation of cysteine-type endopeptidase activity involved in apoptotic process; TAS:Reactome.
DR GO; GO:0006924; P:activation-induced cell death of T cells; IEA:Ensembl.
DR GO; GO:0019724; P:B cell mediated immunity; IEA:Ensembl.
DR GO; GO:0071455; P:cellular response to hyperoxia; IMP:UniProtKB.
DR GO; GO:0071285; P:cellular response to lithium ion; IEA:Ensembl.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB.
DR GO; GO:0097191; P:extrinsic apoptotic signaling pathway; IMP:UniProtKB.
DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; IEA:Ensembl.
DR GO; GO:0010467; P:gene expression; IEA:Ensembl.
DR GO; GO:0002377; P:immunoglobulin production; IEA:Ensembl.
DR GO; GO:0006925; P:inflammatory cell apoptotic process; IEA:Ensembl.
DR GO; GO:0043066; P:negative regulation of apoptotic process; TAS:ProtInc.
DR GO; GO:0050869; P:negative regulation of B cell activation; IEA:Ensembl.
DR GO; GO:0045060; P:negative thymic T cell selection; IEA:Ensembl.
DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0010940; P:positive regulation of necrotic cell death; IMP:BHF-UCL.
DR GO; GO:0032464; P:positive regulation of protein homooligomerization; IEA:Ensembl.
DR GO; GO:0006461; P:protein complex assembly; TAS:ProtInc.
DR GO; GO:0051260; P:protein homooligomerization; IEA:Ensembl.
DR GO; GO:2001239; P:regulation of extrinsic apoptotic signaling pathway in absence of ligand; TAS:Reactome.
DR GO; GO:0045619; P:regulation of lymphocyte differentiation; IEA:Ensembl.
DR GO; GO:0045637; P:regulation of myeloid cell differentiation; IEA:Ensembl.
DR GO; GO:0003014; P:renal system process; IEA:Ensembl.
DR GO; GO:0051384; P:response to glucocorticoid stimulus; IEA:Ensembl.
DR GO; GO:0009636; P:response to toxic substance; IEA:Ensembl.
DR GO; GO:0048536; P:spleen development; IEA:Ensembl.
DR GO; GO:0006927; P:transformed cell apoptotic process; IEA:Ensembl.
DR Gene3D; 1.10.533.10; -; 1.
DR InterPro; IPR011029; DEATH-like_dom.
DR InterPro; IPR000488; Death_domain.
DR InterPro; IPR008063; Fas_rcpt.
DR InterPro; IPR001368; TNFR/NGFR_Cys_rich_reg.
DR Pfam; PF00531; Death; 1.
DR Pfam; PF00020; TNFR_c6; 2.
DR PRINTS; PR01680; TNFACTORR6.
DR SMART; SM00005; DEATH; 1.
DR SMART; SM00208; TNFR; 3.
DR SUPFAM; SSF47986; SSF47986; 1.
DR PROSITE; PS50017; DEATH_DOMAIN; 1.
DR PROSITE; PS00652; TNFR_NGFR_1; 2.
DR PROSITE; PS50050; TNFR_NGFR_2; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Apoptosis; Cell membrane;
KW Complete proteome; Direct protein sequencing; Disease mutation;
KW Disulfide bond; Glycoprotein; Membrane; Phosphoprotein; Polymorphism;
KW Receptor; Reference proteome; Repeat; Secreted; Signal; Transmembrane;
KW Transmembrane helix.
FT SIGNAL 1 25 Potential.
FT CHAIN 26 335 Tumor necrosis factor receptor
FT superfamily member 6.
FT /FTId=PRO_0000034563.
FT TOPO_DOM 26 173 Extracellular (Potential).
FT TRANSMEM 174 190 Helical; (Potential).
FT TOPO_DOM 191 335 Cytoplasmic (Potential).
FT REPEAT 47 83 TNFR-Cys 1.
FT REPEAT 84 127 TNFR-Cys 2.
FT REPEAT 128 166 TNFR-Cys 3.
FT DOMAIN 230 314 Death.
FT REGION 212 317 Interaction with HIPK3 (By similarity).
FT MOD_RES 209 209 Phosphoserine.
FT CARBOHYD 28 28 O-linked (GalNAc...).
FT CARBOHYD 118 118 N-linked (GlcNAc...).
FT CARBOHYD 136 136 N-linked (GlcNAc...) (Potential).
FT DISULFID 59 73 By similarity.
FT DISULFID 63 82 By similarity.
FT DISULFID 85 101 By similarity.
FT DISULFID 104 119 By similarity.
FT DISULFID 107 127 By similarity.
FT DISULFID 129 143 By similarity.
FT DISULFID 146 157 By similarity.
FT DISULFID 149 165 By similarity.
FT VAR_SEQ 66 103 GERKARDCTVNGDEPDCVPCQEGKEYTDKAHFSSKCRR ->
FT DVNMESSRNAHSPATPSAKRKDPDLTWGGFVFFFCQFH
FT (in isoform 2).
FT /FTId=VSP_006481.
FT VAR_SEQ 66 86 GERKARDCTVNGDEPDCVPCQ -> DVNMESSRNAHSPATP
FT SAKRK (in isoform 3).
FT /FTId=VSP_006483.
FT VAR_SEQ 87 335 Missing (in isoform 3).
FT /FTId=VSP_006484.
FT VAR_SEQ 104 335 Missing (in isoform 2).
FT /FTId=VSP_006482.
FT VAR_SEQ 112 149 GLEVEINCTRTQNTKCRCKPNFFCNSTVCEHCDPCTKC ->
FT DVNMESSRNAHSPATPSAKRKDPDLTWGGFVFFFCQFH
FT (in isoform 4).
FT /FTId=VSP_006485.
FT VAR_SEQ 112 132 GLEVEINCTRTQNTKCRCKPN -> DVNMESSRNAHSPATP
FT SAKRK (in isoform 5).
FT /FTId=VSP_006487.
FT VAR_SEQ 133 335 Missing (in isoform 5).
FT /FTId=VSP_006488.
FT VAR_SEQ 150 335 Missing (in isoform 4).
FT /FTId=VSP_006486.
FT VAR_SEQ 169 189 Missing (in isoform 6).
FT /FTId=VSP_006489.
FT VAR_SEQ 218 220 ETV -> MLT (in isoform 7).
FT /FTId=VSP_045235.
FT VAR_SEQ 221 335 Missing (in isoform 7).
FT /FTId=VSP_045236.
FT VARIANT 16 16 A -> T (in dbSNP:rs3218619).
FT /FTId=VAR_020008.
FT VARIANT 25 25 A -> T (in non-Hodgkin lymphoma; somatic
FT mutation).
FT /FTId=VAR_013416.
FT VARIANT 28 28 T -> A (in ALPS1A; associated with
FT autoimmune hepatitis type 2).
FT /FTId=VAR_013417.
FT VARIANT 82 82 C -> R (in ALPS1A).
FT /FTId=VAR_013418.
FT VARIANT 118 118 N -> S (in squamous cell carcinoma; burn-
FT scar related; somatic mutation).
FT /FTId=VAR_018321.
FT VARIANT 121 121 R -> W (in ALPS1A).
FT /FTId=VAR_013419.
FT VARIANT 122 122 T -> I (in dbSNP:rs3218614).
FT /FTId=VAR_020009.
FT VARIANT 178 178 C -> R (in squamous cell carcinoma; burn-
FT scar related; somatic mutation).
FT /FTId=VAR_018322.
FT VARIANT 180 180 L -> F (in non-Hodgkin lymphoma; somatic
FT mutation).
FT /FTId=VAR_013420.
FT VARIANT 183 183 P -> L (in non-Hodgkin lymphoma; somatic
FT mutation).
FT /FTId=VAR_013421.
FT VARIANT 184 184 I -> V (in dbSNP:rs28362322).
FT /FTId=VAR_052347.
FT VARIANT 198 198 T -> I (in non-Hodgkin lymphoma; somatic
FT mutation).
FT /FTId=VAR_013422.
FT VARIANT 232 232 Y -> C (in ALPS1A; no effect on
FT interaction with FADD).
FT /FTId=VAR_013423.
FT VARIANT 241 241 T -> K (in ALPS1A).
FT /FTId=VAR_013424.
FT VARIANT 241 241 T -> P (in ALPS1A).
FT /FTId=VAR_013425.
FT VARIANT 249 249 V -> L (in ALPS1A).
FT /FTId=VAR_065128.
FT VARIANT 250 250 R -> P (in ALPS1A).
FT /FTId=VAR_013426.
FT VARIANT 250 250 R -> Q (in ALPS1A; no effect on
FT interaction with FADD).
FT /FTId=VAR_013427.
FT VARIANT 253 253 G -> D (in ALPS1A).
FT /FTId=VAR_065129.
FT VARIANT 253 253 G -> S (in ALPS1A).
FT /FTId=VAR_065130.
FT VARIANT 255 255 N -> D (in squamous cell carcinoma; burn-
FT scar related; somatic mutation).
FT /FTId=VAR_018323.
FT VARIANT 257 257 A -> D (in ALPS1A; loss of interaction
FT with FADD).
FT /FTId=VAR_013428.
FT VARIANT 259 259 I -> R (in ALPS1A).
FT /FTId=VAR_065131.
FT VARIANT 260 260 D -> G (in ALPS1A).
FT /FTId=VAR_013429.
FT VARIANT 260 260 D -> V (in ALPS1A; also found in non-
FT Hodgkin lymphoma; somatic mutation; loss
FT of interaction with FADD;
FT dbSNP:rs28929498).
FT /FTId=VAR_013431.
FT VARIANT 260 260 D -> Y (in ALPS1A; loss of interaction
FT with FADD).
FT /FTId=VAR_013430.
FT VARIANT 262 262 I -> S (in ALPS1A).
FT /FTId=VAR_058910.
FT VARIANT 264 264 N -> K (in non-Hodgkin lymphoma; somatic
FT mutation).
FT /FTId=VAR_013432.
FT VARIANT 270 270 T -> I (in ALPS1A).
FT /FTId=VAR_013433.
FT VARIANT 270 270 T -> K (in ALPS1A; loss of interaction
FT with FADD).
FT /FTId=VAR_065132.
FT VARIANT 272 272 E -> G (in ALPS1A).
FT /FTId=VAR_013434.
FT VARIANT 272 272 E -> K (in ALPS1A; also found in non-
FT Hodgkin lymphoma; somatic mutation; loss
FT of interaction with FADD).
FT /FTId=VAR_013435.
FT VARIANT 278 278 L -> F (in non-Hodgkin lymphoma; somatic
FT mutation).
FT /FTId=VAR_013436.
FT VARIANT 299 299 K -> N (in non-Hodgkin lymphoma; somatic
FT mutation).
FT /FTId=VAR_013437.
FT VARIANT 305 305 T -> I (in dbSNP:rs3218611).
FT /FTId=VAR_020942.
FT VARIANT 310 310 I -> S (in ALPS1A).
FT /FTId=VAR_013438.
FT MUTAGEN 250 250 R->E: Strongly decreased interaction with
FT FADD.
FT MUTAGEN 261 261 E->K: Loss of interaction with FADD.
FT MUTAGEN 283 283 Q->K: Loss of interaction with FADD.
FT MUTAGEN 287 287 K->D: Strongly decreased interaction with
FT FADD.
FT MUTAGEN 291 291 Y->D: Decreased interaction with FADD.
FT MUTAGEN 313 313 I->D: Constitutive activation. Promotes
FT apoptosis, both in the presence and in
FT the absence of stimulation by a ligand.
FT CONFLICT 224 224 L -> F (in Ref. 11; AAR08906).
FT CONFLICT 242 242 L -> P (in Ref. 9; CAR92543).
FT STRAND 67 71
FT STRAND 75 77
FT STRAND 82 84
FT TURN 87 89
FT HELIX 109 111
FT STRAND 113 117
FT STRAND 126 129
FT STRAND 137 139
FT HELIX 232 242
FT TURN 251 253
FT HELIX 256 265
FT HELIX 270 282
FT HELIX 287 319
FT HELIX 327 334
SQ SEQUENCE 335 AA; 37732 MW; 0139942535111410 CRC64;
MLGIWTLLPL VLTSVARLSS KSVNAQVTDI NSKGLELRKT VTTVETQNLE GLHHDGQFCH
KPCPPGERKA RDCTVNGDEP DCVPCQEGKE YTDKAHFSSK CRRCRLCDEG HGLEVEINCT
RTQNTKCRCK PNFFCNSTVC EHCDPCTKCE HGIIKECTLT SNTKCKEEGS RSNLGWLCLL
LLPIPLIVWV KRKEVQKTCR KHRKENQGSH ESPTLNPETV AINLSDVDLS KYITTIAGVM
TLSQVKGFVR KNGVNEAKID EIKNDNVQDT AEQKVQLLRN WHQLHGKKEA YDTLIKDLKK
ANLCTLAEKI QTIILKDITS DSENSNFRNE IQSLV
//

MIM 134637
*RECORD*
*FIELD* NO
134637
*FIELD* TI
*134637 TUMOR NECROSIS FACTOR RECEPTOR SUPERFAMILY, MEMBER 6; TNFRSF6
;;APOPTOSIS ANTIGEN 1; APT1;;
read moreFAS ANTIGEN;;
SURFACE ANTIGEN APO1; APO1;;
CD95
*FIELD* TX

CLONING

Itoh et al. (1991) isolated cDNAs encoding the human FAS antigen from a
human T-cell lymphoma cDNA library. Sequence analysis predicted a
16-amino acid signal sequence followed by a mature protein of 319 amino
acids with a single transmembrane domain and a molecular mass of
approximately 36 kD. The FAS antigen shows structural homology with a
number of cell surface receptors, including tumor necrosis factor (TNF)
receptors (191190, 191191) and the low-affinity nerve growth factor
receptor (NGFR; 162010). Northern blot analysis detected 2.7- and 1.9-kb
FAS mRNAs in thymus, liver, ovary, and heart. Functional expression
studies in mouse cells showed that the FAS antigen induced
antibody-triggered apoptosis.

