RBCC Red Blood Cell Collection

TNFRSF1A (TNFAR, TNFR1) [Confidence: high (a blood group or CD marker)]
Tumor necrosis factor receptor superfamily member 1A (Tumor necrosis factor receptor 1; TNF-R1; Tumor necrosis factor receptor type I; TNF-RI; TNFR-I; p55; p60; CD120a; Tumor necrosis factor receptor superfamily member 1A, membrane form; Tumor necrosis factor-binding protein 1; TBPI; Flags: Precursor)

UniProt P19438
ID TNR1A_HUMAN Reviewed; 455 AA.
AC P19438; A8K4X3; B2RDE4; B3KPQ1; B4DQB7; B4E309; B5M0B5; D3DUR1;
read moreAC Q9UCA4;
DT 01-FEB-1991, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1991, sequence version 1.
DT 22-JAN-2014, entry version 181.
DE RecName: Full=Tumor necrosis factor receptor superfamily member 1A;
DE AltName: Full=Tumor necrosis factor receptor 1;
DE Short=TNF-R1;
DE AltName: Full=Tumor necrosis factor receptor type I;
DE Short=TNF-RI;
DE Short=TNFR-I;
DE AltName: Full=p55;
DE AltName: Full=p60;
DE AltName: CD_antigen=CD120a;
DE Contains:
DE RecName: Full=Tumor necrosis factor receptor superfamily member 1A, membrane form;
DE Contains:
DE RecName: Full=Tumor necrosis factor-binding protein 1;
DE Short=TBPI;
DE Flags: Precursor;
GN Name=TNFRSF1A; Synonyms=TNFAR, TNFR1;
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=2158862; DOI=10.1016/0092-8674(90)90815-V;
RA Loetscher H., Pan Y.-C.E., Lahm H.-W., Gentz R., Brockhaus M.,
RA Tabuchi H., Lesslauer W.;
RT "Molecular cloning and expression of the human 55 kd tumor necrosis
RT factor receptor.";
RL Cell 61:351-359(1990).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=2158863; DOI=10.1016/0092-8674(90)90816-W;
RA Schall T.J., Lewis M., Koller K.J., Lee A., Rice G.C., Wong G.H.W.,
RA Getanaga T., Granger G.A., Lentz R., Raab H., Kohr W.J., Goeddel D.V.;
RT "Molecular cloning and expression of a receptor for human tumor
RT necrosis factor.";
RL Cell 61:361-370(1990).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RX PubMed=1702293; DOI=10.1089/dna.1990.9.705;
RA Himmler A., Maurer-Fogy I., Kroenke M., Scheurich P., Pfizenmaier K.,
RA Lantz M., Olsson I., Hauptmann R., Stratowa C., Adolf G.R.;
RT "Molecular cloning and expression of human and rat tumor necrosis
RT factor receptor chain (p60) and its soluble derivative, tumor necrosis
RT factor-binding protein.";
RL DNA Cell Biol. 9:705-715(1990).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND PROTEIN SEQUENCE OF 41-53;
RP 110-124 AND 199-201 (ISOFORM 1).
RX PubMed=1698610;
RA Nophar Y., Kemper O., Brakebusch C., Engelmann H., Zwang R.,
RA Aderka D., Holtmann H., Wallach D.;
RT "Soluble forms of tumor necrosis factor receptors (TNF-Rs). The cDNA
RT for the type I TNF-R, cloned using amino acid sequence data of its
RT soluble form, encodes both the cell surface and a soluble form of the
RT receptor.";
RL EMBO J. 9:3269-3278(1990).
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC TISSUE=Placenta;
RX PubMed=2170974; DOI=10.1073/pnas.87.19.7380;
RA Gray P.W., Barrett K., Chantry D., Turner M., Feldman M.;
RT "Cloning of human tumor necrosis factor (TNF) receptor cDNA and
RT expression of recombinant soluble TNF-binding protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:7380-7384(1990).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=1315717; DOI=10.1016/0888-7543(92)90226-I;
RA Fuchs P., Strehl S., Dworzak M., Himmler A., Ambros P.F.;
RT "Structure of the human TNF receptor 1 (p60) gene (TNFR1) and
RT localization to chromosome 12p13.";
RL Genomics 13:219-224(1992).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS LEU-75 AND GLN-121.
RG SeattleSNPs variation discovery resource;
RL Submitted (JUL-2002) to the EMBL/GenBank/DDBJ databases.
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1; 2 AND 3).
RC TISSUE=Neutrophil, Teratocarcinoma, Tongue, and Uterus;
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 [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 5).
RX PubMed=19906316; DOI=10.1186/1471-2164-10-518;
RA Wang P., Yu P., Gao P., Shi T., Ma D.;
RT "Discovery of novel human transcript variants by analysis of intronic
RT single-block EST with polyadenylation site.";
RL BMC Genomics 10:518-518(2009).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16541075; DOI=10.1038/nature04569;
RA Scherer S.E., Muzny D.M., Buhay C.J., Chen R., Cree A., Ding Y.,
RA Dugan-Rocha S., Gill R., Gunaratne P., Harris R.A., Hawes A.C.,
RA Hernandez J., Hodgson A.V., Hume J., Jackson A., Khan Z.M.,
RA Kovar-Smith C., Lewis L.R., Lozado R.J., Metzker M.L.,
RA Milosavljevic A., Miner G.R., Montgomery K.T., Morgan M.B.,
RA Nazareth L.V., Scott G., Sodergren E., Song X.-Z., Steffen D.,
RA Lovering R.C., Wheeler D.A., Worley K.C., Yuan Y., Zhang Z.,
RA Adams C.Q., Ansari-Lari M.A., Ayele M., Brown M.J., Chen G., Chen Z.,
RA Clerc-Blankenburg K.P., Davis C., Delgado O., Dinh H.H., Draper H.,
RA Gonzalez-Garay M.L., Havlak P., Jackson L.R., Jacob L.S., Kelly S.H.,
RA Li L., Li Z., Liu J., Liu W., Lu J., Maheshwari M., Nguyen B.-V.,
RA Okwuonu G.O., Pasternak S., Perez L.M., Plopper F.J.H., Santibanez J.,
RA Shen H., Tabor P.E., Verduzco D., Waldron L., Wang Q., Williams G.A.,
RA Zhang J., Zhou J., Allen C.C., Amin A.G., Anyalebechi V., Bailey M.,
RA Barbaria J.A., Bimage K.E., Bryant N.P., Burch P.E., Burkett C.E.,
RA Burrell K.L., Calderon E., Cardenas V., Carter K., Casias K.,
RA Cavazos I., Cavazos S.R., Ceasar H., Chacko J., Chan S.N., Chavez D.,
RA Christopoulos C., Chu J., Cockrell R., Cox C.D., Dang M.,
RA Dathorne S.R., David R., Davis C.M., Davy-Carroll L., Deshazo D.R.,
RA Donlin J.E., D'Souza L., Eaves K.A., Egan A., Emery-Cohen A.J.,
RA Escotto M., Flagg N., Forbes L.D., Gabisi A.M., Garza M., Hamilton C.,
RA Henderson N., Hernandez O., Hines S., Hogues M.E., Huang M.,
RA Idlebird D.G., Johnson R., Jolivet A., Jones S., Kagan R., King L.M.,
RA Leal B., Lebow H., Lee S., LeVan J.M., Lewis L.C., London P.,
RA Lorensuhewa L.M., Loulseged H., Lovett D.A., Lucier A., Lucier R.L.,
RA Ma J., Madu R.C., Mapua P., Martindale A.D., Martinez E., Massey E.,
RA Mawhiney S., Meador M.G., Mendez S., Mercado C., Mercado I.C.,
RA Merritt C.E., Miner Z.L., Minja E., Mitchell T., Mohabbat F.,
RA Mohabbat K., Montgomery B., Moore N., Morris S., Munidasa M.,
RA Ngo R.N., Nguyen N.B., Nickerson E., Nwaokelemeh O.O., Nwokenkwo S.,
RA Obregon M., Oguh M., Oragunye N., Oviedo R.J., Parish B.J.,
RA Parker D.N., Parrish J., Parks K.L., Paul H.A., Payton B.A., Perez A.,
RA Perrin W., Pickens A., Primus E.L., Pu L.-L., Puazo M., Quiles M.M.,
RA Quiroz J.B., Rabata D., Reeves K., Ruiz S.J., Shao H., Sisson I.,
RA Sonaike T., Sorelle R.P., Sutton A.E., Svatek A.F., Svetz L.A.,
RA Tamerisa K.S., Taylor T.R., Teague B., Thomas N., Thorn R.D.,
RA Trejos Z.Y., Trevino B.K., Ukegbu O.N., Urban J.B., Vasquez L.I.,
RA Vera V.A., Villasana D.M., Wang L., Ward-Moore S., Warren J.T.,
RA Wei X., White F., Williamson A.L., Wleczyk R., Wooden H.S.,
RA Wooden S.H., Yen J., Yoon L., Yoon V., Zorrilla S.E., Nelson D.,
RA Kucherlapati R., Weinstock G., Gibbs R.A.;
RT "The finished DNA sequence of human chromosome 12.";
RL Nature 440:346-351(2006).
RN [11]