Watanabe-Fukunaga et al. (1992) isolated mouse Fas antigen from a murine
macrophage cDNA library. The deduced 306-amino acid sequence shares
49.3% sequence identity with the human sequence. Northern blot analysis
detected a 2.1-kb Fas antigen mRNA in mouse thymus, heart, liver, and
ovary.

Oehm et al. (1992) demonstrated that the 48-kD APO1 antigen, defined by
the mouse monoclonal antibody anti-APO1, is the same as the FAS antigen.
APO1 was expressed on the cell surface of various normal and malignant
cells, including activated human T and B lymphocytes and a variety of
malignant human lymphoid cell lines, and binding of anti-APO1 antibody
to the APO1 antigen induced apoptosis.

- Antisense Transcript SAF

Yan et al. (2005) described a novel RNA transcribed from the opposite
strand of intron 1 of the human FAS gene, which they named SAF. The
1.5-kb transcript was expressed in human heart, placenta, liver, muscle,
and pancreas, as well as in several cancer cell lines. SAF-transfected
Jurkat cells were highly resistant to FAS-mediated but not to TNF-alpha
(191160)-mediated apoptosis, compared to control transfectants. Although
the overall mRNA expression level of FAS was not affected, expression of
some novel forms of FAS transcripts was increased in SAF-transfected
cells. Yan et al. (2005) hypothesized that SAF may protect T lymphocytes
from FAS-mediated apoptosis by blocking the binding of FASL or its
agonistic FAS antibody, and that SAF may regulate expression of FAS
alternative splice forms through pre-mRNA processing.

GENE STRUCTURE

Yan et al. (2005) noted that the TNFRSF6 gene contains 9 exons. They
identified an antisense transcript SAF within the 12.1-kb intron 1 that
is transcribed in the opposite direction as the TNFRSF6 gene.

MAPPING

Inazawa et al. (1992) mapped the human FAS gene to chromosome 10q24.1 by
fluorescence in situ hybridization. Using cosmid DNA containing the FAS
gene as a probe for fluorescence in situ hybridization, Lichter et al.
(1992) mapped the FAS gene to a subregion of chromosomal band 10q23; the
analysis showed that the FAS gene is located just distal to the central
part of band 10q23.

Watanabe-Fukunaga et al. (1992) mapped the mouse Fas gene to the distal
region of chromosome 19.

GENE FUNCTION

Talal (1994) used the term 'autogene,' a neologism, to refer to a gene
whose abnormal function contributes to the development of autoimmune
disease; the term is parallel to the term oncogene and the role of its
product in malignancy. Mountz and Talal (1993) suggested that FAS is the
first known autogene.

Dhein et al. (1995) found that T-cell receptor-induced apoptosis was
mediated by an APO1 ligand and APO1 in vitro. Apoptosis was
significantly reduced by inhibition of anti-APO1 antibodies. Brunner et
al. (1995) showed that the Fas antigen receptor was rapidly expressed on
T cells following activation of T-cell hybridomas, and that the
interaction between FAS and FAS ligand (FASL, CD95L, or TNFSF6; 134638)
induced cell death in a cell-autonomous manner consistent with
apoptosis. Interference with the FAS/FASL interaction inhibited
activation-induced apoptosis. Ju et al. (1995) also showed that the
interaction between FAS and FASL results in activation-induced T-cell
death.

Viard et al. (1998) detected high levels of soluble FASL in the sera of
patients with toxic epidermal necrolysis (TEN; 608579). Keratinocytes of
TEN patients produced FASL, which induced keratinic apoptosis. In vitro,
intravenous immunoglobulin (IVIG) completely inhibited FAS-mediated
keratinocyte apoptosis, and in vivo, 10 TEN patients treated with IVIG
showed rapid improvement in skin disease. The authors noted that a
naturally occurring anti-FAS immunoglobulin present in IVIG blocked the
FAS receptor and mediated this response.

Hueber et al. (1997) demonstrated that MYC (190080)-induced apoptosis
required interaction on the cell surface between CD95 and its ligand.
The findings linked 2 apoptotic pathways previously thought to be
independent and established the dependence of MYC on CD95 signaling for
its killing activity.

Pestano et al. (1999) identified a differentiative pathway taken by CD8
cells bearing receptors that cannot engage class I MHC (see 142800)
self-peptide molecules because of incorrect thymic selection, defects in
peripheral MHC class I expression, or antigen presentation. In any of
these cases, failed CD8 T-cell receptor coengagement results in
downregulation of genes that account for specialized cytolytic
T-lymphocyte function and resistance to cell death (CD8-alpha/beta, see
186730; granzyme B, 123910; and LKLF, 602016), and upregulation of FAS
and FASL death genes. Thus, MHC engagement is required to inhibit
expression and delivery of a death program rather than to supply a
putative trophic factor for T cell survival. Pestano et al. (1999)
hypothesized that defects in delivery of the death signal to these
aberrant T cells underlie the explosive growth and accumulation of
double-negative T cells in animals bearing FAS and FASL mutations, in
patients who carry inherited mutations of these genes, and in about 25%
of systemic lupus erythematosus patients who display the cellular
signature of defects in this mechanism of quality control of CD8 cells.

Mannick et al. (1999) demonstrated that FAS activates caspase-3 (600636)
by inducing the cleavage of the caspase zymogen to its active subunits
and by stimulating the denitrosylation of its active site thiol.

Hueber (2000) described the signaling pathway leading to apoptosis. FAS
(CD95) crosslinking with FAS ligand (CD95L) results in the formation of
a death-inducing signaling complex (DISC) composed of CD95, the signal
adaptor protein FADD (602457), and procaspase-8. This association
generates CASP8 (601763), activating a cascade of caspases.
Lepple-Wienhues et al. (1999) showed that in addition to the role of
CD95 in inducing cell death, stimulation of CD95 inhibits the influx of
calcium normally induced by activation of the T-cell antigen receptor,
in part by not affecting the release of calcium from intracellular
stores. This block in calcium entry can be mimicked by stimulating T
cells with acid sphingomyelinase metabolites of the plasma membrane
lipid sphingomyelin, such as ceramide and sphingosine.

Arscott et al. (1999) examined FAS expression in thyroid tissue derived
from patients with papillary carcinoma and follicular cancer. More
intense immunohistologic staining for the FAS protein was observed on
papillary cancer cells as compared with adjacent normal follicles. FAS
expression was detected at levels up to 3-fold higher in cancerous
thyrocytes compared with paired normal cells. The authors concluded that
the FAS antigen is expressed and functional on papillary thyroid cancer
cells and that this may have potential therapeutic significance.

Grassme et al. (2000) showed that Pseudomonas aeruginosa infection
induced apoptosis of lung epithelial cells by activation of the
endogenous CD95/CD95L system. Deficiency of CD95 or CD95L on epithelial
cells prevented apoptosis of lung epithelial cells in vivo as well as in
vitro. The importance of CD95/CD95L-mediated lung epithelial cell
apoptosis was demonstrated by the rapid development of sepsis in mice
deficient in either CD95 or CD95L, but not in normal mice, after P.
aeruginosa infection.

Natural inhibitors of angiogenesis are able to block pathologic
neovascularization without harming the preexisting vasculature. Volpert
et al. (2002) demonstrated that 2 such inhibitors, thrombospondin I
(188060) and pigment epithelium-derived factor (172860), induced
FAS/FASL-mediated apoptosis to block angiogenesis. Both inhibitors
upregulated FASL on endothelial cells. Expression of FAS antigen on
endothelial cells and vessels was greatly enhanced by inducers of
angiogenesis, thereby specifically sensitizing the stimulated cells to
apoptosis by inhibitor-generated FASL. The antiangiogenic activity of
thrombospondin I and pigment epithelium-derived factor both in vitro and
in vivo was dependent on this dual induction of FAS and FASL and the
resulting apoptosis. Volpert et al. (2002) concluded that this example
of cooperation between pro- and antiangiogenic factors in the inhibition
of angiogenesis provided one explanation for the ability of inhibitors
to select remodeling capillaries for destruction.

Raoul et al. (2002) showed that FAS triggers cell death specifically in
motor neurons by transcriptional upregulation of neuronal nitric oxide
synthase (nNOS; 163731) mediated by p38 kinase (600289). ASK1 (602448)
and Daxx (603186) act upstream of p38 in the FAS signaling pathway. The
authors also showed that synergistic activation of the NO pathway and
the classic FADD/CASP8 pathway were needed for motor neuron cell death.
No evidence for involvement of the FAS/NO pathway was found in other
cell types. Motor neurons from transgenic mice expressing amyotrophic
lateral sclerosis (ALS; 105400)-linked SOD1 (147450) mutations displayed
increased susceptibility to activation of the FAS/NO pathway. Raoul et
al. (2002) emphasized that this signaling pathway was unique to motor
neurons and suggested that these cell pathways may contribute to motor
neuron loss in ALS. Raoul et al. (2006) reported that exogenous NO
triggered expression of FASL in cultured motoneurons. In motoneurons
from ALS model mice with mutations in the SOD1 gene, this upregulation
resulted in activation of Fas, leading through Daxx and p38 to further
NO synthesis. The authors suggested that chronic low-activation of this
feedback loop may underlie the slowly progressive motoneuron loss
characteristic of ALS.

Using mouse primary neurons and a human neuroblastoma cell line,
Desbarats et al. (2003) determined that FAS can mediate neurite growth.
Activation of FAS resulted in axon regeneration in primary neurons and
accelerated functional recovery after sciatic nerve injury in vivo.
Desbarats et al. (2003) determined that activation triggered a nerve
growth factor (162030)-independent signaling pathway that included
activation of ERK (see 176872) and the expression of p35 (603460).

Zou et al. (2007) reported that the hepatocyte growth factor receptor
MET (164860) plays an important part in preventing FAS-mediated
apoptosis of hepatocytes by sequestering FAS. They also showed that FAS
antagonism by MET is abrogated in human fatty liver disease. Through
structure-function studies, the authors found that a YLGA amino acid
motif located near the extracellular N terminus of the MET alpha subunit
is necessary and sufficient to specifically bind the extracellular
portion of FAS and to act as a potential FAS ligand (FASL; 134638)
antagonist and inhibitor of FAS trimerization. Using mouse models of
fatty liver disease, Zou et al. (2007) showed that synthetic YLGA
peptide tempers hepatocyte apoptosis and liver damage and therefore has
therapeutic potential.

As summarized by Jost et al. (2009), distinct cell types differ in the
mechanisms by which the 'death receptor' FAS triggers their apoptosis.
In type I cells, such as lymphocytes, activation of effector caspases by
FAS-induced activation of caspase-8 (601763) suffices for cell killing;
in type II cells, including hepatocytes and pancreatic beta-cells,
caspase cascade amplification through caspase-8-mediated activation of
the proapoptotic BID (601197) is essential. Jost et al. (2009)
demonstrated that loss of XIAP (300079) function by gene targeting or
treatment with a DIABLO (605219) mimetic drug in mice rendered
hepatocytes and beta-cells independent of BID for FAS-induced apoptosis.
Jost et al. (2009) concluded that their results showed that XIAP is the
critical discriminator between type I and type II apoptosis signaling
and suggested that IAP inhibitors should be used with caution in cancer
patients with underlying liver conditions.

Chen et al. (2010) demonstrated that cancer cells in general, regardless
of their CD95 apoptosis sensitivity, depend on constitutive activity of
CD95, stimulated by a cancer-produced CD95L (134638), for optimal
growth. Consistently, loss of CD95 in mouse models of ovarian cancer and
liver cancer reduces cancer incidence as well as the size of the tumors.
The tumorigenic activity of CD95 is mediated by a pathway involving JNK
(601158) and JUN (165160). These results demonstrated that CD95 has a
growth-promoting role during tumorigenesis and indicated that efforts to
inhibit its activity should be considered during cancer therapy.

BIOCHEMICAL FEATURES

- Crystal Structure

FAS, FADD (602457), and caspase-8 (CASP8; 601763) form a death-inducing
signaling complex (DISC) that is a pivotal trigger of apoptosis. Scott
et al. (2009) successfully formed and isolated the human FAS-FADD death
domain complex and reported the 2.7-angstrom crystal structure. The
complex shows a tetrameric arrangement of 4 FADD death domains bound to
4 FAS death domains. Scott et al. (2009) showed that an opening of the
FAS death domain exposes the FADD binding site and simultaneously
generates a FAS-FAS bridge. The result is a regulatory FAS-FADD complex
bridge governed by weak protein-protein interactions revealing a model
where the complex itself functions as a mechanistic switch. This switch
prevents accidental DISC assembly, yet allows for highly processive DISC
formation and clustering upon a sufficient stimulus. Scott et al. (2009)
concluded that, in addition to depicting a previously unknown mode of
death domain interactions, their results further uncovered a mechanism
for receptor signaling solely by oligomerization and clustering events.

MOLECULAR GENETICS

In 5 unrelated children with a rare autoimmune lymphoproliferative
syndrome (ALPS; 601859) Fisher et al. (1995) identified a heterozygous
mutation in the FAS antigen gene (134637.0001-134637.0005). The disorder
was characterized by massive nonmalignant lymphadenopathy, autoimmune
phenomena, and expanded populations of TCR-CD3(+)CD4(-)CD8(-)
lymphocytes, and each child had defective FAS-mediated T-lymphocyte
apoptosis in vitro. One mutation appeared to cause a simple loss of
function (134637.0001); however, 4 others had a dominant-negative
phenotype when coexpressed with normal FAS. One of the patients studied
by Fisher et al. (1995) was included in the report by Sneller et al.
(1992), delineating this disorder and pointing out its resemblance to
autosomal recessive lpr/gld disease in the mouse. The lpr and gld mice
bear mutated genes for CD95 and CD95 ligand, respectively.

Rieux-Laucat et al. (1995) analyzed expression of the FAS antigen and
its function in 3 children with a lymphoproliferative syndrome, 2 of
whom also had autoimmune disorders. The most severely affected patient
had a large deletion in the FAS gene and no detectable cell surface
expression. Clinical manifestations in the other 2 patients were less
severe: FAS-mediated apoptosis was impaired and a deletion within the
intracytoplasmic domain was detected.

Aspinall et al. (1999) identified 2 novel mutations in FAS that cause
ALPS.

Holzelova et al. (2004) reported 6 children with type III ALPS, defined
as having phenotypic features of ALPS, including elevated numbers of
double-negative T cells and hypergammaglobulinemia, but normal
FAS-mediated apoptosis of T cells in vitro. Double-negative T cells from
all 6 patients showed heterozygous mutations in the FAS gene (see, e.g.,
134637.0018). In 2 affected patients, FAS mutations were found in a
fraction of CD4+ and CD8+ T cells, monocytes, and CD34+ hematopoietic
precursors, but not in hair or mucosal epithelial cells, demonstrating
somatic mosaicism. The study demonstrated that peripheral lymphocytes
with a dominant somatic FAS mutation exhibit a selective advantage by
resisting apoptosis, thus accumulating and becoming double-negative T
cells.

Clementi et al. (2004) reported a 27-year-old man with ALPS who
developed a large B-cell lymphoma. Genetic analysis identified a
heterozygous mutation in the FAS gene and another in the perforin gene
(PRF1; 170280). The FAS mutation was inherited from his healthy father
and was also carried by his healthy brother, whereas the PRF1 mutation
was inherited from his healthy mother. The authors concluded that the
combined effect of the 2 mutant genes contributed to the development of
ALPS and lymphoma in this patient.

Dowdell et al. (2010) found that 12 (38.7%) of 31 ALPS patients who were
negative for germline FAS mutations carried heterozygous somatic FAS
mutations in their double-negative T cells. All of the 12 somatic
mutations resulted in known or predicted functional loss of normal FAS
signaling; 10 mutations led to a premature stop codon. Patients with
somatic FAS mutations were clinically similar to those with germline FAS
mutations, although they had a slightly lower incidence of splenectomy
and lower lymphocyte counts.

- Role in Neoplasms

Using microdissection techniques to isolate tumor cells from biopsies of
21 burn scar-related squamous cell carcinomas, Lee et al. (1999)
analyzed the entire FAS coding region and all of the splice sites and
found somatic point mutations in 3 cases. No mutations were detected in
50 cases of conventional squamous cell carcinoma. The FAS mutations were
located within the death domain (N239D; 134637.0014), ligand-binding
domain (N102S; 134637.0015) and transmembrane domain (C162R;
134637.0016). Loss of heterozygosity (LOH) of the other FAS allele was
demonstrated in tumors carrying the N239D and C162R mutations, and
expression of FAS was confirmed in all tumors with FAS mutations. Burn
scar-related squamous cell carcinomas are usually more aggressive than
conventional squamous cell carcinomas, and Lee et al. (1999) suggested
that somatic mutations in FAS may contribute to the development and/or
progression of burn scar-related squamous cell carcinomas.

Zhang et al. (2005) genotyped 1,000 Han Chinese lung cancer (211980)
patients and 1,270 controls for 2 functional polymorphisms in the
promoter regions of the FAS and FASL genes, -1377G-A (134637.0021) and
-844T-C (134638.0002), respectively. Compared to noncarriers, there was
an increased risk of developing lung cancer for carriers of either the
FAS -1377AA or the FASL -844CC genotype; carriers of both homozygous
genotypes had a more than 4-fold increased risk. Zhang et al. (2005)
stated that these results support the hypothesis that the FAS- and
FASL-triggered apoptosis pathway plays an important role in human
carcinogenesis.

- Other Associations

The TNFRSF6 gene is situated on 10q in a region implicated in several
linkage studies of Alzheimer disease (AD6; 605526). Feuk et al. (2000)
found an association between early-onset nonfamilial AD and a promoter
polymorphism in the TNFRSF6 gene. Feuk et al. (2003) further
investigated the TNFRSF6 region in 121 patients with early-onset
dementia and 152 controls. Analysis showed linkage disequilibrium
clustered in 2 large blocks containing a limited number of haplotypes.
Genotyping of haplotype tagging markers in an additional 204 late-onset
AD cases and 177 controls showed that the previously associated marker,
located in the promoter of TNFRSF6, had significant association with
cognitive status in Scottish early-onset dementia samples, with the
strongest signals being evident in the subgroup who carried APOE4 (see
107741). The results, together with previous data, suggested that a
promoter marker in TNFRSF6 plays a moderate but demonstrable role in AD
etiology.

GENOTYPE/PHENOTYPE CORRELATIONS

In a study of 8 patients with ALPS caused by mutation in the CD95 gene,
Vaishnaw et al. (1999) found that mutations in and around the death
domain had a dominant-negative effect that was explained by interference
with the recruitment of the signal adaptor protein FADD to the death
domain. The intracellular domain (ICD) mutations were associated with a
highly penetrant phenotype and an autosomal dominant inheritance
pattern. In contrast, mutations affecting the extracellular domain (ECD)
of the protein resulted in failure of extracellular expression of CD95
or impaired binding to CD95 ligand; these mutations did not have a
dominant-negative effect. In each of the families with an ECD mutation,
only a single individual was affected. These observations were
consistent with different mechanisms of action and modes of inheritance
of ICD and ECD mutations, suggesting that individuals with an ECD
mutation may require additional defect(s) for expression of ALPS.

Jackson et al. (1999) found that of 17 unique APT1 mutations in
unrelated ALPS probands, 12 (71%) occurred in exons 7 to 9, which encode
the intracellular portion of FAS. In vitro, activated lymphocytes from
all 17 patients showed apoptotic defects when exposed to an anti-FAS
agonist monoclonal antibody. In cotransfection experiments, FAS
constructs with either intra- or extracellular mutations caused dominant
inhibition of apoptosis mediated by wildtype FAS; however, mutations
affecting the intracellular domain resulted in more severe inhibition of
apoptosis and showed a higher penetrance of the ALPS phenotype.
Significant ALPS-related morbidity occurred in 44% of relatives with
intracellular mutations, versus 0% of relatives with extracellular
mutations. Jackson et al. (1999) concluded that the location of
mutations within APT1 strongly influences the development and the
severity of ALPS.

Martin et al. (1999) contributed to the understanding of the mechanism
by which heterozygous mutations in the CD95 receptor result in dominant
interference with apoptosis leading to ALPS. They showed that local or
global alterations in the structure of the cytoplasmic death domain from
9 independent ALPS CD95 death-domain mutations resulted in a failure to
bind the FADD/MORT1 signaling protein. Despite heterozygosity for the
abnormal allele, lymphocytes from ALPS patients showed markedly
decreased FADD association and a loss of caspase recruitment and
activation after CD95 crosslinking. These data suggested that
intracytoplasmic CD95 mutations in ALPS impair apoptosis chiefly by
disrupting death-domain interactions with the signaling protein
FADD/MORT1.

Siegel et al. (2000) found that dominant interference of FAS mutations
stems from ligand-independent interaction of wildtype and mutant FAS
receptors through a specific region of the extracellular domain, rather
than depending upon ligand-induced receptor oligomerization, This
domain, located within the first cysteine-rich domain, is termed the
pre-ligand assembly domain (PLAD). Siegel et al. (2000) identified
preassociated FAS complexes in living cells by means of fluorescence
resonance energy transfer. In a large number of ALPS patients, they
found that the PLAD was preserved in every example of dominant-negative
mutation. To cause dominant interference, the mutant protein must
physically interact with the wildtype protein in a preassociated
receptor complex which normally permits FAS signaling.

ANIMAL MODEL

Watanabe-Fukunaga et al. (1992) noted that the murine phenotype
autosomal recessive lymphoproliferation (lpr) is characterized by
lymphadenopathy, hypergammaglobulinemia, multiple autoantibodies, and
the accumulation of large numbers of nonmalignant CD4-, CD8- T cells.
Affected mice usually develop a systemic lupus erythematosus (SLE;
152700)-like autoimmune disease. Studies suggested a defect in the
negative selection of self-reactive T lymphocytes in the thymus. In lpr
mice, Watanabe-Fukunaga et al. (1992) identified a 786T-A transversion
in the Fas gene, resulting in an asparagine-to-isoleucine substitution
in a highly conserved cytoplasmic region of the protein, demonstrating
that lpr is the gene for the mouse Fas antigen. The authors noted that
Frizzera et al. (1989) had identified human patients displaying a
phenotype similar to that of lpr mice (see 601859).

Wu et al. (1993) observed autoimmune disease in mice due to integration
of endogenous retrovirus in the Fas gene.