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 [12]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Muscle;
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 [13]
RP PROTEIN SEQUENCE OF 41-57 (ISOFORM 1).
RC TISSUE=Urine;
RX PubMed=8015639;
RA Suzuki J., Tomizawa S., Arai H., Seki Y., Maruyama K., Kuroume T.;
RT "Purification of two types of TNF inhibitors in the urine of the
RT patient with chronic glomerulonephritis.";
RL Nephron 66:386-390(1994).
RN [14]
RP PROTEIN SEQUENCE OF 41-45 (ISOFORM 1).
RX PubMed=2153136;
RA Engelmann H., Novick D., Wallach D.;
RT "Two tumor necrosis factor-binding proteins purified from human urine.
RT Evidence for immunological cross-reactivity with cell surface tumor
RT necrosis factor receptors.";
RL J. Biol. Chem. 265:1531-1536(1990).
RN [15]
RP INTERACTION WITH HCV CORE PROTEIN.
RX PubMed=9557650;
RA Zhu N., Khoshnan A., Schneider R., Matsumoto M., Dennert G.,
RA Ware C.F., Lai M.M.C.;
RT "Hepatitis C virus core protein binds to the cytoplasmic domain of
RT tumor necrosis factor (TNF) receptor 1 and enhances TNF-induced
RT apoptosis.";
RL J. Virol. 72:3691-3697(1998).
RN [16]
RP INTERACTION WITH RIPK1 AND SQSTM1.
RX PubMed=10356400; DOI=10.1093/emboj/18.11.3044;
RA Sanz L., Sanchez P., Lallena M.-J., Diaz-Meco M.T., Moscat J.;
RT "The interaction of p62 with RIP links the atypical PKCs to NF-kappaB
RT activation.";
RL EMBO J. 18:3044-3053(1999).
RN [17]
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 [18]
RP INTERACTION WITH GRB2.
RX PubMed=10359574; DOI=10.1084/jem.189.11.1707;
RA Hildt E., Oess S.;
RT "Identification of Grb2 as a novel binding partner of tumor necrosis
RT factor (TNF) receptor I.";
RL J. Exp. Med. 189:1707-1714(1999).
RN [19]
RP INTERACTION WITH BAG4.
RX PubMed=9915703; DOI=10.1126/science.283.5401.543;
RA Jiang Y., Woronicz J.D., Liu W., Goeddel D.V.;
RT "Prevention of constitutive TNF receptor 1 signaling by silencer of
RT death domains.";
RL Science 283:543-546(1999).
RN [20]
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 [21]
RP INTERACTION WITH HHV-5 PROTEIN UL138.
RX PubMed=21976655; DOI=10.1128/JVI.06005-11;
RA Le V.T., Trilling M., Hengel H.;
RT "The cytomegaloviral protein pUL138 acts as potentiator of tumor
RT necrosis factor (TNF) receptor 1 surface density to enhance ULb'-
RT encoded modulation of TNF-alpha signaling.";
RL J. Virol. 85:13260-13270(2011).
RN [22]
RP INVOLVEMENT IN MS5, SUBCELLULAR LOCATION, AND ALTERNATIVE SPLICING
RP (ISOFORM 4).
RX PubMed=22801493; DOI=10.1038/nature11307;
RA Gregory A.P., Dendrou C.A., Attfield K.E., Haghikia A., Xifara D.K.,
RA Butter F., Poschmann G., Kaur G., Lambert L., Leach O.A., Promel S.,
RA Punwani D., Felce J.H., Davis S.J., Gold R., Nielsen F.C.,
RA Siegel R.M., Mann M., Bell J.I., McVean G., Fugger L.;
RT "TNF receptor 1 genetic risk mirrors outcome of anti-TNF therapy in
RT multiple sclerosis.";
RL Nature 488:508-511(2012).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (2.85 ANGSTROMS) OF 30-211 IN COMPLEX WITH TNFB.
RX PubMed=8387891; DOI=10.1016/0092-8674(93)90132-A;
RA Banner D.W., D'Arcy A., Janes W., Gentz R., Schoenfeld H.-J.,
RA Broger C., Loetscher H., Lesslauer W.;
RT "Crystal structure of the soluble human 55 kd TNF receptor-human TNF
RT beta complex: implications for TNF receptor activation.";
RL Cell 73:431-445(1993).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 41-202.
RX PubMed=8939750; DOI=10.1016/S0969-2126(96)00134-7;
RA Naismith J.H., Devine T.Q., Khono H., Sprang S.R.;
RT "Structures of the extracellular domain of the type I tumor necrosis
RT factor receptor.";
RL Structure 4:1251-1262(1996).
RN [25]
RP VARIANTS FHF ARG-59; TYR-62; MET-79; PHE-81; ARG-117 AND TYR-117.
RX PubMed=10199409; DOI=10.1016/S0092-8674(00)80721-7;
RA McDermott M.F., Aksentijevich I., Galon J., McDermott E.M.,
RA Ogunkolade B.W., Centola M., Mansfield E., Gadina M., Karenko L.,
RA Pettersson T., McCarthy J., Frucht D.M., Aringer M., Torosyan Y.,
RA Teppo A.-M., Wilson M., Karaarslan H.M., Wan Y., Todd I., Wood G.,
RA Schlimgen R., Kumarajeewa T.R., Cooper S.M., Vella J.P., Amos C.I.,
RA Mulley J., Quane K.A., Molloy M.G., Rnaki A., Powell R.J.,
RA Hitman G.A., O'Shea J., Kastner D.L.;
RT "Germline mutations in the extracellular domains of the 55 kDa TNF
RT receptor, TNFR1, define a family of dominantly inherited
RT autoinflammatory syndromes.";
RL Cell 97:133-144(1999).
RN [26]
RP VARIANT FHF SER-59.
RX PubMed=10902757;
RX DOI=10.1002/1529-0131(200007)43:7<1535::AID-ANR18>3.3.CO;2-3;
RA Dode C., Papo T., Fieschi C., Pecheux C., Dion E., Picard F.,
RA Godeau P., Bienvenu J., Piette J.-C., Delpech M., Grateau G.;
RT "A novel missense mutation (C30S) in the gene encoding tumor necrosis
RT factor receptor 1 linked to autosomal-dominant recurrent fever with
RT localized myositis in a French family.";
RL Arthritis Rheum. 43:1535-1542(2000).
RN [27]
RP VARIANTS FHF GLN-51; SER-59; GLY-62; LEU-75; GLY-115 AND GLN-121.
RX PubMed=11443543; DOI=10.1086/321976;
RA Aksentijevich I., Galon J., Soares M., Mansfield E., Hull K.,
RA Oh H.-H., Goldbach-Mansky R., Dean J., Athreya B., Reginato A.J.,
RA Henrickson M., Pons-Estel B., O'Shea J.J., Kastner D.L.;
RT "The tumor-necrosis-factor receptor-associated periodic syndrome: new
RT mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies,
RT and evidence for further genetic heterogeneity of periodic fevers.";
RL Am. J. Hum. Genet. 69:301-314(2001).
RN [28]
RP VARIANTS FHF SER-99 AND PRO-121.
RX PubMed=13130484; DOI=10.1002/art.11215;
RA Aganna E., Hammond L., Hawkins P.N., Aldea A., McKee S.A.,
RA Ploos van Amstel H.K., Mischung C., Kusuhara K., Saulsbury F.T.,
RA Lachmann H.J., Bybee A., McDermott E.M., La Regina M., Arostegui J.I.,
RA Campistol J.M., Worthington S., High K.P., Molloy M.G., Baker N.,
RA Bidwell J.L., Castaner J.L., Whiteford M.L., Janssens-Korpola P.L.,
RA Manna R., Powell R.J., Woo P., Solis P., Minden K., Frenkel J.,
RA Yague J., Mirakian R.M., Hitman G.A., McDermott M.F.;
RT "Heterogeneity among patients with tumor necrosis factor receptor-
RT associated periodic syndrome phenotypes.";
RL Arthritis Rheum. 48:2632-2644(2003).
RN [29]
RP VARIANT FHF SER-99.
RX PubMed=14610673; DOI=10.1007/s00431-003-1338-0;
RA Kusuhara K., Nomura A., Nakao F., Hara T.;
RT "Tumour necrosis factor receptor-associated periodic syndrome with a
RT novel mutation in the TNFRSF1A gene in a Japanese family.";
RL Eur. J. Pediatr. 163:30-32(2004).
CC -!- FUNCTION: Receptor for TNFSF2/TNF-alpha and homotrimeric
CC TNFSF1/lymphotoxin-alpha. The adapter molecule FADD recruits
CC caspase-8 to the activated receptor. The resulting death-inducing
CC signaling complex (DISC) performs caspase-8 proteolytic activation
CC which initiates the subsequent cascade of caspases (aspartate-
CC specific cysteine proteases) mediating apoptosis. Contributes to
CC the induction of non-cytocidal TNF effects including anti-viral
CC state and activation of the acid sphingomyelinase.
CC -!- SUBUNIT: Binding of TNF to the extracellular domain leads to
CC homotrimerization. The aggregated death domains provide a novel
CC molecular interface that interacts specifically with the death
CC domain of TRADD. Various TRADD-interacting proteins such as TRAFS,