Savinov et al. (2003) evaluated the importance of Fas in the
pathogenesis of diabetes by generating NOD mice (nonobese diabetic mice
that develop spontaneous autoimmune diabetes) with beta cell-specific
expression of a dominant-negative point mutation in the Fas death
domain. Spontaneous diabetes was significantly delayed in these mice,
and the effect depended on the expression level of the transgene.
However, mice bearing the transgene were still sensitive to diabetes
transferred by splenocytes from overtly diabetic NOD mice. At the same
time, expression of the transgene neutralized the accelerating effect of
transgenic Fas ligand expressed by the same beta cells. The authors
concluded that both Fas-dependent and -independent mechanisms are
involved in beta cell destruction, but interference with the Fas pathway
early in disease development may retard or prevent diabetes progression.

Song et al. (2003) investigated the in vivo silencing effect of small
interfering RNA (siRNA) duplexes targeting the FAS gene to protect mice
from liver failure and fibrosis in 2 models of autoimmune hepatitis.
Intravenous injection of Fas siRNA specifically reduced Fas mRNA levels
and expression of Fas protein in mouse hepatocytes, and the effects
persisted without diminution for 10 days. Hepatocytes isolated from
these mice were resistant to apoptosis when exposed to Fas-specific
antibody or cocultured with concanavalin-A-stimulated hepatic
mononuclear cells. Treatment with Fas siRNA 2 days before concanavalin-A
challenge abrogated hepatocyte necrosis and inflammatory infiltration
and markedly reduced serum concentrations of transaminases. In a more
fulminant hepatitis induced by injecting agonistic Fas-specific
antibody, 82% of mice treated with siRNA that effectively silenced Fas
survived for 10 days of observation, whereas all control mice died
within 3 days.

Ma et al. (2004) observed that Fas-deficient (lpr/lpr) mice had less
severe collagen-induced arthritis, but higher levels of Il1b (147720) in
joints, than control mice, suggesting inefficient activation through
Il1r1 (147810). Fas- and Fasl-deficient mouse macrophages and human
macrophages treated with an antagonistic FASL antibody had suppressed
NFKB (see 164011) activation and cytokine production in response to IL1B
or lipopolysaccharide. Ectopic expression of FADD or dominant-negative
FADD (containing the death domain only) suppressed MYD88
(602170)-induced NFKB and IL6 (147620) promoter activation and cytokine
expression. Ma et al. (2004) concluded that the FAS-FASL interaction
enhances activation through the IL1R1 or TLR4 (603030) pathway, possibly
contributing to the pathogenesis of chronic arthritis.

Landau et al. (2005) found that Fas-deficient lymphoproliferative mice
developed a Parkinson disease (PD; 168600) phenotype, characterized by
extensive nigrostriatal degeneration accompanied by tremor, hypokinesia,
and loss of motor coordination, after treatment with the dopaminergic
neurotoxin MPTP at a dose that caused no phenotype in wildtype mice.
Mice with mutated Fasl and generalized lymphoproliferative disease had
an intermediate phenotype. Treatment of cultured midbrain neurons with
Fasl to induce Fas signaling protected them from MPTP toxicity. Mice
lacking only Fas exon 9, which encodes the death domain, but retaining
the intracellular Fas domain and cell surface expression of Fas, were
resistant to MPTP. Peripheral blood lymphocytes from patients with
idiopathic PD showed a highly significant deficit in their ability to
upregulate Fas after mitogen stimulation. Landau et al. (2005) concluded
that reduced FAS expression increases susceptibility to
neurodegeneration and that FAS has a role in neuroprotection.

Hutcheson et al. (2008) found that patients with SLE displayed increased
expression of antiapoptotic members of the BCL2 (151430) and FAS
apoptotic pathways in mononuclear cells. They found that Fas lpr/lpr
mice that also lacked the BCL2 proapoptotic member Bim (Bim -/-)
developed severe SLE-like disease by 16 weeks of age, whereas Bim -/- or
Fas lpr/lpr mice did not. Antigen-presenting cells (APCs) from Bim -/-
Fas lpr/lpr double-mutant mice were markedly activated and their numbers
were increased in lymphoid tissues and kidneys, though numerous
apoptotic (TUNEL-positive) cells were observed in glomeruli of these
mice. Hutcheson et al. (2008) concluded that dysregulation of the BCL2
or FAS pathways can alter the function of APCs and lead to SLE
pathogenesis.

Weant et al. (2008) found that mice lacking both Bim and Fas showed a
synergistic disruption of lymphoid homeostasis, rapid onset of
autoimmunity, and organ-specific blocks on contraction of antiviral
immune responses. The double-mutant mice had 100-fold more
antigen-specific memory Cd8-positive T cells in their lymph nodes than
did wildtype mice. Weant et al. (2008) concluded that multiple death
pathways function concurrently to balance proliferation and apoptosis
and to prevent autoimmunity and downsize T-cell responses.

NOMENCLATURE

Beautyman (1995) stated that the word 'apoptosis' was 'taken straight
from Liddell and Scott's classical Greek-English lexicon complete with
examples of its use in medicine by Hippocrates and Dioscorides (the
physician, not the poet).' He stated, furthermore, that for this reason
it should be pronounced with 2 'p's. He pointed out that Kerr et al.
(1972), in introducing the term into modern science, suggested silencing
the second p. Silencing the p seems so well established in words of
similar derivation, such as 'ptosis' and 'pneumonia,' that silencing of
the second p would seem appropriate in modern speech.

*FIELD* AV
.0001
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA
TNFRSF6, 1-BP DEL, 429G

In a patient with ALPS1A (601859), Fisher et al. (1995) identified a
heterozygous 1-bp deletion (429delG) in exon 3 of the FAS gene,
resulting in a frameshift and premature termination. The authors
predicted reduced surface expression of the Fas antigen and a loss of
function. As the patient's unaffected mother was also heterozygous for
the same mutation, the authors suggested that additional modifier genes
may be involved in the development of the phenotype.

.0002
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA
TNFRSF6, EX3DEL

In a patient with ALPS1A (601859), Fisher et al. (1995) found in-frame
deletion of exon 3 of the FAS gene, resulting from a 1-bp insertion in
the 5-prime splice site of intron 3 and leading to a change in the
extracellular domain of the protein. Although the patient's mother, who
was heterozygous for the same mutation, had no clinical abnormalities,
in vitro analysis showed impaired T-lymphocyte apoptosis. Fisher et al.
(1995) concluded that the exon 3 deletion had a dominant interfering
effect, but also noted that genetic modifiers must be involved.

.0003
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA
TNFRSF6, THR225PRO

In a patient with ALPS1A (601859), Fisher et al. (1995) identified a
heterozygous 915A-C transversion in the FAS gene, resulting in a
thr225-to-pro (T225P) substitution in the death domain of the protein.
The father had died of Hodgkin disease, but the paternal uncle, who also
had Hodgkin disease, was heterozygous for the T225P mutation, indicating
that the patient's father was the source of the mutation. The mutation
resulted in a dominant interfering effect.

.0004
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA
TNFRSF6, IVS7AS, A-C, -2

In a patient with ALPS1A (601859), Fisher et al. (1995) identified an
A-to-C change at the 3-prime splice site of intron 6 of the FAS gene,
resulting in aberrant splicing and truncation at the intracellular side
of the membrane-spanning domain. The asymptomatic mother was
heterozygous for the same mutation, but appeared to be a mosaic. In
vitro studies showed that the mother had defective T-lymphocyte
apoptosis. The authors concluded that the mutation had a dominant
interfering effect.

.0005
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA
TNFRSF6, GLN257TER

In a patient with ALPS1A (601859), Fisher et al. (1995) identified a
1011C-T transition in the FAS gene, resulting in a gln257-to-ter (Q257X)
substitution in the death domain of the protein. The patient's
asymptomatic mother had the same heterozygous mutation, suggesting that
other genetic modifiers were involved in phenotypic expression.

.0006
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA, AUTOSOMAL RECESSIVE
TNFRSF6, ARG105TRP

Bettinardi et al. (1997) described a family in which 3 sibs affected
with ALPS1A (601859) were compound heterozygotes for 2 mutations in the
FAS gene: a 555C-T transition, resulting in an arg105-to-trp (R105W)
substitution, was inherited from the mother, and an 889A-G transition,
resulting in a tyr216-to-cys (Y216C; 134637.0007) substitution, was
inherited from the father. The children shared common features,
including splenomegaly and lymphadenopathy, but only 1 developed severe
autoimmune hemolytic anemia and thrombocytopenia. Another child
developed hypergammaglobulinemia, with increased IgG and IgA serum
levels. No clinical or immunologic defect and no evidence of defective
FAS function was identified in the heterozygous parents.

.0007
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA, AUTOSOMAL RECESSIVE
TNFRSF6, TYR216CYS

See 134637.0006 and Bettinardi et al. (1997).

.0008
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA
TNFRSF6, ASP244VAL

In a family with ALPS1A (601859) containing 11 affected individuals in 4
generations, Infante et al. (1998) identified a 973A-T transversion in
the FAS cDNA, resulting in a nonconservative asp244-to-val (D244V)
substitution in the intracellular domain of the protein. Although 1
affected individual died of postsplenectomy sepsis and 1 had been
treated for lymphoma, the FAS mutation in this family was compatible
with a healthy adulthood, as clinical features of ALPS receded with
increasing age.

.0009
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA
TNFRSF6, ARG234PRO

In a family with autosomal dominant ALPS1A (601859), Vaishnaw et al.
(1999) identified a G-to-C transversion in the FAS gene, resulting in an
arg234-to-pro (R234P) substitution in the intracellular domain of the
protein. The family was originally reported by Rao et al. (1974).

.0010
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA
TNFRSF6, THR254ILE

In a family with autosomal dominant ALPS1A (601859), Vaishnaw et al.
(1999) identified a heterozygous C-to-T transition in the FAS gene,
resulting in a thr254-to-ile (T254I) substitution.

.0011
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA
TNFRSF6, IVS7DS, T-A, +2

In a family with autosomal dominant ALPS1A (601859), Vaishnaw et al.
(1999) identified a heterozygous splice site mutation in the FAS gene,
resulting in a frameshift and premature termination at position 209
(ser209-to-ter; S209X).

.0012
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA
TNFRSF6, A-T, -1

Jackson et al. (1999) found a variant A(-1)T at the FAS signal sequence
cleavage site in 13% of African American TNFRSF6 alleles. The variant
mediated apoptosis less well than wildtype FAS and was partially
inhibitory.

.0013
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA, AUTOSOMAL RECESSIVE
TNFRSF6, IVS9, 20-BP DUP

In a child with ALPS1A (601859) born of consanguineous parents, van der
Burg et al. (2000) identified a homozygous 20-nucleotide duplication in
the last exon of the FAS gene, affecting the cytoplasmic signaling
domain. The patient's unaffected parents and sibs were heterozygous for
the mutation. The findings indicated that this phenotype was the human
homolog of the FAS-null mouse, since the patient carried a homozygous
mutation in the FAS gene and showed a severe and accelerated ALPS
phenotype. Van der Burg et al. (2000) noted that Rieux-Laucat et al.
(1995) had reported a severe case of ALPS with a homozygous FAS
deletion, and that Bettinardi et al. (1997) had reported 3 sibs who were
compound heterozygous for 2 FAS mutations (see 134637.0006 and
134637.0007).

.0014
SQUAMOUS CELL CARCINOMA, BURN SCAR-RELATED, SOMATIC
TNFRSF6, ASN239ASP

In a burn scar-related squamous cell carcinoma, Lee et al. (1999)
identified a 957A-G transition in the TNFRSF6 gene, resulting in an
asn239-to-asp (N239D) substitution in the FAS death domain.

.0015
SQUAMOUS CELL CARCINOMA, BURN SCAR-RELATED, SOMATIC
TNFRSF6, ASN102SER

In a burn scar-related squamous cell carcinoma, Lee et al. (1999)
identified a 547A-G transition in the TNFRSF6 gene, resulting in an
asn102-to-ser (N102S) substitution in the FAS ligand-binding domain.

.0016
SQUAMOUS CELL CARCINOMA, BURN SCAR-RELATED, SOMATIC
TNFRSF6, CYS162ARG

In a burn scar-related squamous cell carcinoma, Lee et al. (1999)
identified a 726T-to-C transition in the TNFRSF6 gene, resulting in a
cys162-to-arg (C162R) substitution in the FAS transmembrane domain.

.0017
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA
TNFRSF6, GLY231ALA

In a patient with ALPS1A (601859), Martin et al. (1999) identified a
934G-C transversion in the TNFRSF6 gene, resulting in a gly231-to-ala
(G231A) substitution. (The authors originally referred to the nucleotide
transversion as 943G-C and the substitution as ARG234PRO, which they
later corrected in an erratum.)

.0018
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA
TNFRSF6, PRO201FS, 204TER

In 3 of 6 patients with heterozygous mosaic cases of ALPS1A (601859),
Holzelova et al. (2004) identified a frameshift mutation in exon 8 of
the FAS gene, resulting in a premature stop at codon 204. Clinical
manifestations in the 3 mosaic cases were highly variable. The same
mutation had been described as a germline mutation in a patient with
ALPS1A by Rieux-Laucat et al. (1999).

.0019
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA
TNFRSF6, 1-BP INS

In a patient with ALPS1A (601859) reported by Canale and Smith (1967),
Drappa et al. (1996) identified a heterozygous 1-bp insertion within the
death domain of the FAS gene, resulting in a lys230to-ter (K230X)
substitution.

.0020
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA
TNFRSF6, ASP244TYR

In a patient with ALPS1A (601859) reported by Canale and Smith (1967),
and in his affected son, Drappa et al. (1996) identified a heterozygous
972G-T transversion within the death domain of the FAS gene, resulting
in an asp244-to-tyr (D244Y) substitution.

.0021
LUNG CANCER, SUSCEPTIBILITY TO
TNFRSF6, -1377G-A

Zhang et al. (2005) genotyped 1,000 Han Chinese lung cancer (211980)
patients and 1,270 controls for 2 functional polymorphisms in the
promoter regions of the FAS and FASL genes, -1377G-A and -844T-C
(134638.0002), respectively. Compared to noncarriers, there was a
1.6-fold increased risk of developing lung cancer for carriers of the
FAS -1377AA genotype and a 1.8-fold increased risk for carriers of the
FASL -844CC genotype. Carriers of both homozygous genotypes had a more
than 4-fold increased risk, indicative of multiplicative gene-gene
interaction.

*FIELD* RF
1. Arscott, P. L.; Stokes, T.; Myc, A.; Giordano, T. J.; Thompson,
N. W.; Baker, J. R., Jr.: Fas (CD95) expression is up-regulated on
papillary thyroid carcinoma. J. Clin. Endocr. Metab. 84: 4246-4252,
1999.

2. Aspinall, A. I.; Pinto, A.; Auer, I. A.; Bridges, P.; Luider, J.;
Dimnik, L.; Patel, K. D.; Jorgenson, K.; Woodman, R. C.: Identification
of new Fas mutations in a patient with autoimmune lymphoproliferative
syndrome (ALPS) and eosinophilia. Blood Cells Molec. Dis. 25: 227-238,
1999.

3. Beautyman, W.: Apoptosis again. (Letter) Nature 376: 380 only,
1995.

4. Bettinardi, A.; Brugnoni, D.; Quiros-Roldan, E.; Malagoli, A.;
La Grutta, S.; Correra, A.; Notarangelo, L. D.: Missense mutations
in the Fas gene resulting in autoimmune lymphoproliferative syndrome:
a molecular and immunological analysis. Blood 89: 902-909, 1997.

5. Brunner, T.; Mogil, R. J.; LaFace, D.; Yoo, N. J.; Mahboubi, A.;
Echeverri, F.; Martin, S. J.; Force, W. R.; Lynch, D. H.; Ware, C.
F.; Green, D. R.: Cell-autonomous Fas (CD95)/Fas-ligand interaction
mediates activation-induced apoptosis in T-cell hybridomas. Nature 373:
441-444, 1995.

6. Canale, V. C.; Smith, C. H.: Chronic lymphadenopathy simulating
malignant lymphoma. J. Pediat. 70: 891-899, 1967.

7. Chen, L.; Park, S.-M.; Tumanov, A. V.; Hau, A.; Sawada, K.; Feig,
C.; Turner, J. R.; Fu, Y.-X.; Romero, I. L.; Lengyel, E.; Peter, M.
E.: CD95 promotes tumour growth. Nature 465: 492-496, 2010. Note:
Erratum: Nature 471: 254 only, 2011. Erratum: Nature 475: 254 only,
2011. Erratum: Nature 491: 784 only, 2012.

8. Clementi, R.; Dagna, L.; Dianzani, U.; Dupre, L.; Dianzani, I.;
Ponzoni, M.; Cometa, A.; Chiocchetti, A.; Sabbadini, M. G.; Rugarli,
C.; Ciceri, F.; Maccario, R.; Locatelli, F.; Danesino, C.; Ferrarini,
M.; Bregni, M.: Inherited perforin and Fas mutations in a patient
with autoimmune lymphoproliferative syndrome and lymphoma. New Eng.
J. Med. 351: 1419-1424, 2004.

9. Desbarats, J.; Birge, R. B.; Mimouni-Rongy, M.; Weinstein, D. E.;
Palerme, J.-S.; Newell, M. K.: Fas engagement induces neurite growth
through ERK activation and p35 upregulation. Nature Cell Biol. 5:
118-125, 2003.

10. Dhein, J.; Walczak, H.; Baumler, C.; Debatin, K.-M.; Krammer,
P. H.: Autocrine T-cell suicide mediated by APO-1/(Fas/CD95). Nature 373:
438-441, 1995.

11. Dowdell, K. C.; Niemela, J. E.; Price, S.; Davis, J.; Hornung,
R. L.; Oliveira, J. B.; Puck, J. M.; Jaffe, E. S.; Pittaluga, S.;
Cohen, J. I.; Fleisher, T. A.; Rao, V. K.: Somatic FAS mutations
are common in patients with genetically undefined autoimmune lymphoproliferative
syndrome. Blood 115: 5164-5169, 2010.

12. Drappa, J.; Vaishnaw, A. K.; Sullivan, K. E.; Chu, J.-L.; Elkon,
K. B.: Fas gene mutations in the Canale-Smith syndrome, an inherited
lymphoproliferative disorder associated with autoimmunity. New Eng.
J. Med. 335: 1643-1649, 1996.

13. Feuk, L.; Prince, J. A.; Blennow, K.; Brookes, A. J.: Further
evidence for role of a promoter variant in the TNFRSF6 gene in Alzheimer
disease. Hum. Mutat. 21: 53-60, 2003.

14. Feuk, L.; Prince, J. A.; Breen, G.; Emahazion, T.; Carothers,
A.; St Clair, D.; Brookes, A. J.: Apolipoprotein-E dependent role
for the FAS receptor in early onset Alzheimer's disease: finding of
a positive association for a polymorphism in the TNFRSF6 gene. Hum.
Genet. 107: 391-396, 2000.

15. Fisher, G. H.; Rosenberg, F. J.; Straus, S. E.; Dale, J. K.; Middelton,
L. A.; Lin, A. Y.; Strober, W.; Lenardo, M. J.; Puck, J. M.: Dominant
interfering Fas gene mutations impair apoptosis in a human autoimmune
lymphoproliferative syndrome. Cell 81: 935-946, 1995.

16. Frizzera, G.; Kaneko, Y.; Sakurai, M.: Angioimmunoblastic lymphadenopathy
and related disorders: a retrospective look in search of definitions. Leukemia 3:
1-5, 1989.

17. Grassme, H.; Kirschnek, S.; Riethmueller, J.; Riehle, A.; von
Kurthy, G.; Lang, F.; Weller, M.; Gulbins, E.: CD95/CD95 ligand interactions
on epithelial cells in host defense to Pseudomonas aeruginosa. Science 290:
527-530, 2000.

18. Holzelova, E.; Vonarbourg, C.; Stolzenberg, M.-C.; Arkwright,
P. D.; Selz, F.; Prieur, A.-M.; Blanche, S.; Bartunkova, J.; Vilmer,
E.; Fischer, A.; Le Deist, F.; Rieux-Laucat, F.: Autoimmune lymphoproliferative
syndrome with somatic Fas mutations. New Eng. J. Med. 351: 1409-1418,
2004.

19. Hueber, A.-O.: CD95: more than just a death factor? Nature Cell
Biol. 2: E23-E25, 2000. Note: Erratum: Nature Cell Biol. 2: E50,
2000.

20. Hueber, A.-O.; Zornig, M.; Lyon, D.; Suda, T.; Nagata, S.; Evan,
G. I.: Requirement for the CD95 receptor-ligand pathway in c-Myc-induced
apoptosis. Science 278: 1305-1309, 1997.

21. Hutcheson, J.; Scatizzi, J. C.; Siddiqui, A. M.; Haines, G. K.,
III; Wu, T.; Li, Q.-Z.; Davis, L. S.; Mohan, C.; Perlman, H.: Combined
deficiency of proapoptotic regulators Bim and Fas results in the early
onset of systemic autoimmunity. Immunity 28: 206-217, 2008.

22. Inazawa, J.; Itoh, N.; Abe, T.; Nagata, S.: Assignment of the
human Fas antigen gene (FAS) to 10q24.1. Genomics 14: 821-822, 1992.

23. Infante, A. J.; Britton, H. A.; DeNapoli, T.; Middleton, L. A.;
Lenardo, M. J.; Jackson, C. E.; Wang, J.; Fleisher, T.; Straus, S.
E.; Puck, J. M.: The clinical spectrum in a large kindred with autoimmune
lymphoproliferative syndrome caused by a Fas mutation that impairs
lymphocyte apoptosis. J. Pediat. 133: 629-633, 1998.

24. Itoh, N.; Yonehara, S.; Ishii, A.; Yonehara, M.; Mizushima, S.-I.;
Sameshima, M.; Hase, A.; Seto, Y.; Nagata, S.: The polypeptide encoded
by the cDNA for human cell surface antigen Fas can mediate apoptosis. Cell 66:
233-243, 1991.

25. Jackson, C. E.; Fischer, R. E.; Hsu, A. P.; Anderson, S. M.; Choi,
Y.; Wang, J.; Dale, J. K.; Fleisher, T. A.; Middelton, L. A.; Sneller,
M. C.; Lenardo, M. J.; Straus, S. E.; Puck, J. M.: Autoimmune lymphoproliferative
syndrome with defective Fas: genotype influences penetrance. Am.
J. Hum. Genet. 64: 1002-1014, 1999.

26. Jost, P. J.; Grabow, S.; Gray, D.; McKenzie, M. D.; Nachbur, U.;
Huang, D. C. S.; Bouillet, P.; Thomas, H. E.; Borner, C.; Silke, J.;
Strasser, A.; Kaufmann, T.: XIAP discriminates between type I and
type II FAS-induced apoptosis. Nature 460: 1035-1039, 2009.

27. Ju, S.-T.; Panka, D. J.; Cui, H.; Ettinger, R.; El-Khatib, M.;
Sherr, D. H.; Stanger, B. Z.; Marshak-Rothstein, A.: Fas(CD95)/FasL
interactions required for programmed cell death after T-cell activation. Nature 373:
444-448, 1995.

28. Kerr, J. F. R.; Wyllie, A. H.; Currie, A. R.: Apoptosis: a basic
biological phenomenon with wide-ranging implications in tissue kinetics. Brit.
J. Cancer 26: 239-257, 1972.

29. Landau, A. M.; Luk, K. C.; Jones, M.-L.; Siegrist-Johnstone, R.;
Young, Y. K.; Kouassi, E.; Rymar, V. V.; Dagher, A.; Sadikot, A. F.;
Desbarats, J.: Defective Fas expression exacerbates neurotoxicity
in a model of Parkinson's disease. J. Exp. Med. 202: 575-581, 2005.

30. Lee, S. H.; Shin, M. S.; Kim, H. S.; Park, W. S.; Kim, S. Y.;
Jang, J. J.; Rhim, K. J.; Jang, J.; Lee, H. K.; Park, J. Y.; Oh, R.
R.; Han, S. Y.; Lee, J. H.; Lee, J. Y.; Yoo, N. J.: Somatic mutations
of Fas (Apo-1/CD95) gene in cutaneous squamous cell carcinoma arising
from a burn scar. J. Invest. Derm. 114: 122-126, 1999.