CC RIPK1 and possibly FADD, are recruited to the complex by their
CC association with TRADD. This complex activates at least two
CC distinct signaling cascades, apoptosis and NF-kappa-B signaling.
CC Interacts with BAG4, BRE, FEM1B, GRB2, SQSTM1 and TRPC4AP.
CC Interacts with HCV core protein. Interacts with human
CC cytomegalovirus/HHV-5 protein UL138.
CC -!- INTERACTION:
CC P28799:GRN; NbExp=4; IntAct=EBI-299451, EBI-747754;
CC Q13546:RIPK1; NbExp=6; IntAct=EBI-299451, EBI-358507;
CC P01375:TNF; NbExp=7; IntAct=EBI-299451, EBI-359977;
CC Q15628:TRADD; NbExp=11; IntAct=EBI-299451, EBI-359215;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Single-pass type I membrane
CC protein. Golgi apparatus membrane; Single-pass type I membrane
CC protein. Secreted. Note=A secreted form is produced through
CC proteolytic processing.
CC -!- SUBCELLULAR LOCATION: Isoform 4: Secreted. Note=Lacks a Golgi-
CC retention motif, is not membrane bound and therefore is secreted.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=5;
CC Name=1; Synonyms=FL-TNFR1;
CC IsoId=P19438-1; Sequence=Displayed;
CC Name=2;
CC IsoId=P19438-2; Sequence=VSP_037153;
CC Note=No experimental confirmation available;
CC Name=4; Synonyms=Delta6-TNFR1;
CC IsoId=P19438-4; Sequence=VSP_044949;
CC Note=Disease-associated isoform. Isoform 4 splicing pattern is
CC driven by a variation in the exon 6/intron 6 boundary region
CC that alters exon 6 splicing. Exon 6 skipping introduces a
CC frameshift and the translation of a protein lacking the
CC intracellular, the transmembrane and part of the extracellular
CC domain;
CC Name=3;
CC IsoId=P19438-3; Sequence=VSP_037154;
CC Note=No experimental confirmation available;
CC Name=5;
CC IsoId=P19438-5; Sequence=VSP_047613, VSP_047614;
CC Note=No experimental confirmation available;
CC -!- DOMAIN: The domain that induces A-SMASE is probably identical to
CC the death domain. The N-SMASE activation domain (NSD) is both
CC necessary and sufficient for activation of N-SMASE.
CC -!- DOMAIN: Both the cytoplasmic membrane-proximal region and the C-
CC terminal region containing the death domain are involved in the
CC interaction with TRPC4AP (By similarity).
CC -!- PTM: The soluble form is produced from the membrane form by
CC proteolytic processing.
CC -!- DISEASE: Familial hibernian fever (FHF) [MIM:142680]: A hereditary
CC periodic fever syndrome characterized by recurrent fever,
CC abdominal pain, localized tender skin lesions and myalgia.
CC Reactive amyloidosis is the main complication and occurs in 25% of
CC cases. Note=The disease is caused by mutations affecting the gene
CC represented in this entry.
CC -!- DISEASE: Multiple sclerosis 5 (MS5) [MIM:614810]: A
CC multifactorial, inflammatory, demyelinating disease of the central
CC nervous system. Sclerotic lesions are characterized by
CC perivascular infiltration of monocytes and lymphocytes and appear
CC as indurated areas in pathologic specimens (sclerosis in plaques).
CC The pathological mechanism is regarded as an autoimmune attack of
CC the myelin sheath, mediated by both cellular and humoral immunity.
CC Clinical manifestations include visual loss, extra-ocular movement
CC disorders, paresthesias, loss of sensation, weakness, dysarthria,
CC spasticity, ataxia and bladder dysfunction. Genetic and
CC environmental factors influence susceptibility to the disease.
CC Note=Disease susceptibility is associated with variations
CC affecting the gene represented in this entry. An intronic mutation
CC affecting alternative splicing and skipping of exon 6 directs
CC increased expression of isoform 4 a transcript encoding a C-
CC terminally truncated protein which is secreted and may function as
CC a TNF antagonist.
CC -!- SIMILARITY: Contains 1 death domain.
CC -!- SIMILARITY: Contains 4 TNFR-Cys repeats.
CC -!- WEB RESOURCE: Name=INFEVERS; Note=Repertory of FMF and hereditary
CC autoinflammatory disorders mutations;
CC URL="http://fmf.igh.cnrs.fr/ISSAID/infevers/search.php?n=2";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/TNFRSF1A";
CC -!- WEB RESOURCE: Name=SeattleSNPs;
CC URL="http://pga.gs.washington.edu/data/tnfrsf1a/";
CC -----------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see http://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution-NoDerivs License
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DR EMBL; M58286; AAA36753.1; -; mRNA.
DR EMBL; M33294; AAA03210.1; -; mRNA.
DR EMBL; M63121; AAA36754.1; -; mRNA.
DR EMBL; X55313; CAA39021.1; -; mRNA.
DR EMBL; M60275; AAA36756.1; -; mRNA.
DR EMBL; M75866; AAA61201.1; -; Genomic_DNA.
DR EMBL; M75864; AAA61201.1; JOINED; Genomic_DNA.
DR EMBL; M75865; AAA61201.1; JOINED; Genomic_DNA.
DR EMBL; AY131997; AAM77802.1; -; Genomic_DNA.
DR EMBL; AK056611; BAG51763.1; -; mRNA.
DR EMBL; AK291088; BAF83777.1; -; mRNA.
DR EMBL; AK298729; BAG60879.1; -; mRNA.
DR EMBL; AK304517; BAG65321.1; -; mRNA.
DR EMBL; AK315509; BAG37891.1; -; mRNA.
DR EMBL; EU927389; ACH57451.1; -; mRNA.
DR EMBL; AC006057; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471116; EAW88805.1; -; Genomic_DNA.
DR EMBL; CH471116; EAW88806.1; -; Genomic_DNA.
DR EMBL; BC010140; AAH10140.1; -; mRNA.
DR PIR; A38208; GQHUT1.
DR RefSeq; NP_001056.1; NM_001065.3.
DR RefSeq; XP_005253815.1; XM_005253758.1.
DR RefSeq; XP_005253816.1; XM_005253759.1.
DR UniGene; Hs.279594; -.
DR PDB; 1EXT; X-ray; 1.85 A; A/B=41-201.
DR PDB; 1FT4; X-ray; 2.90 A; A/B=41-201.
DR PDB; 1ICH; NMR; -; A=345-455.
DR PDB; 1NCF; X-ray; 2.25 A; A/B=41-201.
DR PDB; 1TNR; X-ray; 2.85 A; R=44-182.
DR PDBsum; 1EXT; -.
DR PDBsum; 1FT4; -.
DR PDBsum; 1ICH; -.
DR PDBsum; 1NCF; -.
DR PDBsum; 1TNR; -.
DR ProteinModelPortal; P19438; -.
DR SMR; P19438; 42-201, 356-442.
DR DIP; DIP-407N; -.
DR IntAct; P19438; 25.
DR MINT; MINT-135026; -.
DR STRING; 9606.ENSP00000162749; -.
DR BindingDB; P19438; -.
DR ChEMBL; CHEMBL3378; -.
DR GuidetoPHARMACOLOGY; 1870; -.
DR PhosphoSite; P19438; -.
DR DMDM; 135959; -.
DR PaxDb; P19438; -.
DR PRIDE; P19438; -.
DR DNASU; 7132; -.
DR Ensembl; ENST00000162749; ENSP00000162749; ENSG00000067182.
DR Ensembl; ENST00000366159; ENSP00000380389; ENSG00000067182.
DR GeneID; 7132; -.
DR KEGG; hsa:7132; -.
DR UCSC; uc010sfa.2; human.
DR CTD; 7132; -.
DR GeneCards; GC12M006412; -.
DR HGNC; HGNC:11916; TNFRSF1A.
DR HPA; CAB010309; -.
DR HPA; HPA004102; -.
DR MIM; 142680; phenotype.
DR MIM; 191190; gene.
DR MIM; 614810; phenotype.
DR neXtProt; NX_P19438; -.
DR Orphanet; 329967; Intermittent hydrarthrosis.
DR Orphanet; 802; Multiple sclerosis.
DR Orphanet; 32960; TRAPS syndrome.
DR PharmGKB; PA36609; -.
DR eggNOG; NOG39168; -.
DR HOVERGEN; HBG058842; -.
DR InParanoid; P19438; -.
DR KO; K03158; -.
DR OMA; CLREAHY; -.
DR PhylomeDB; P19438; -.
DR Reactome; REACT_578; Apoptosis.
DR ChiTaRS; TNFRSF1A; human.
DR EvolutionaryTrace; P19438; -.
DR GeneWiki; TNFRSF1A; -.
DR GenomeRNAi; 7132; -.
DR NextBio; 27905; -.
DR PMAP-CutDB; P19438; -.
DR PRO; PR:P19438; -.
DR ArrayExpress; P19438; -.
DR Bgee; P19438; -.
DR CleanEx; HS_TNFRSF1A; -.
DR Genevestigator; P19438; -.
DR GO; GO:0030424; C:axon; IEA:Ensembl.
DR GO; GO:0009986; C:cell surface; IEA:Ensembl.
DR GO; GO:0005615; C:extracellular space; IDA:BHF-UCL.
DR GO; GO:0000139; C:Golgi membrane; IDA:UniProtKB.
DR GO; GO:0005887; C:integral to plasma membrane; TAS:ProtInc.
DR GO; GO:0045121; C:membrane raft; IDA:BHF-UCL.
DR GO; GO:0005634; C:nucleus; IEA:Ensembl.
DR GO; GO:0043234; C:protein complex; IEA:Ensembl.
DR GO; GO:0005031; F:tumor necrosis factor-activated receptor activity; TAS:UniProtKB.
DR GO; GO:0071392; P:cellular response to estradiol stimulus; IEA:Ensembl.
DR GO; GO:0071260; P:cellular response to mechanical stimulus; IEP:UniProtKB.
DR GO; GO:0042742; P:defense response to bacterium; IEA:Ensembl.
DR GO; GO:0016101; P:diterpenoid metabolic process; IEA:Ensembl.
DR GO; GO:0008625; P:extrinsic apoptotic signaling pathway via death domain receptors; TAS:BHF-UCL.
DR GO; GO:0009812; P:flavonoid metabolic process; IEA:Ensembl.
DR GO; GO:0006954; P:inflammatory response; ISS:UniProtKB.
DR GO; GO:0019048; P:modulation by virus of host morphology or physiology; IEA:UniProtKB-KW.
DR GO; GO:0010629; P:negative regulation of gene expression; IEA:Ensembl.
DR GO; GO:0050728; P:negative regulation of inflammatory response; IMP:BHF-UCL.
DR GO; GO:0032715; P:negative regulation of interleukin-6 production; IEA:Ensembl.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IEA:Ensembl.
DR GO; GO:0043123; P:positive regulation of I-kappaB kinase/NF-kappaB cascade; IEP:UniProtKB.
DR GO; GO:0050729; P:positive regulation of inflammatory response; ISS:UniProtKB.
DR GO; GO:0033160; P:positive regulation of protein import into nucleus, translocation; IEA:Ensembl.
DR GO; GO:0045944; P:positive regulation of transcription from RNA polymerase II promoter; ISS:UniProtKB.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IEA:Ensembl.
DR GO; GO:0042511; P:positive regulation of tyrosine phosphorylation of Stat1 protein; IMP:BHF-UCL.
DR GO; GO:0006693; P:prostaglandin metabolic process; IEA:InterPro.
DR GO; GO:0051291; P:protein heterooligomerization; IEA:Ensembl.
DR GO; GO:0042981; P:regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0043279; P:response to alkaloid; IEA:Ensembl.
DR GO; GO:0043200; P:response to amino acid stimulus; IEA:Ensembl.
DR GO; GO:0045471; P:response to ethanol; IEA:Ensembl.
DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR GO; GO:0032496; P:response to lipopolysaccharide; IEA:Ensembl.
DR GO; GO:0033013; P:tetrapyrrole metabolic process; IEA:Ensembl.
DR Gene3D; 1.10.533.10; -; 1.
DR InterPro; IPR011029; DEATH-like_dom.
DR InterPro; IPR000488; Death_domain.
DR InterPro; IPR001368; TNFR/NGFR_Cys_rich_reg.
DR InterPro; IPR020419; TNFR_1A.
DR Pfam; PF00531; Death; 1.
DR Pfam; PF00020; TNFR_c6; 3.
DR PRINTS; PR01918; TNFACTORR1A.
DR SMART; SM00005; DEATH; 1.
DR SMART; SM00208; TNFR; 4.
DR SUPFAM; SSF47986; SSF47986; 1.
DR PROSITE; PS50017; DEATH_DOMAIN; 1.
DR PROSITE; PS00652; TNFR_NGFR_1; 3.
DR PROSITE; PS50050; TNFR_NGFR_2; 3.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Amyloidosis; Apoptosis;
KW Cell membrane; Cleavage on pair of basic residues; Complete proteome;
KW Direct protein sequencing; Disease mutation; Disulfide bond;
KW Glycoprotein; Golgi apparatus; Host-virus interaction; Membrane;
KW Polymorphism; Receptor; Reference proteome; Repeat; Secreted; Signal;
KW Transmembrane; Transmembrane helix.
FT SIGNAL 1 21
FT CHAIN 22 455 Tumor necrosis factor receptor
FT superfamily member 1A, membrane form.
FT /FTId=PRO_0000034543.
FT CHAIN 41 201 Tumor necrosis factor-binding protein 1.
FT /FTId=PRO_0000034544.
FT TOPO_DOM 22 211 Extracellular (Potential).
FT TRANSMEM 212 234 Helical; (Potential).
FT TOPO_DOM 235 455 Cytoplasmic (Potential).
FT REPEAT 43 82 TNFR-Cys 1.
FT REPEAT 83 125 TNFR-Cys 2.
FT REPEAT 126 166 TNFR-Cys 3.
FT REPEAT 167 196 TNFR-Cys 4.
FT DOMAIN 356 441 Death.
FT REGION 338 348 N-SMase activation domain (NSD).
FT CARBOHYD 54 54 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 145 145 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 151 151 N-linked (GlcNAc...) (Potential).
FT DISULFID 44 58
FT DISULFID 59 72
FT DISULFID 62 81
FT DISULFID 84 99
FT DISULFID 102 117
FT DISULFID 105 125
FT DISULFID 127 143
FT DISULFID 146 158
FT DISULFID 149 166
FT DISULFID 168 179
FT DISULFID 182 195
FT DISULFID 185 191
FT VAR_SEQ 1 232 Missing (in isoform 3).
FT /FTId=VSP_037154.
FT VAR_SEQ 1 108 Missing (in isoform 2).
FT /FTId=VSP_037153.
FT VAR_SEQ 184 455 NCKKSLECTKLCLPQIENVKGTEDSGTTVLLPLVIFFGLCL
FT LSLLFIGLMYRYQRWKSKLYSIVCGKSTPEKEGELEGTTTK
FT PLAPNPSFSPTPGFTPTLGFSPVPSSTFTSSSTYTPGDCPN
FT FAAPRREVAPPYQGADPILATALASDPIPNPLQKWEDSAHK
FT PQSLDTDDPATLYAVVENVPPLRWKEFVRRLGLSDHEIDRL
FT ELQNGRCLREAQYSMLATWRRRTPRREATLELLGRVLRDMD
FT LLGCLEDIEEALCGPAALPPAPSLLR -> KHHSAVAPGHF
FT LWSLPFIPPLHWFNVSLPTVEVQALLHCLWEIDT (in
FT isoform 4).
FT /FTId=VSP_044949.
FT VAR_SEQ 184 218 NCKKSLECTKLCLPQIENVKGTEDSGTTVLLPLVI -> KV
FT LLCRPGWNAVARSRLTATSASQIQAILLLQPPK (in
FT isoform 5).
FT /FTId=VSP_047613.
FT VAR_SEQ 219 455 Missing (in isoform 5).
FT /FTId=VSP_047614.
FT VARIANT 51 51 H -> Q (in FHF).
FT /FTId=VAR_019329.
FT VARIANT 59 59 C -> R (in FHF).
FT /FTId=VAR_013410.
FT VARIANT 59 59 C -> S (in FHF).
FT /FTId=VAR_019302.
FT VARIANT 62 62 C -> G (in FHF).
FT /FTId=VAR_019303.
FT VARIANT 62 62 C -> Y (in FHF).
FT /FTId=VAR_013411.
FT VARIANT 75 75 P -> L (in FHF; may be a polymorphism;
FT dbSNP:rs4149637).
FT /FTId=VAR_019330.
FT VARIANT 79 79 T -> M (in FHF).
FT /FTId=VAR_013412.
FT VARIANT 81 81 C -> F (in FHF).
FT /FTId=VAR_013413.
FT VARIANT 99 99 C -> S (in FHF).
FT /FTId=VAR_019304.
FT VARIANT 115 115 S -> G (in FHF).
FT /FTId=VAR_019331.
FT VARIANT 117 117 C -> R (in FHF).
FT /FTId=VAR_013414.
FT VARIANT 117 117 C -> Y (in FHF).
FT /FTId=VAR_013415.
FT VARIANT 121 121 R -> P (in FHF; dbSNP:rs4149584).
FT /FTId=VAR_019305.
FT VARIANT 121 121 R -> Q (in FHF; may be a polymorphism;
FT dbSNP:rs4149584).
FT /FTId=VAR_019332.
FT VARIANT 305 305 P -> T (in dbSNP:rs1804532).
FT /FTId=VAR_011813.
FT CONFLICT 13 13 L -> LILPQ (in Ref. 8; BAG51763).
FT CONFLICT 255 255 K -> E (in Ref. 8; BAG37891).
FT CONFLICT 286 286 S -> G (in Ref. 8; BAG51763).
FT CONFLICT 394 394 R -> L (in Ref. 8; BAF83777).
FT CONFLICT 412 412 Missing (in Ref. 5; AAA36756).
FT CONFLICT 443 446 GPAA -> APP (in Ref. 5; AAA36756).
FT STRAND 48 50
FT STRAND 52 54
FT STRAND 58 60
FT STRAND 66 70
FT STRAND 80 83
FT STRAND 92 94
FT HELIX 107 109
FT STRAND 112 115
FT STRAND 124 126
FT STRAND 131 137
FT STRAND 140 145
FT STRAND 152 156
FT STRAND 160 162
FT STRAND 165 168
FT STRAND 172 175
FT STRAND 178 181
FT HELIX 182 184
FT HELIX 192 195
FT HELIX 357 365
FT HELIX 371 378
FT HELIX 382 391
FT HELIX 396 410
FT HELIX 417 427
FT HELIX 431 441
SQ SEQUENCE 455 AA; 50495 MW; 4CEFBA96D03B8225 CRC64;
MGLSTVPDLL LPLVLLELLV GIYPSGVIGL VPHLGDREKR DSVCPQGKYI HPQNNSICCT
KCHKGTYLYN DCPGPGQDTD CRECESGSFT ASENHLRHCL SCSKCRKEMG QVEISSCTVD
RDTVCGCRKN QYRHYWSENL FQCFNCSLCL NGTVHLSCQE KQNTVCTCHA GFFLRENECV
SCSNCKKSLE CTKLCLPQIE NVKGTEDSGT TVLLPLVIFF GLCLLSLLFI GLMYRYQRWK
SKLYSIVCGK STPEKEGELE GTTTKPLAPN PSFSPTPGFT PTLGFSPVPS STFTSSSTYT
PGDCPNFAAP RREVAPPYQG ADPILATALA SDPIPNPLQK WEDSAHKPQS LDTDDPATLY
AVVENVPPLR WKEFVRRLGL SDHEIDRLEL QNGRCLREAQ YSMLATWRRR TPRREATLEL
LGRVLRDMDL LGCLEDIEEA LCGPAALPPA PSLLR
//