31. Lepple-Wienhues, A.; Belka, C.; Laun, T.; Jekle, A.; Walter, B.;
Wieland, U.; Welz, M.; Heil, L.; Kun, J.; Busch, G.; Weller, M.; Bamberg,
M.; Gulbins, E.; Lang, F.: Stimulation of CD95 (Fas) blocks T lymphocyte
calcium channels through sphingomyelinase and sphingolipids. Proc.
Nat. Acad. Sci. 96: 13795-13800, 1999.

32. Lichter, P.; Walczak, H.; Weitz, S.; Behrmann, I.; Krammer, P.
H.: The human APO-1 (APT) antigen maps to 10q23, a region that is
syntenic with mouse chromosome 19. Genomics 14: 179-180, 1992.

33. Ma, Y.; Liu, H.; Tu-Rapp, H.; Thiesen, H.-J.; Ibrahim, S. M.;
Cole, S. M.; Pope, R. M.: Fas ligation on macrophages enhances IL-1R1-Toll-like
receptor 4 signaling and promotes chronic inflammation. Nature Immun. 5:
380-387, 2004.

34. Mannick, J. B.; Hausladen, A.; Liu, L.; Hess, D. T.; Zeng, M.;
Miao, Q. X.; Kane, L. S.; Gow, A. J.; Stamler, J. S.: Fas-induced
caspase denitrosylation. Science 284: 651-654, 1999.

35. Martin, D. A.; Zheng, L.; Siegel, R. M.; Huang, B.; Fisher, G.
H.; Wang, J.; Jackson, C. E.; Puck, J. M.; Dale, J.; Straus, S. E.;
Peter, M. E.; Krammer, P. H.; Fesik, S.; Lenardo, M. J.: Defective
CD95/APO-1/Fas signal complex formation in the human autoimmune lymphoproliferative
syndrome, type Ia. Proc. Nat. Acad. Sci. 96: 4552-4557, 1999. Note:
Erratum: Proc. Nat. Acad. Sci. 101: 7840 only, 2004.

36. Mountz, J. D.; Talal, N.: Retroviruses, apoptosis and autogenes. Immun.
Today 14: 532-536, 1993.

37. Oehm, A.; Behrmann, I.; Falk, W.; Pawlita, M.; Maier, G.; Klas,
C.; Li-Weber, M.; Richards, S.; Dhein, J.; Trauth, B. C.; Ponstingl,
H.; Krammer, P. H.: Purification and molecular cloning of the APO-1
cell surface antigen, a member of the tumor necrosis factor/nerve
growth factor receptor superfamily: sequence identity with the FAS
antigen. J. Biol. Chem. 267: 10709-10715, 1992.

38. Pestano, G. A.; Zhou, Y.; Trimble, L. A.; Daley, J.; Weber, G.
F.; Cantor, H.: Inactivation of misselected CD8 T cells by CD8 gene
methylation and cell death. Science 284: 1187-1191, 1999.

39. Rao, L. M.; Shahidi, N. T.; Opitz, J. M.: Hereditary splenomegaly
with hypersplenism. Clin. Genet. 5: 379-386, 1974.

40. Raoul, C.; Buhler, E.; Sadeghi, C.; Jacquier, A.; Aebischer, P.;
Pettmann, B.; Henderson, C. E.; Haase, G.: Chronic activation in
presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback
loop involving Fas, Daxx, and FasL. Proc. Nat. Acad. Sci. 103: 6007-6012,
2006.

41. Raoul, C.; Estevez, A. G.; Nishimune, H.; Cleveland, D. W.; deLapeyriere,
O.; Henderson, C. E.; Hasse, G.; Pettmann, B.: Motoneuron death triggered
by a specific pathway downstream of Fas: potentiation by ALS-linked
SOD1 mutations. Neuron 35: 1067-1083, 2002.

42. Rieux-Laucat, F.; Blachere, S.; Danielan, S.; De Villartay, J.
P.; Oleastro, M.; Solary, E.; Bader-Meunier, B.; Arkwright, P.; Pondare,
C.; Bernaudin, F.; Chapel, H.; Nielsen, S.; Berrah, M.; Fischer, A.;
Le Deist, F.: Lymphoproliferative syndrome with autoimmunity: a possible
genetic basis for dominant expression of the clinical manifestations. Blood 94:
2575-2582, 1999.

43. Rieux-Laucat, F.; Le Deist, F.; Hivroz, C.; Roberts, I. A. G.;
Debatin, K. M.; Fischer, A.; de Villartay, J. P.: Mutations in Fas
associated with human lymphoproliferative syndrome and autoimmunity. Science 268:
1347-1349, 1995.

44. Savinov, A. Y.; Tcherepanov, A.; Green, E. A.; Flavell, R. A.;
Chervonsky, A. V.: Contribution of Fas to diabetes development. Proc.
Nat. Acad. Sci. 100: 628-632, 2003.

45. Scott, F. L.; Stec, B.; Pop, C.; Dobaczewska, M. K.; Lee, J. J.;
Monosov, E.; Robinson, H.; Salvesen, G. S.; Schwarzenbacher, R.; Riedl,
S. J.: The Fas-FADD death domain complex structure unravels signalling
by receptor clustering. Nature 457: 1019-1022, 2009.

46. Siegel, R. M.; Frederiksen, J. K.; Zacharias, D. A.; Chan, F.
K.-M.; Johnson, M.; Lynch, D.; Tsien, R. Y.; Lenardo, M. J.: Fas
preassociation required for apoptosis signaling and dominant inhibition
by pathogenic mutations. Science 288: 2354-2357, 2000.

47. Sneller, M. C.; Straus, S. E.; Jaffe, E. S.; Jaffe, J. S.; Fleisher,
T. A.; Stetler-Stevenson, M.; Strober, W.: A novel lymphoproliferative/autoimmune
syndrome resembling murine lpr/gld disease. J. Clin. Invest. 90:
334-341, 1992.

48. Song, E.; Lee, S.-K.; Wang, J.; Ince, N.; Ouyang, N.; Min, J.;
Chen, J.; Shankar, P.; Lieberman, J.: RNA interference targeting
Fas protects mice from fulminant hepatitis. Nature Med. 9: 347-351,
2003.

49. Talal, N.: Oncogenes, autogenes, and rheumatic diseases.(Editorial) Arthritis
Rheum. 37: 1421-1422, 1994.

50. Vaishnaw, A. K.; Orlinick, J. R.; Chu, J.-L.; Krammer, P. H.;
Chao, M. V.; Elkton, K. B.: The molecular basis for apoptotic defects
in patients with CD95 (Fas/Apo-1) mutations. J. Clin. Invest. 103:
355-363, 1999. Note: Erratum: J. Clin. Invest. 103: 1099 only, 1999.

51. van der Burg, M.; de Groot, R.; Comans-Bitter, W. M.; den Hollander,
J. C.; Hooijkaas, H.; Neijens, H. J.; Berger, R. M. F.; Oranje, A.
P.; Langerak, A. W.; van Dongen, J. J. M.: Autoimmune lymphoproliferative
syndrome (ALPS) in a child from consanguineous parents: a dominant
or recessive disease? Pediat. Res. 47: 336-343, 2000.

52. Viard, I.; Wehrli, P.; Bullani, R.; Schneider, P.; Holler, N.;
Salomon, D.; Hunziker, T.; Saurat, J.-H.; Tschopp, J.; French, L.
E.: Inhibition of toxic epidermal necrolysis by blockade of CD95
with human intravenous immunoglobulin. Science 282: 490-493, 1998.

53. Volpert, O. V.; Zaichuk, T.; Zhou, W.; Reiher, F.; Ferguson, T.
A.; Stuart, P. M.; Amin, M.; Bouck, N. P.: Inducer-stimulated Fas
targets activated endothelium for destruction by anti-angiogenic thrombospondin-1
and pigment epithelium-derived factor. Nature Med. 8: 349-357, 2002.

54. Watanabe-Fukunaga, R.; Brannan, C. I.; Copeland, N. G.; Jenkins,
N. A.; Nagata, S.: Lymphoproliferation disorder in mice explained
by defects in Fas antigen that mediates apoptosis. Nature 356: 314-317,
1992.

55. Watanabe-Fukunaga, R.; Brannan, C. I.; Itoh, N.; Yonehara, S.;
Copeland, N. G.; Jenkins, N. A.; Nagata, S.: The cDNA structure,
expression, and chromosomal assignment of the mouse Fas antigen. J.
Immun. 148: 1274-1279, 1992.

56. Weant, A. E.; Michalek, R. D.; Khan, I. U.; Holbrook, B. C.; Willingham,
M. C.; Grayson, J. M.: Apoptosis regulators Bim and Fas function
concurrently to control autoimmunity and CD8+ T cell contraction. Immunity 28:
218-230, 2008.

57. Wu, J.; Zhou, T.; He, J.; Mountz, J. D.: Autoimmune disease in
mice due to integration of an endogenous retrovirus in an apoptosis
gene. J. Exp. Med. 178: 461-468, 1993.

58. Yan, M.-D.; Hong, C.-C.; Lai, G.-M.; Cheng, A.-L.; Lin, Y.-W.;
Chuang, S.-E.: Identification and characterization of a novel gene
Saf transcribed from the opposite strand of Fas. Hum. Molec. Genet. 14:
1465-1474, 2005.

59. Zhang, X.; Miao, X.; Sun, T.; Tan, W.; Qu, S.; Xiong, P.; Zhou,
Y.; Lin, D.: Functional polymorphisms in cell death pathway genes
FAS and FASL contribute to the risk of lung cancer. J. Med. Genet. 42:
479-484, 2005.

60. Zou, C.; Ma, J.; Wang, X.; Guo, L.; Zhu, Z.; Stoops, J.; Eaker,
A. E.; Johnson, C. J.; Strom, S.; Michalopoulos, G. K.; DeFrances,
M. C.; Zarnegar, R.: Lack of Fas antagonism by Met in human fatty
liver disease. Nature Med. 13: 1078-1085, 2007.

*FIELD* CN
Paul J. Converse - updated: 8/9/2012
Paul J. Converse - updated: 8/3/2012
Cassandra L. Kniffin - updated: 5/10/2011
Ada Hamosh - updated: 6/30/2010
Ada Hamosh - updated: 9/15/2009
Ada Hamosh - updated: 3/10/2009
George E. Tiller - updated: 6/5/2008
Ada Hamosh - updated: 3/27/2008
Cassandra L. Kniffin - updated: 6/2/2006
Paul J. Converse - updated: 4/3/2006
Marla J. F. O'Neill - updated: 7/21/2005
Cassandra L. Kniffin - reorganized: 11/17/2004
Victor A. McKusick - updated: 10/22/2004
Victor A. McKusick - updated: 7/2/2004
Paul J. Converse - updated: 4/19/2004
Cassandra L. Kniffin - updated: 6/6/2003
Patricia A. Hartz - updated: 4/28/2003
Ada Hamosh - updated: 2/27/2003
Victor A. McKusick - updated: 2/12/2003
Victor A. McKusick - updated: 1/15/2003
Ada Hamosh - updated: 4/9/2002
Ada Hamosh - updated: 10/30/2000
John A. Phillips, III - updated: 10/2/2000
Ada Hamosh - updated: 6/29/2000
Gary A. Bellus - updated: 6/13/2000
Victor A. McKusick - updated: 5/1/2000
Paul J. Converse - updated: 4/20/2000
Victor A. McKusick - updated: 1/19/2000
Ada Hamosh - updated: 5/13/1999
Ada Hamosh - updated: 5/10/1999
Victor A. McKusick - updated: 5/4/1999
Victor A. McKusick - updated: 4/9/1999
Victor A. McKusick - updated: 4/2/1999
Victor A. McKusick - updated: 3/16/1999
Victor A. McKusick - updated: 1/25/1999
Ada Hamosh - updated: 10/15/1998
Victor A. McKusick - updated: 11/13/1997
Victor A. McKusick - updated: 4/4/1997
Victor A. McKusick - updated: 3/4/1997