MIM 142680
*RECORD*
*FIELD* NO
142680
*FIELD* TI
#142680 PERIODIC FEVER, FAMILIAL, AUTOSOMAL DOMINANT
;;FPF;;
HIBERNIAN FEVER, FAMILIAL; FHF;;
read moreFAMILIAL HIBERNIAN FEVER;;
TUMOR NECROSIS FACTOR RECEPTOR-ASSOCIATED PERIODIC SYNDROME; TRAPS;;
TNF RECEPTOR-ASSOCIATED PERIODIC SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because of evidence that
autosomal dominant periodic fever is caused by mutations in the tumor
necrosis factor receptor-1 gene (TNFRSF1A; 191190).

Drenth and van der Meer (2001) reviewed hereditary periodic fever
syndromes, including TNF receptor-associated periodic syndrome.

CLINICAL FEATURES

Williamson et al. (1982) described an Irish-Scottish family with an
autosomal dominant 'periodic disease' characterized by recurrent attacks
of fever, abdominal pain, localized tender skin lesions, and myalgia.
Pleurisy, leukocytosis, and high erythrocyte sedimentation rate were
other features. The disease pursued a benign course and no patient had
developed amyloidosis. At least 13 persons in 5 sibships of 3
generations were affected, with 4 instances of male-to-male
transmission.

Bouroncle and Doan (1957) described 12 cases of periodic fever in 6
sibships in 5 generations of a family. No abnormality was detected by
clinical examinations during and between attacks or by many laboratory
studies.

In 2 brothers with periodic fever, Driessen et al. (1968) found that the
nonesterified etiocholanolone level of the blood was raised not only
during febrile attacks but also in fever-free periods. A sister had
attacks of fever of unexplained origin accompanied by abdominal pain and
rash but had no symptoms after menarche. Drenth et al. (1994) included
the family of Driessen et al. (1968) in a series of cases of the
hyper-IgD syndrome (260920). They stated that measurements on subsequent
occasions in both brothers showed normal values of etiocholanolone.

Wang et al. (1999) reported a 10-year-old Ashkenazi Jewish boy who
developed lymphadenopathy at age 11 months, followed by bouts of
prolonged fever, splenomegaly, elevated sedimentation rate, anemia, and
reticulocytosis. At age 3 years, he had noninfectious lymphocytic
meningitis followed by optic neuritis, indicating a pattern of disparate
inflammatory conditions. At the time of report, he exhibited adenopathy
and splenomegaly. Autoantibodies were not detected, but lymphocyte
phenotyping showed a dramatic T and B lymphocytosis and increased CD4-,
CD8- T cells, especially a striking increase in CD4-, CD8- gamma/delta T
cells. Both parents were clinically normal. Although the boy was
originally diagnosed with autoimmune lymphoproliferative syndrome type
IIA (ALPS2A; 603909), he was later found to have a pathogenic mutation
in the TNFRSF1A gene, consistent with a diagnosis of TRAPS (Zhu et al.,
2006).

Toro et al. (2000) described the cutaneous features of 25 patients with
clinically and molecularly diagnosed FPF, which they referred to as
'tumor necrosis factor receptor-associated periodic syndrome' (TRAPS).
Twenty-one patients (84%) had cutaneous manifestations. Migratory
macules and patches were the most common findings. In addition, 10
patients (40%) exhibited erythematous edematous plaques. Lesions usually
occurred during febrile episodes, were most commonly seen on the
extremities, were often associated with myalgia, and lasted 4 to 21
days. Biopsies of lesional skin were obtained from 10 patients. The
histologic findings were nonspecific, consisting of infiltrating T
lymphocytes and monocytes, and could not be distinguished from a viral
exanthem or serum sickness-like reaction.

Wildemann et al. (2007) reported a man with periodic fever syndrome who
developed central nervous system involvement. Since childhood, he had
experienced recurrent attacks of fever, myalgias, arthralgias, and
painful migratory rashes. At age 38, he developed brainstem and
cerebellar symptoms from a T-cell predominant inflammatory infiltrate
without evidence of demyelination. Treatment with a TNF-alpha antagonist
resulted in marked clinical improvement with mild residual symptoms.
Genetic analysis identified a heterozygous mutation in the TNFRSF1A gene
(C55A; 191190.0012).

CLINICAL MANAGEMENT

Weyhreter et al. (2003) reported a Danish family with TRAPS in which the
youngest affected member was treated successfully with etanercept (a
fusion protein of the extracellular domain of TNFRSF1A and the Fc
portion of IgG1) at age 18 months following lack of response to
infliximab or of a sustained response to prednisolone.

MAPPING

Mulley et al. (1997, 1998) found frequent recombination of FPF with the
marker D16S2622 located within 1 Mb of familial Mediterranean fever at
16p13.3, thus excluding allelism between these clinically similar
conditions. By a genomewide search, they detected linkage to a cluster
of markers at 12p13, with a multipoint lod score of 6.14 at D12S356.
Assuming penetrance of 90%, they assigned the relevant gene (symbolized
FPF by them) to a 19-cM interval between D12S314 and D12S364.

McDermott et al. (1998) confirmed the assignment of familial Hibernian
fever to 12p13 by studies in the originally reported Irish-Scottish
family (6:Williamson et al., 1982) and in 2 Irish families with similar
clinical features (Quane et al., 1997). Cumulative multipoint linkage
analyses indicated that the gene, which they symbolized FHF (in parallel
with the FMF of familial Mediterranean fever), is likely to be located
in an 8-cM interval between D12S77 and D12S356, with a maximum lod score
of 3.79. The 2-point maximum lod score was 3.11 for D12S77. There was no
evidence of genetic heterogeneity in these 3 families.

MOLECULAR GENETICS

McDermott et al. (1999) identified germline mutations in the TNFRSF1A
gene, which had been identified as a candidate gene by linkage studies.
The families studied included those reported by Mulley et al. (1998) and
McDermott et al. (1998), a Finnish family reported by Karenko et al.
(1992), and 3 small North American families of Irish/English/German,
Irish, and French-Canadian ancestry.

Aganna et al. (2001) identified a mutation in the TNFRSF1A gene
(191190.0007) in a 2-generation Dutch family with TRAPS. The mutation
was present in the affected father and in all of his 4 children (the
affected proposita, a mildly affected son, and 2 unaffected children)
but was not found in 120 control chromosomes from unaffected Dutch
individuals. Low soluble plasma levels of TNFRSF1A segregated with the
mutation in all the children, including those who were unaffected. The
authors suggested that low levels of soluble TNFRSF1A in combination
with particular environmental insults may be necessary to produce the
full-blown phenotype. They also raised the possibility that TNFRSF1A
mutations may be present in mildly symptomatic or indeed asymptomatic
persons.

NOMENCLATURE

According to Kastner (2003), the gene for 'Hibernian fever' came from
the Scottish (mother's) side of the family; hence, it should be called
Caledonian fever rather than Hibernian fever.

*FIELD* RF
1. Aganna, E.; Aksentijevich, I.; Hitman, G. A.; Kastner, D. L.; Hoepelman,
A. I. M.; Posma, F. D.; Zweers, E. J. K.; McDermott, M. F.: Tumor
necrosis factor receptor-associated periodic syndrome (TRAPS) in a
Dutch family: evidence for a TNFRSF1A mutation with reduced penetrance. Europ.
J. Hum. Genet. 9: 63-66, 2001.

2. Bouroncle, B. A.; Doan, C. A.: 'Periodic fever': occurrence in
five generations. Am. J. Med. 23: 502-506, 1957.

3. Drenth, J. P. H.; Haagsma, C. J.; van der Meer, J. W. M.; the
International Hyper-IgD Study Group: Hyperimmunoglobulinemia D and
periodic fever syndrome: the clinical spectrum in a series of 50 patients. Medicine 73:
133-144, 1994.

4. Drenth, J. P. H.; van der Meer, J. W. M.: Hereditary periodic
fever. New Eng. J. Med. 345: 1748-1757, 2001.

5. Driessen, O.; Voute, P. A., Jr.; Vermeulen, A.: A description
of two brothers with permanently raised non-esterified aetiocholanolone
blood level. Acta Endocr. 57: 177-186, 1968.

6. Karenko, L.; Pettersson, T.; Roberts, P.: Autosomal dominant 'Mediterranean
fever' in a Finnish family. J. Int. Med. 232: 365-369, 1992.

7. Kastner, D. L.: Personal Communication. Bethesda, Md. 1/27/2003.

8. McDermott, M. F.; Aksentijevich, I.; Galon, J.; McDermott, E. M.;
Ogunkolade, B. W.; Centola, M.; Mansfield, E.; Gadina, M.; Karenko,
L.; Pettersson, T.; McCarthy, J.; Frucht, D. M.; and 21 others:
Germline mutations in the extracellular domains of the 55 kDa TNF
receptor, TNFR1, define a family of dominantly inherited autoinflammatory
syndromes. Cell 97: 133-144, 1999.

9. McDermott, M. F.; Ogunkolade, B. W.; McDermott, E. M.; Jones, L.
C.; Wan, Y.; Quane, K. A.; McCarthy, J.; Phelan, M.; Molloy, M. G.;
Powell, R. J.; Amos, C. I.; Hitman, G. A.: Linkage of familial Hibernian
fever to chromosome 12p13. Am. J. Hum. Genet. 62: 1446-1451, 1998.

10. Mulley, J.; Saar, K.; Hewitt, G.; Ruschendorf, F.; Phillips, H.;
Colley, A.; Sillence, D.; Reis, A.; Wilson, M.: Gene localization
for an autosomal dominant familial periodic fever to 12p13. Am. J.
Hum. Genet. 62: 884-889, 1998.

11. Mulley, J.; Saar, K.; Hewitt, G.; Ruschendorf, F.; Phillips, H.;
Colley, A.; Sillence, D.; Reis, A.; Wilson, M.: Gene localisation
for an autosomal dominant familial periodic fever. (Abstract) Am.
J. Hum. Genet. 61 (suppl.): A287 only, 1997.

12. Quane, K. A.; McDermott, M. F.; McCarthy, J.; Daly, M.; Phelan,
M.; Davey, S. R.; Sachs, J. A.; Hitman, G. A.; Shanahan, F.; Molloy,
M. G.: Autosomal dominant periodic fever in two Irish pedigrees.
(Abstract) Brit. J. Rheum. 36 (suppl. 1): 142 only, 1997.

13. Toro, J. R.; Aksentijevich, I.; Hull, K.; Dean, J.; Kastner, D.
: Tumor necrosis factor receptor-associated periodic syndrome: a novel
syndrome with cutaneous manifestations. Arch. Derm. 136: 1487-1494,
2000.

14. Wang, J.; Zheng, L.; Lobito, A.; Chan, F. K.; Dale, J.; Sneller,
M.; Yao, X.; Puck, J. M.; Straus, S. E.; Lenardo, M. J.: Inherited
human caspase 10 mutations underlie defective lymphocyte and dendritic
cell apoptosis in autoimmune lymphoproliferative syndrome type II. Cell 98:
47-58, 1999.

15. Weyhreter, H.; Schwartz, M.; Kristensen, T. D.; Valerius, N. H.;
Paerregaard, A.: A new mutation causing autosomal dominant periodic
fever syndrome in a Danish family. J. Pediat. 142: 191-193, 2003.

16. Wildemann, B.; Rudofsky, G., Jr.; Kress, B.; Jarius, S.; Konig,
F.; Schwenger, V.: The tumor necrosis factor-associated periodic
syndrome, the brain, and tumor necrosis factor-A antagonists. Neurology 68:
1742-1744, 2007.

17. Williamson, L. M.; Hull, D.; Mehta, R.; Reeves, W. G.; Robinson,
B. H. B.; Toghill, P. J.: Familial hibernian fever. Quart. J. Med. 51:
469-480, 1982.

18. Zhu, S.; Hsu, A. P.; Vacek, M. M.; Zheng, L.; Schaffer, A. A.;
Dale, J. K.; Davis, J.; Fischer, R. E.; Straus, S. E.; Boruchov, D.;
Saulsbury, F. T.; Lenardo, M. J.; Puck, J. M.: Genetic alterations
in caspase-10 may be causative or protective in autoimmune lymphoproliferative
syndrome. Hum. Genet. 119: 284-294, 2006.

*FIELD* CS
INHERITANCE:
Autosomal dominant

HEAD AND NECK:
[Eyes];
Periorbital edema;
Conjunctival injection

CHEST:
Pleuritic pain

ABDOMEN:
Recurrent abdominal pains;
[Liver];
Hepatic amyloidosis

SKELETAL:
Arthralgias

SKIN, NAILS, HAIR:
[Skin];
Migratory rashes, painful

MUSCLE, SOFT TISSUE:
Myalgias;
Muscle stiffness

METABOLIC FEATURES:
Fever, periodic, recurrent

LABORATORY ABNORMALITIES:
Increased erythrocyte sedimentation rate;
Increased white blood cell count;
Systemic amyloidosis may occur

MISCELLANEOUS:
Variable age at onset;
Favorable response to high-dose steroids;
Prevalence of 1 in 150 to 1 in 1,000;
High incidence in Iraqis and Sephardic Jewish individuals

MOLECULAR BASIS:
Caused by mutation in the tumor necrosis factor receptor superfamily
member 1A gene (TNFRSF1A, 191190.0001).

*FIELD* CN
Cassandra L. Kniffin - revised: 1/15/2008

*FIELD* CD
John F. Jackson: 6/15/1995

*FIELD* ED
joanna: 03/14/2008
ckniffin: 1/15/2008

*FIELD* CN
Cassandra L. Kniffin - updated: 1/7/2008
Cassandra L. Kniffin - updated: 5/11/2006
Natalie E. Krasikov - updated: 3/2/2004
Victor A. McKusick - updated: 2/6/2003
Victor A. McKusick - updated: 1/9/2002
Michael B. Petersen - updated: 4/26/2001
Gary A. Bellus - updated: 3/26/2001
Victor A. McKusick - updated: 4/5/1999
Victor A. McKusick - updated: 6/23/1998
Victor A. McKusick - updated: 10/23/1997

*FIELD* CD
Victor A. McKusick: 6/4/1986

*FIELD* ED
carol: 05/18/2010
wwang: 1/31/2008
ckniffin: 1/7/2008
wwang: 5/23/2006
ckniffin: 5/11/2006
carol: 5/12/2005
carol: 3/2/2004
carol: 2/6/2003
carol: 1/24/2003
carol: 7/9/2002
mcapotos: 1/9/2002
carol: 4/26/2001
cwells: 4/3/2001
cwells: 3/26/2001
carol: 4/5/1999
dholmes: 7/22/1998
carol: 7/9/1998
carol: 6/26/1998
terry: 6/23/1998
alopez: 5/19/1998
terry: 5/13/1998
terry: 10/28/1997
alopez: 10/27/1997
terry: 10/23/1997
mimadm: 9/24/1994
supermim: 3/16/1992
supermim: 3/20/1990
ddp: 10/27/1989
marie: 3/25/1988
reenie: 6/4/1986

MIM 191190
*RECORD*
*FIELD* NO
191190
*FIELD* TI
*191190 TUMOR NECROSIS FACTOR RECEPTOR SUPERFAMILY, MEMBER 1A; TNFRSF1A
;;TUMOR NECROSIS FACTOR RECEPTOR 1; TNFR1;;
read moreTUMOR NECROSIS FACTOR-ALPHA RECEPTOR; TNFAR;;
TNFR, 55-KD;;
TNFR, 60-KD
*FIELD* TX

CLONING

Tumor necrosis factor-alpha (TNFA; 191160), a potent cytokine, elicits a
broad spectrum of biologic responses which are mediated by binding to a
cell surface receptor. Stauber et al. (1988) isolated the receptor for
human TNF-alpha from a human histiocytic lymphoma cell line.

Hohmann et al. (1989) concluded that there are 2 different proteins that
serve as major receptors for TNF-alpha, one associated with myeloid
cells and one associated with epithelial cells.

Using monoclonal antibodies, Brockhaus et al. (1990) obtained evidence
for 2 distinct TNF-binding proteins, both of which bind TNF-alpha and
TNF-beta (TNFB; 153440) specifically and with high affinity. Gray et al.
(1990) isolated the cDNA for one of the receptors. They found that it
encodes a protein of 455 amino acids that is divided into an
extracellular domain of 171 residues in the cytoplasmic domain of 221
residues. Aggarwal et al. (1985) showed that tumor necrosis factors
alpha and beta initiate their effects on cell function by binding to
common cell surface receptors. The TNFA and TNFB receptors are different
sizes and are expressed differentially in different cell lines (Hohmann
et al., 1989; Engelmann et al., 1990). TNFAR, referred to by some as
TNFR55, is the smaller of the 2 receptors. cDNAs for both receptors have
been cloned and their nucleic acid sequence determined (Loetscher et
al., 1990; Nophar et al., 1990; Schall et al., 1990; Smith et al.,
1990). Whereas the extracellular domains of the 2 receptors are
strikingly similar in structure, their intracellular domains appear to
be unrelated. Southern blot analysis of human genomic DNA, using the
cDNAs of the 2 receptors as probes, indicated that each is encoded by a
single gene.

GENE FUNCTION

Preassembly or self-association of cytokine receptor dimers (e.g., IL1R,
see 147810; IL2R, 147730; and EPOR, 133171) occurs via the same amino
acid contacts that are critical for ligand binding. Chan et al. (2000)
found that, in contrast, the p60 (TNFRSF1A) and p80 (TNFRSF1B; 191191)
TNFA receptors self-assemble through a distinct functional domain in the
TNFR extracellular domain, termed the pre-ligand assembly domain (PLAD),
in the absence of ligand. Deletion of the PLAD results in monomeric
presentation of p60 or p80. Flow cytometric analysis showed that
efficient TNFA binding depends on receptor self-assembly. They also
found that other members of the TNF receptor superfamily, including the
extracellular domains of TRAIL receptor-1 (TNFRSF10A; 603611), CD40
(109535), and FAS (TNFRSF6; 134637), all self-associate but do not
interact with heterologous receptors.

Using targeted deletion mutagenesis of the TNFR1 protein, Tartaglia et
al. (1993) identified an approximately 80-amino acid death domain
responsible for signaling cytotoxicity within the intracellular region
near the C terminus.

Castellino et al. (1997) found that PIP5K2B (603261) interacts
specifically with the juxtamembrane region of TNFR1 and that treatment
of mammalian cells with TNF-alpha increases PIP5K2B activity. They
suggested that a subset of TNF responses may result from the direct
association of PIP5K2B with TNFR1 and the induction of the
phosphatidylinositol pathway.

Schievella et al. (1997) showed that TNFR1 associates with the MADD
protein (603584) through a death domain-death domain interaction. They
suggested that MADD provides a physical link between TNFR1 and the
induction of mitogen-activated protein (MAP) kinase (e.g., ERK2; 176948)
activation and arachidonic acid release.