*FIELD* CD
Victor A. McKusick: 5/28/1992

*FIELD* ED
carol: 04/11/2013
carol: 12/10/2012
mgross: 9/4/2012
terry: 8/9/2012
mgross: 8/6/2012
terry: 8/3/2012
carol: 5/23/2012
terry: 1/17/2012
alopez: 8/25/2011
alopez: 6/17/2011
wwang: 5/23/2011
ckniffin: 5/10/2011
alopez: 7/1/2010
terry: 6/30/2010
alopez: 9/15/2009
terry: 9/15/2009
alopez: 3/12/2009
terry: 3/10/2009
wwang: 6/18/2008
terry: 6/5/2008
alopez: 3/27/2008
wwang: 6/2/2006
mgross: 4/5/2006
terry: 4/3/2006
carol: 10/3/2005
carol: 9/30/2005
wwang: 7/25/2005
terry: 7/21/2005
carol: 11/17/2004
ckniffin: 11/3/2004
terry: 10/22/2004
tkritzer: 7/7/2004
terry: 7/2/2004
mgross: 4/19/2004
alopez: 4/13/2004
carol: 6/12/2003
ckniffin: 6/6/2003
tkritzer: 5/7/2003
cwells: 5/1/2003
terry: 4/28/2003
alopez: 3/4/2003
terry: 2/27/2003
mgross: 2/21/2003
terry: 2/12/2003
cwells: 1/15/2003
terry: 1/15/2003
terry: 4/22/2002
cwells: 4/17/2002
cwells: 4/15/2002
terry: 4/9/2002
mcapotos: 10/4/2001
mgross: 10/30/2000
mgross: 10/11/2000
terry: 10/2/2000
carol: 6/29/2000
alopez: 6/13/2000
mcapotos: 5/26/2000
mcapotos: 5/25/2000
terry: 5/1/2000
carol: 4/20/2000
terry: 1/19/2000
carol: 10/26/1999
alopez: 5/13/1999
terry: 5/13/1999
alopez: 5/10/1999
mgross: 5/10/1999
mgross: 5/7/1999
terry: 5/4/1999
carol: 4/12/1999
terry: 4/9/1999
carol: 4/2/1999
carol: 3/17/1999
terry: 3/16/1999
mgross: 2/8/1999
terry: 1/25/1999
alopez: 12/18/1998
alopez: 10/15/1998
dkim: 9/11/1998
terry: 5/29/1998
terry: 11/13/1997
terry: 11/12/1997
mark: 7/22/1997
alopez: 7/21/1997
mark: 6/11/1997
jenny: 4/4/1997
terry: 4/1/1997
mark: 3/4/1997
jamie: 3/4/1997
terry: 3/3/1997
mark: 6/25/1996
mark: 10/18/1995
carol: 3/7/1995
carol: 4/6/1993
carol: 11/5/1992
carol: 10/13/1992
carol: 10/7/1992

MIM 601859
*RECORD*
*FIELD* NO
601859
*FIELD* TI
#601859 AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME; ALPS
;;CANALE-SMITH SYNDROME;;
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE I, AUTOSOMAL DOMINANT
read moreAUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IA, INCLUDED; ALPS1A,
INCLUDED;;
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE IB, INCLUDED; ALPS1B,
INCLUDED;;
AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME, TYPE I, AUTOSOMAL RECESSIVE,
INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because autoimmune
lymphoproliferative syndrome (ALPS) type IA is caused by heterozygous
mutation in the FAS gene (TNFRSF6, or CD95; 134637); ALPS type IB is
caused by heterozygous mutation in the FAS ligand (FASL) gene (TNFSF6 or
CD95L; 134638). Both germline and somatic mutations in the FAS gene have
been identified in patients with ALPS type IA.

DESCRIPTION

Autoimmune lymphoproliferative syndrome is a heritable disorder of
apoptosis, resulting in the accumulation of autoreactive lymphocytes. It
manifests in early childhood as nonmalignant lymphadenopathy with
hepatosplenomegaly and autoimmune cytopenias (summary by Dowdell et al.,
2010).

For a review of the autoimmune lymphoproliferative syndromes, see
Teachey et al. (2009).

- Genetic Heterogeneity of Autoimmune Lymphoproliferative
Syndrome

Type IIA ALPS (ALPS2A; 603909) is caused by mutation in the caspase-10
gene (CASP10; 601762). Puck and Straus (2004) designated caspase-8
deficiency (607271), caused by mutations in the CASP8 gene (601763), as
type IIB ALPS. They stated that type III ALPS comprises cases in which a
mutation has not been identified. Type IV ALPS (614470) is caused by
mutation in the NRAS gene (164790).

CLINICAL FEATURES

Canale and Smith (1967) described a childhood syndrome of
lymphadenopathy and splenomegaly associated with autoimmune hemolytic
anemia and thrombocytopenia.

Sneller et al. (1992) reported 2 unrelated girls with a
lymphoproliferative/autoimmune syndrome. The first patient developed
cervical lymphadenopathy at age 18 months and anemia associated with
splenomegaly at age 24 months. Over the next months, she developed renal
insufficiency, and a renal biopsy showed mesangiopathic
glomerulonephritis with crescent formation. Serologic studies for
infectious etiology, including EBV, CMV, toxoplasmosis, HIV, brucella,
and hepatitis were all negative. The second patient was diagnosed with
autoimmune hemolytic anemia at age 9 months with a positive direct
Coomb's test. At age 4 years, she developed peripheral lymphadenopathy,
and CT scan at age 8 years showed hepatomegaly and mediastinal,
mesenteric, and retroperitoneal adenopathy. Peripheral blood analysis
showed that both patients had increased numbers of B lymphocytes and
increased numbers of mature CD3+, CD4-, CD8- T lymphocytes expressing
alpha/beta T-cell receptors; these T cells accounted for 40 to 60% of
all T cells. Neither lymphocyte population was monoclonal. Lymph node
biopsy showed paracortical infiltration of the CD4-, CD8- T cells.
Sneller et al. (1992) noted that the phenotype in these girls was
similar to that of lpr (see 134637) and gld (see 134638) mice.

Fisher et al. (1995) reported 4 unrelated children with ALPS who
presented with nonmalignant lymphadenopathy or splenomegaly between 2
months and 5 years of age. All patients had autoimmune hemolytic anemia,
thrombocytopenia, and recurrent urticarial rashes consistent with immune
vasculitis. Peripheral blood analysis showed hypergammaglobulinemia and
expanded populations of CD3+, CD4-, CD8- T lymphocytes in all patients.
In vitro studies showed that the expanded T lymphocyte population had
impaired TCR-induced apoptosis. Fisher et al. (1995) concluded that the
disorder was caused by impaired control of mature lymphocyte
homeostasis.

Drappa et al. (1996) provided follow-up on 2 patients reported by Canale
and Smith (1967). One patient was a 43-year-old woman who had continued
lymphadenopathy and hypergammaglobulinemia throughout her life. She also
had several neoplastic lesions, including a breast adenoma, 3 thyroid
adenomas, and 2 basal cell carcinomas. Another patient was a 43-year-old
man whose lymphadenopathy had gradually diminished during adolescence
and was mild during adulthood. He died of hepatocellular carcinoma
associated with hepatitis C infection. The patient's son had
lymphadenopathy with T-cell hyperplasia and autoimmune hemolytic anemia
and thrombocytopenia. Activated T cells from the patients were almost
completely resistant to apoptosis induced by ligating the Fas receptor
with an anti-Fas antibody. The findings indicated that ALPS is
compatible with long-term survival. Sneller et al. (1997) reported 9
unrelated patients with ALPS characterized by moderate to massive
splenomegaly and lymphadenopathy, hypergammaglobulinemia, autoimmunity,
B-cell lymphocytosis, and the expansion of an unusual population of
CD3+, CD4-, CD8- T cells. Hemolytic anemia was the most frequent form of
autoimmune disease, occurring in 6 patients with or without idiopathic
thrombocytopenic purpura. All patients showed defective lymphocyte
apoptosis in vitro. Heterozygous mutations of the FAS gene were detected
in 8 patients, and 7 of 8 kindreds had healthy relatives with FAS
mutations. These relatives also showed in vitro abnormalities of
FAS-mediated lymphocyte apoptosis, but clinical features of ALPS were
not present. In 1 ALPS patient, no FAS or FASL gene mutations were
identified, and Sneller et al. (1997) proposed the designation ALPS type
II to refer to the syndrome in the absence of mutations in these genes.

Van der Burg et al. (2000) reported a girl, born of consanguineous
parents, who presented immediately after birth with petechiae,
generalized edema, and hepatosplenomegaly. During the first month of
life, autoantibodies against red blood cells and platelets were
demonstrated. A liver biopsy showed extensive extramedullary
hematopoiesis, and she had massive generalized adenopathy of the
cervical, mesenteric, and paraaortic lymph nodes. Hypergammaglobulinemia
persisted for several years; a cutaneous lupus-like disease appeared at
a later stage. The patient had histologically malignant lymph nodes,
although monoclonal or oligoclonal rearrangements could not be detected
on analysis of the gene encoding the T-cell antigen receptor beta
subunit (TCRB; see 186930). There was no detectable FAS expression on
freshly isolated blood leukocytes.

OTHER FEATURES

Straus et al. (1997) stated that their experience with over 20 patients
with ALPS from 13 kindreds indicated a wider clinical spectrum than that
described by Canale and Smith (1967) or by Drappa et al. (1996),
including Guillain-Barre syndrome (139393) and panniculitis. In
addition, Straus et al. (1997) noted that B-lymphomas developed in early
adulthood in 2 brothers with FAS mutations. Four different patients with
ALPS had normal FAS and FASL genes, but impaired apoptosis caused by an
abnormality in the FAS pathway, suggesting that abnormalities of other
proteins in the FAS-signaling cascade or in parallel apoptotic pathways
may also cause ALPS.

Straus et al. (2001) found that 130 individuals in 39 families
segregating ALPS had heterozygous germline FAS mutations. Eleven B-cell
and T-cell lymphomas of diverse types developed in 10 individuals with
mutations in 8 families, up to 48 years after lymphoproliferation was
first documented. Their risk of non-Hodgkin and Hodgkin lymphomas,
respectively, was 14 and 51 times greater than expected. All 10 patients
with FAS mutations had defective lymphocyte apoptosis and most had other
features of ALPS. The average age of ALPS onset was 5 years, whereas the
average age of lymphoma diagnosis was 28 years. The cases in which
somatic alterations in FAS were described in lymphomas (e.g., Gronbaek
et al., 1998) more typically arose later in life. Straus et al. (2001)
stated that the mechanism by which FAS defects in ALPS predispose to
lymphomas might involve several components. They suggested that the most
obvious possibility is that a general expansion of the lymphoid pool
provides a larger target cell population for other transforming events.

Lim et al. (2005) reported a case of bilateral uveitis in an 8-year old
child with ALPS1A. The authors concluded that despite a Th2 immune
predominance in ALPS, uveitis, a Th1-mediated disease, might still
manifest in these patients. They hypothesized that the pathogenesis of
uveitis in ALPS might differ from that of the systemic disease overall.

INHERITANCE

ALPS is most often transmitted in an autosomal dominant manner. However,
autosomal recessive inheritance of ALPS1A due to homozygous or compound
heterozygous mutations in the FAS gene has been described. In addition,
up to one-third of patients can have somatic mutations in the FAS gene
(Dowdell et al., 2010),

In a girl with severe ALPS1A, born of consanguineous parents, van der
Burg et al. (2000) identified a homozygous 20-bp duplication in the FAS
gene (134637.0013). The findings indicated that the disorder can be
autosomal recessive. Van der Burg et al. (2000) noted that Rieux-Laucat
et al. (1995) and Bettinardi et al. (1997) had reported similar patients
with 2 FAS gene mutations (see 134637.0006 and 134637.0007).

MOLECULAR GENETICS

- ALPS1A Due to Mutations in the FAS Gene

In 5 unrelated patients with ALPS1A, 1 of whom was reported by Sneller
et al. (1992), Fisher et al. (1995) identified heterozygous mutations in
the FAS gene (134637.0001-134637.0005).

In 2 patients with ALPS1A first reported by Canale and Smith (1967),
Drappa et al. (1996) identified heterozygous mutations in the FAS gene
(134637.0019; 134637.0020).

In a girl with severe ALPS1A, born of consanguineous parents, van der
Burg et al. (2000) identified a homozygous 20-bp duplication in the FAS
gene (134637.0013).

Holzelova et al. (2004) reported 6 children with an unusual form of
ALPS, characterized by elevated numbers of double-negative T cells and
hypergammaglobulinemia, but normal Fas-mediated apoptosis of T cells in
vitro. Double-negative T cells from all 6 patients showed heterozygous
mutations in the FAS gene (see, e.g., 134637.0018). In 2 affected
patients, FAS mutations were found in a fraction of CD4+ and CD8+ T
cells, monocytes, and CD34+ hematopoietic precursors, but not in hair or
mucosal epithelial cells, demonstrating somatic mosaicism.