Micheau and Tschopp (2003) reported that TNFR1-induced apoptosis
involves 2 sequential signaling complexes. Complex I, the initial plasma
membrane-bound complex, consists of TNFR1, the adaptor TRADD (603500),
the kinase RIP1 (603453), and TRAF2 (601895) and rapidly signals
activation of NF-kappa-B (see 164011). In a second step, TRADD and RIP1
associate with FADD (602457) and caspase-8 (601763), forming a
cytoplasmic complex, complex II. When NF-kappa-B is activated by complex
I, complex II harbors the caspase-8 inhibitor FLIP-L (603599) and the
cell survives. Thus, TNFR1-mediated signal transduction includes a
checkpoint, resulting in cell death (via complex II) in instances where
the initial signal (via complex I and NF-kappa-B) fails to be activated.

Yazdanpanah et al. (2009) identified riboflavin kinase (RFK, formerly
known as flavokinase; 613010) as a TNFR1-binding protein that physically
and functionally couples TNFR1 to NADPH oxidase (300225). In mouse and
human cells, RFK binds to both the TNFR1 death domain and to p22(phox)
(608508), the common subunit of NADPH oxidase isoforms. RFK-mediated
bridging of TNFR1 and p22(phox) is a prerequisite for TNF-induced but
not for Toll-like receptor (see 601194)-induced reactive oxygen species
(ROS) production. Exogenous flavin mononucleotide or FAD was able to
substitute fully for TNF stimulation of NADPH oxidase in RFK-deficient
cells. RFK is rate-limiting in the synthesis of FAD, an essential
prosthetic group of NADPH oxidase. Yazdanpanah et al. (2009) concluded
that TNF, through the activation of RFK, enhances the incorporation of
FAD in NADPH oxidase enzymes, a critical step for the assembly and
activation of NADPH oxidase.

Tang et al. (2011) reported that PGRN (138945) bound directly to tumor
necrosis factor receptors (TNFR1 and TNFR2) and disturbed the TNFA-TNFR
interaction. Pgrn-deficient mice were susceptible to collagen-induced
arthritis, and administration of PGRN reversed inflammatory arthritis.
Atsttrin, an engineered protein composed of 3 PGRN fragments, exhibited
selective TNFR binding. PGRN and Atsttrin prevented inflammation in
multiple arthritis mouse models and inhibited TNFA-activated
intracellular signaling. Tang et al. (2011) concluded that PGRN is a
ligand of TNFR, an antagonist of TNFA signaling, and plays a critical
role in the pathogenesis of inflammatory arthritis in mice.

Braumuller et al. (2013) showed that the combined action of the T
helper-1-cell cytokines IFN-gamma (IFNG; 147570) and tumor necrosis
factor (TNF; 191160) directly induces permanent growth arrest in
cancers. To safely separate senescence induced by tumor immunity from
oncogene-induced senescence, Braumuller et al. (2013) used a mouse model
in which the Simian virus-40 large T antigen (Tag) expressed under the
control of the rat insulin promoter creates tumors by attenuating p53
(191170)- and Rb (614041)-mediated cell cycle control. When combined,
Ifng and Tnf drive Tag-expressing cancers into senescence by inducing
permanent growth arrest in G1/G0, activation of p16Ink4a (CDKN2A;
600160), and downstream Rb hypophosphorylation at ser795. This
cytokine-induced senescence strictly requires Stat1 (600555) and Tnfr1
signaling in addition to p16Ink4a. In vivo, Tag-specific T-helper-1
cells permanently arrest Tag-expressing cancers by inducing Ifng- and
Tnfr1-dependent senescence. Conversely, Tnfr1-null Tag-expressing
cancers resist cytokine-induced senescence and grow aggressively, even
in Tnfr1-expressing hosts. Braumuller et al. (2013) concluded that as
IFNG and TNF induce senescence in numerous murine and human cancers,
this may be a general mechanism for arresting cancer progression.

Li et al. (2013) discovered that death domains in several proteins,
including TRADD, FADD, RIPK1, and TNFR1, were directly inactivated by
NleB, an enteropathogenic E. coli type III secretion system effector
known to inhibit host NF-kappa-B signaling. NleB contained an
unprecedented N-acetylglucosamine (GlcNAc) transferase activity that
specifically modified a conserved arginine in these death domains
(arg235 in the TRADD death domain). NleB GlcNAcylation of death domains
blocked homotypic/heterotypic death domain interactions and assembly of
the oligomeric TNFR1 complex, thereby disrupting TNF signaling in
enteropathogenic E. coli infected cells, including NF-kappa-B signaling,
apoptosis, and necroptosis. Type III-delivered NleB also blocked FAS
ligand (134638) and TRAIL (603598)-induced cell death by preventing
formation of a FADD-mediated death-inducing signaling complex (DISC).
The arginine GlcNAc transferase activity of NleB was required for
bacterial colonization in the mouse model of enteropathogenic E. coli
infection.

Pearson et al. (2013) reported that the type III secretion system (T3SS)
effector NleB1 from enteropathogenic E. coli binds to host cell
death-domain-containing proteins and thereby inhibits death receptor
signaling. Protein interaction studies identified FADD, TRADD, and RIPK1
as binding partners of NleB1. NleB1 expressed ectopically or injected by
the bacterial T3SS prevented Fas ligand or TNF-induced formation of the
canonical DISC and proteolytic activation of caspase-8 (601763), an
essential step in death receptor-induced apoptosis. This inhibition
depended on the N-acetylglucosamine transferase activity of NleB1, which
specifically modified arg117 in the death domain of FADD. The importance
of the death receptor apoptotic pathway to host defense was demonstrated
using mice deficient in the FAS signaling pathway, which showed delayed
clearance of the enteropathogenic E. coli-like mouse pathogen
Citrobacter rodentium and reversion to virulence of an NleB mutant.
Pearson et al. (2013) concluded that the activity of NleB suggested that
enteropathogenic E. coli and other attaching and effacing pathogens
antagonize death receptor-induced apoptosis of infected cells, thereby
blocking a major antimicrobial host response.

GENE STRUCTURE

Fuchs et al. (1992) demonstrated that the coding region and the 3-prime
untranslated region of TNFR1 are distributed over 10 exons.

MAPPING

By Southern blot analysis of human/Chinese hamster somatic cell hybrid
DNA, Milatovich et al. (1991, 1991) mapped the TNFR1 gene to 12pter-cen.
Derre et al. (1991) found by nonradioactive in situ hybridization that
the type 1 receptor (the p55 TNF receptor) is encoded by a gene located
on chromosome 12p13.2. By in situ hybridization and Southern blot
analysis of human/mouse hybrid cell lines, Baker et al. (1991) confirmed
the assignment of TNFR1 to 12p13. By PCR analysis of human-mouse somatic
cell hybrids and by in situ hybridization using biotinylated genomic
TNFR1 DNA, Fuchs et al. (1992) localized the TNFR1 gene to 12p13. The
homologous murine gene is located on mouse chromosome 6.

MOLECULAR GENETICS

- Autosomal Dominant Periodic Fever Syndrome

Autosomal dominant periodic fever syndromes are characterized by
unexplained episodes of fever and severe localized inflammation. In
affected individuals from 7 families with TNF receptor-associated
periodic fever syndrome (TRAPS; 142680), McDermott et al. (1999) found 6
different heterozygous missense mutations in the 55-kD TNF receptor
gene, 5 of which disrupted conserved extracellular disulfide bonds
(191190.0001-191190.0006). Soluble plasma TNFR1 levels in patients were
approximately half normal. Leukocytes bearing a C52F mutation
(191190.0004) showed increased membrane TNFR1 and reduced receptor
cleavage following stimulation. McDermott et al. (1999) proposed that
the autoinflammatory phenotype resulted from impaired downregulation of
membrane TNFR1 and diminished shedding of potentially antagonistic
soluble receptors. These results established an important class of
mutations in TNF receptors. A detailed analysis of 1 such mutation
suggested impaired cytokine receptor clearance as a novel mechanism of
disease.

Five of the 6 missense mutations described by McDermott et al. (1999)
involved cysteines participating in disulfide bonds in the first and
second extracellular TNFR1 domains, while the sixth substituted a
methionine for a highly conserved threonine adjacent to a cysteine
involved in disulfide bonding. In considering mechanisms by which these
mutations might induce inflammation, the authors evaluated several
possibilities, including (1) increased affinity of mutant TNFR1 for
ligand; (2) constitutive activation, possibly through the formation of
intermolecular disulfide bonds between unpaired cysteines in mutant
receptors; and (3) resistance of mutant TNFR1 to the normal homeostatic
effects of activation-induced cleavage. Analysis of leukocytes from the
3 affected members of a family with a C52F mutation favored the third
possibility.

The families studied by McDermott et al. (1999) included the most
thoroughly characterized pedigree, a large Irish/Scottish family with a
periodic inflammatory condition that had been termed familial Hibernian
fever. In addition to the difference in mode of inheritance, a number of
clinical features distinguish the disorder from familial Mediterranean
fever (249100), including longer average duration of attacks, presence
of conjunctivitis and periorbital edema, the distribution of cutaneous
involvement, and less pronounced response to colchicine prophylaxis. The
disease locus was mapped to 12p, which led to the identification of a
number of plausible positional candidate genes, including the TNFR1
gene.