Dowdell et al. (2010) found that 12 (38.7%) of 31 ALPS patients who were
negative for germline FAS mutations carried heterozygous somatic FAS
mutations in their double-negative T cells. All of the 12 somatic
mutations resulted in known or predicted functional loss of normal FAS
signaling; 10 mutations led to a premature stop codon. Patients with
somatic FAS mutations were clinically similar to those with germline FAS
mutations, although they had a slightly lower incidence of splenectomy
and lower lymphocyte counts.

- ALPS1B Due to Mutations in the FASL Gene

Wu et al. (1996) reported an African American man with systemic lupus
erythematosus (SLE; 152700) and lymphadenopathy who had a heterozygous
mutation in the FASL gene (134638.0001). Peripheral blood mononuclear
cells from this patient showed decreased FASL activity, decreased
activation-induced cell death, and increased T-cell proliferation after
activation. Although the patient did not have increased numbers of CD4-,
CD8- T cells, Wu et al. (1996) suggested that the lymphadenopathy and
autoimmune disease were consistent with an adult type of ALPS. Lenardo
(1999) noted that although this patient satisfied the rheumatologic
criteria for a diagnosis of SLE, the features were more consistent with
ALPS.

NOMENCLATURE

Vaishnaw et al. (1997) urged the use of the eponym 'Canale-Smith
syndrome.' They argued that the term 'lymphoproliferative syndrome'
connotes malignancy, but that lymphadenopathy associated with FAS
mutations results primarily from the accumulation of lymphocytes due to
the failure of FAS-mediated apoptosis.

ANIMAL MODEL

Krammer (2000) and Nagata (1998) pointed out that the recessive
lymphoproliferation (lpr) phenotype and the generalized
lymphoproliferative disease (gld) phenotype are mouse models of aberrant
T-cell accumulation. In lpr mice, a splicing defect in the Fas gene
results in greatly decreased expression of Fas. In mice with the lpr/cg
(complementing gld) allele, a point mutation in the intracellular death
domain of Fas abolishes the transmission of the apoptotic signal. In gld
mice, a point mutation in the C terminus of Fasl impairs its ability to
interact successfully with its receptor. These mutations lead to a
failure of apoptosis and complex immune disorders in lpr and gld mutant
mice that are analogous to the human disorders ALPS1A and ALPS1B.

*FIELD* RF
1. Bettinardi, A.; Brugnoni, D.; Quiros-Roldan, E.; Malagoli, A.;
La Grutta, S.; Correra, A.; Notarangelo, L. D.: Missense mutations
in the Fas gene resulting in autoimmune lymphoproliferative syndrome:
a molecular and immunological analysis. Blood 89: 902-909, 1997.

2. Canale, V. C.; Smith, C. H.: Chronic lymphadenopathy simulating
malignant lymphoma. J. Pediat. 70: 891-899, 1967.

3. Dowdell, K. C.; Niemela, J. E.; Price, S.; Davis, J.; Hornung,
R. L.; Oliveira, J. B.; Puck, J. M.; Jaffe, E. S.; Pittaluga, S.;
Cohen, J. I.; Fleisher, T. A.; Rao, V. K.: Somatic FAS mutations
are common in patients with genetically undefined autoimmune lymphoproliferative
syndrome. Blood 115: 5164-5169, 2010.

4. Drappa, J.; Vaishnaw, A. K.; Sullivan, K. E.; Chu, J.-L.; Elkon,
K. B.: Fas gene mutations in the Canale-Smith syndrome, an inherited
lymphoproliferative disorder associated with autoimmunity. New Eng.
J. Med. 335: 1643-1649, 1996.

5. Fisher, G. H.; Rosenberg, F. J.; Straus, S. E.; Dale, J. K.; Middelton,
L. A.; Lin, A. Y.; Strober, W.; Lenardo, M. J.; Puck, J. M.: Dominant
interfering Fas gene mutations impair apoptosis in a human autoimmune
lymphoproliferative syndrome. Cell 81: 935-946, 1995.

6. Gronbaek, K.; Straten, P.; Ralfkiaer, E.; Ahrenkiel, V.; Andersen,
M. K.; Hansen, N. E.; Zeuthen, J.; Hou-Jensen, K.; Guldberg, P.:
Somatic Fas mutations in non-Hodgkin's lymphoma: association with
extranodal disease and autoimmunity. Blood 92: 3018-3024, 1998.

7. Holzelova, E.; Vonarbourg, C.; Stolzenberg, M.-C.; Arkwright, P.
D.; Selz, F.; Prieur, A.-M.; Blanche, S.; Bartunkova, J.; Vilmer,
E.; Fischer, A.; Le Deist, F.; Rieux-Laucat, F.: Autoimmune lymphoproliferative
syndrome with somatic Fas mutations. New Eng. J. Med. 351: 1409-1418,
2004.

8. Krammer, P. H.: CD95's deadly mission in the immune system. Nature 407:
789-795, 2000.

9. Lenardo, M. J.: Personal Communication. Bethesda, Md. 1/14/1999.

10. Lim, W.-K.; Ursea, R.; Rao, K.; Buggage, R. R.; Suhler, E. B.;
Dugan, F.; Chan, C.-C.; Straus, S. E.; Nussenblatt, R. B.: Bilateral
uveitis in a patient with autoimmune lymphoproliferative syndrome. Am.
J. Ophthal. 139: 562-563, 2005.

11. Nagata, S.: Human autoimmune lymphoproliferative syndrome, a
defect in the apoptosis-inducing Fas receptor: a lesson from the mouse
model. J. Hum. Genet. 43: 2-8, 1998.

12. Puck, J. M.; Straus, S. E.: Somatic mutations--not just for cancer
anymore. New Eng. J. Med. 351: 1388-1390, 2004.

13. Rieux-Laucat, F.; Le Deist, F.; Hivroz, C.; Roberts, I. A. G.;
Debatin, K. M.; Fischer, A.; de Villartay, J. P.: Mutations in Fas
associated with human lymphoproliferative syndrome and autoimmunity. Science 268:
1347-1349, 1995.

14. Sneller, M. C.; Straus, S. E.; Jaffe, E. S.; Jaffe, J. S.; Fleisher,
T. A.; Stetler-Stevenson, M.; Strober, W.: A novel lymphoproliferative/autoimmune
syndrome resembling murine lpr/gld disease. J. Clin. Invest. 90:
334-341, 1992.

15. Sneller, M. C.; Wang, J.; Dale, J. K.; Strober, W.; Middleton,
L. A.; Choi, Y.; Fleisher, T. A.; Lim, M. S.; Jaffe, E. S.; Puck,
J. M.; Lenardo, M. J.; Straus, S. E.: Clinical, immunologic, and
genetic features of an autoimmune lymphoproliferative syndrome associated
with abnormal lymphocyte apoptosis. Blood 89: 1341-1348, 1997.

16. Straus, S. E.; Jaffe, E. S.; Puck, J. M.; Dale, J. K.; Elkon,
K. B.; Rosen-Wolff, A.; Peters, A. M. J.; Sneller, M. C.; Hallahan,
C. W.; Wang, J.; Fischer, R. E.; Jackson, C. M.; Lin, A. Y.; Baumler,
C.; Siegert, E.; Marx, A.; Vaishnaw, A. K.; Grodzicky, T.; Fleisher,
T. A.; Lenardo, M. J.: The development of lymphomas in families with
autoimmune lymphoproliferative syndrome with germline Fas mutations
and defective lymphocyte apoptosis. Blood 98: 194-200, 2001.

17. Straus, S. E.; Lenardo, M.; Puck, J. M.: The Canale-Smith syndrome.
(Letter) New Eng. J. Med. 336: 1457 only, 1997.

18. Teachey, D. T.; Seif, A. E.; Grupp, S. A.: Advances in the management
and understanding of autoimmune lymphoproliferative syndrome (ALPS). Brit.
J. Haemat. 148: 205-216, 2009.

19. Vaishnaw, A. K.; Sullivan, K. E.; Elkon, K. B.: Reply to S. E.
Straus. (Letter) New Eng. J. Med. 336: 1457-1458, 1997.

20. van der Burg, M.; de Groot, R.; Comans-Bitter, W. M.; den Hollander,
J. C.; Hooijkaas, H.; Neijens, H. J.; Berger, R. M. F.; Oranje, A.
P.; Langerak, A. W.; van Dongen, J. J. M.: Autoimmune lymphoproliferative
syndrome (ALPS) in a child from consanguineous parents: a dominant
or recessive disease? Pediat. Res. 47: 336-343, 2000.

21. Wu, J.; Wilson, J.; He, J.; Xiang, L.; Schur, P. H.; Mountz, J.
D.: Fas ligand mutation in a patient with systemic lupus erythematosus
and lymphoproliferative disease. J. Clin. Invest. 98: 1107-1113,
1996.

*FIELD* CS
INHERITANCE:
Autosomal dominant

ABDOMEN:
[Liver];
Hepatomegaly;
[Spleen];
Splenomegaly

SKIN, NAILS, HAIR:
[Skin];
Urticaria;
Vasculitis rash

HEMATOLOGY:
Autoimmune hemolytic anemia;
Iron deficiency anemia;
Autoimmune thrombocytopenia;
Autoimmune neutropenia;
Eosinophilia

IMMUNOLOGY:
Defective lymphocyte apoptosis;
Chronic noninfectious lymphadenopathy;
Increased number of peripheral CD3+ T cells;
Increased number of CD4-/CD8- T cells expressing alpha/beta T-cell
receptors;
Increased proportion of HLA DR+ and CD57+ T cells;
Reduced delayed hypersensitivity;
Lymph nodes show florid reactive follicular hyperplasia and marked
paracortical expansion with immunoblasts and plasma cells

NEOPLASIA:
Increased risk of malignant lymphoma

LABORATORY ABNORMALITIES:
Increased levels of IgG;
Increased levels of IgA;
Increased levels of IgM;
Direct Coombs positive;
Platelet antibody positive;
Neutrophil antibody positive;
Phospholipid antibody positive;
Smooth muscle antibody positive;
Rheumatoid factor positive;
Antinuclear antibody positive;
Increased interleukin 10;
Elevated levels of vitamin B12

MISCELLANEOUS:
Onset in early childhood;
Recessive inheritance has been reported

MOLECULAR BASIS:
Caused by mutation in the Fas antigen gene (FAS, 134637.0001);
Caused by mutation in the Fas ligand gene (FASL, 134638.0001)

*FIELD* CN
Cassandra L. Kniffin - updated: 5/10/2011
Ada Hamosh - reviewed: 1/4/2001

*FIELD* CD
Assil Saleh: 8/25/2000

*FIELD* ED
joanna: 06/05/2012
ckniffin: 5/10/2011
joanna: 1/4/2001
kayiaros: 8/25/2000

*FIELD* CN
Cassandra L. Kniffin - updated: 5/10/2011
Jane Kelly - updated: 7/1/2005
Cassandra L. Kniffin - reorganized: 11/17/2004
Victor A. McKusick - updated: 9/20/2001
Paul J. Converse - updated: 10/11/2000
Victor A. McKusick - updated: 5/3/1999
Victor A. McKusick - updated: 3/16/1999
Victor A. McKusick - updated: 6/16/1997

*FIELD* CD
Victor A. McKusick: 6/11/1997

*FIELD* ED
mgross: 10/07/2013
carol: 2/6/2012
wwang: 5/23/2011
ckniffin: 5/10/2011
wwang: 1/30/2008
ckniffin: 12/20/2007
carol: 1/20/2006
alopez: 7/1/2005
carol: 11/17/2004
ckniffin: 11/3/2004
mcapotos: 12/20/2001
mcapotos: 9/27/2001
mcapotos: 9/21/2001
terry: 9/20/2001
alopez: 10/11/2000
carol: 10/27/1999
mgross: 6/21/1999
mgross: 6/16/1999
terry: 5/20/1999
mgross: 5/10/1999
terry: 5/3/1999
carol: 3/17/1999
terry: 3/16/1999
dkim: 7/24/1998
terry: 11/7/1997
alopez: 6/17/1997
alopez: 6/16/1997
mark: 6/11/1997