Among 150 patients with unexplained periodic fevers, Aksentijevich et
al. (2001) identified 4 novel TNFRSF1A mutations, including cys33 to gly
(C33G; 191190.0009); 1 mutation, cys30 to ser (C30S; 191190.0008),
described by Dode et al. (2000); and 2 substitutions (P46L and R92Q) in
approximately 1% of control chromosomes. The increased frequency of P46L
and R92Q among patients with periodic fever, as well as functional
studies of TNFRSF1A, showed that these may be low-penetrance mutations
rather than benign polymorphisms. Genotype-phenotype studies identified,
as carriers of cysteine mutations, 13 of 14 patients with TNF
receptor-associated periodic syndrome and amyloidosis and indicated a
lower penetrance of TRAPS symptoms in individuals with noncysteine
mutations. In 2 families with dominantly inherited disease and in 90
sporadic cases that presented with a compatible clinical history,
Aksentijevich et al. (2001) identified no TNFRSF1A mutation, suggesting
further genetic heterogeneity of the periodic fever syndromes.

Aganna et al. (2003) screened affected members of 18 families in which
multiple members had symptoms compatible with TRAPS and 176 subjects
with sporadic (nonfamilial) 'TRAPS-like' symptoms for mutations in the
TNFRSF1A gene. They identified 3 previously reported and 8 novel
mutations, including a 3-bp deletion (191190.0010) in a northern Irish
family and a cys70-to-ser substitution (C70S; 191190.0011) in a Japanese
family. Only 3 of the patients with sporadic TRAPS-like symptoms were
found to have TNFRSF1A mutations. The authors noted that 3 members of
the 'prototype familial Hibernian fever' family did not possess the C33Y
mutation present in 9 other affected members. In addition, they found
TNFRSF1A shedding defects and low soluble TNFRSF1A levels in both
patients with TRAPS and those with sporadic TRAPS-like symptoms who did
not have a mutation in the TNFRSF1A gene. Aganna et al. (2003) concluded
that the genetic basis among patients with TRAPS-like features is
heterogeneous and that TNFRSF1A mutations are not commonly associated
with nonfamilial recurrent fevers of unknown etiology.

- Other Disease Associations

Poirier et al. (2004) screened the TNFRSF1A gene for polymorphisms in 95
subjects with premature myocardial infarction (MI) who also had 1 parent
who had had an MI. All 10 polymorphisms identified were genotyped in a
large case-control study of patients with MI; one, arg92 to gln (R92Q),
which was the only nonsynonymous polymorphism, was associated with MI
(OR, 2.15; 95% CI, 1.09-4.23). Poirier et al. (2004) analyzed the
distribution of the R92Q genotype in 3 other large studies in which
phenotypes associated with atherosclerosis had been investigated. The
R92Q polymorphism was associated with the presence of carotid plaques in
1 study, and with increased carotid intima-medial thickness in that and
another study; however, no association was found between R92Q and
ischemic stroke in the third study. Poirier et al. (2004) concluded that
the 92Q allele may predispose to atherosclerosis and its coronary artery
complications.

In Caucasian populations, the P46L mutation in TNFRSF1A, which is caused
by a 224C-T transition, is considered as a low-penetrance mutation
because its allele frequency is similar in patients and controls
(approximately 1%). Tchernitchko et al. (2005) found an unexpected high
P46L allele frequency (approximately 10%) in 2 groups from West
Africa--a group of 145 patients with sickle cell anemia (603903) and a
group of 349 healthy controls. These data suggested that the P46L
variant is a polymorphism rather than a TRAPS causative mutation.
Tchernitchko et al. (2005) proposed that the high frequency of P46L in
West African populations could be explained by some biologic advantage
conferred to carriers.

By sequencing the promoter regions 500 bp upstream from the
transcriptional start site of members of the TNF and TNFR superfamilies,
Kim et al. (2005) identified 23 novel regulatory SNPs in Korean donors.
Sequence analysis suggested that 9 of the SNPs altered putative
transcription factor binding sites. Analysis of SNP databases suggested
that the SNP allele frequencies were similar to those for Japanese
subjects but distinct from those of Caucasian or African populations.

As a follow-up to their studies examining TNF levels in response to M.
tuberculosis culture filtrate antigen as an intermediate phenotype model
for tuberculosis (TB) susceptibility in a Ugandan population (see
607948), Stein et al. (2007) studied genes related to TNF regulation by
positional candidate linkage followed by family-based SNP association
analysis. They found that the IL10 (124092), IFNGR1 (107470), and TNFR1
genes were linked and associated to both TB and TNF. These associations
were with active TB rather than susceptibility to latent infection.

- Association with Multiple Sclerosis

Kumpfel et al. (2008) identified 20 patients with multiple sclerosis who
carried a heterozygous R92Q variant in the TNFRSF1A gene and had
clinical features consistent with late-onset of TRAPS, including
myalgias, arthralgias, headache, fatigue, and skin rashes. Most of these
patients experienced severe side effects during immunomodulatory therapy
for MS. The findings suggested that the variants in the TNFRSF1A gene
may play a modifying role in MS. Kumpfel et al. (2008) concluded that
patients with coexistence of MS and features of TRAPS should be
carefully observed during treatment.

Gregory et al. (2012) investigated a SNP in the TNFRSF1A gene that was
discovered through genomewide association studies (GWASs) to be
associated with MS but not with other autoimmune conditions such as
rheumatoid arthritis (180300), psoriasis (see 177900), or Crohn disease
(266600). By analyzing multiple sclerosis GWAS data in conjunction with
the 1000 Genomes Project data, Gregory et al. (2012) provided genetic
evidence that strongly implicated dbSNP rs1800693 as the causal variant
in the TNFRSF1A region. Gregory et al. (2012) further substantiated this
through functional studies showing that the MS risk allele directs
expression of a novel, soluble form of TNFR1 that can block TNF.
Importantly, TNF-blocking drugs can promote onset or exacerbation of MS,
but they have proven highly efficacious in the treatment of autoimmune
diseases for which there is no association with dbSNP rs1800693. This
indicates that the clinical experience with these drugs parallels the
disease association of dbSNP rs1800693, and that the MS-associated TNRF1
variant mimics the effect of TNF-blocking drugs.

ANIMAL MODEL

To investigate the role of TNFR1 in beneficial and detrimental
activities of TNF, Rothe et al. (1993) generated TNFR1-deficient mice by
gene targeting. They found that mice homozygous for a disrupted Tnfr1
allele were resistant to the lethal effect of low doses of
lipopolysaccharide after sensitization with D-galactosamine, but
remained sensitive to high doses of lipopolysaccharide. An increased
susceptibility of the homozygous mutant mice to infection with the
facultative intracellular bacterium Listeria monocytogenes indicated an
essential role of TNF in nonspecific immunity.

Flynn et al. (1995) found that mice lacking the Tnf receptor p55 gene
and infected intravenously with Mycobacterium tuberculosis showed
significantly decreased survival, higher bacterial loads, increased
necrosis, delayed reactive nitrogen intermediate production and Inos
(NOS2A; 163730) expression, and reduced protection after BCG vaccination
than wildtype mice. Based on these results and studies using a
monoclonal antibody to neutralize Tnf in mice, Flynn et al. (1995)
concluded that Tnf and Tnf receptor p55 are necessary, if not solely
responsible, for protection against murine TB infection.

Bruce et al. (1996) used targeted gene disruption to generate mice
lacking either p55 or p75 TNF receptors; mice lacking both p55 and p75
were generated from crosses of the singly deficient mice. The
TNFR-deficient (TNFR-KO) mice exhibited no overt phenotype under
unchallenged conditions. Bruce et al. (1996) reported that damage to
neurons caused by focal cerebral ischemia and epileptic seizures was
exacerbated in the TNFR-KO mice, indicating that TNF serves a
neuroprotective function. Their studies indicated that TNF protects
neurons by stimulating antioxidative pathways. Injury-induced microglial
activation was suppressed in TNFR-KO mice. They concluded that drugs
which target TNF signaling pathways may prove beneficial in treating
stroke or traumatic brain injury.

Qian et al. (2000) studied the effect of topical soluble TNFR1 on
survival of murine orthotopic corneal transplants and on ocular
chemokine gene expression after corneal transplantation. Topical
treatment with soluble TNFR1 promoted the acceptance of allogeneic
corneal transplants and inhibited gene expression of 2 chemokines
associated with corneal graft rejection: RANTES (187011) and macrophage
inflammatory protein 1-beta (182284). The authors concluded that topical
anticytokine treatment is a feasible means of reducing corneal allograft
rejection without resorting to the use of potentially toxic
immunosuppressive drugs.

Zhang et al. (2004) found that the skin of Rela (164014)-deficient mice
showed hyperproliferation that was reversed in Tnfr1-Rela
double-knockout mice. They concluded that RELA antagonizes TNFR1-JNK
(601158) proliferative signals in epidermis.

Vielhauer et al. (2005) studied immune complex-mediated
glomerulonephritis in Tnfr1- and Tnfr2-deficient mice. Proteinuria and
renal pathology were initially milder in Tnfr1-deficient mice, but at
later time points were similar to those in wildtype controls, with
excessive renal T-cell accumulation and reduced T-cell apoptosis. In
contrast, Tnfr2-deficient mice were completely protected from
glomerulonephritis at all time points, despite an intact immune system
response. Tnfr2 expression on intrinsic renal cells, but not leukocytes,
was essential for glomerulonephritis and glomerular complement
deposition. Vielhauer et al. (2005) concluded that the proinflammatory
and immunosuppressive properties of TNF segregate at the level of its
receptors, with TNFR1 promoting systemic immune responses and renal
T-cell death and intrinsic renal cell TNFR2 playing a critical role in
complement-dependent tissue injury.

Wheeler et al. (2006) found that Tnfr1 -/- mice with experimental
autoimmune encephalomyelitis (EAE) had more Ifng (147570)-secreting T
cells in the central nervous system than wildtype mice, and EAE symptoms
were milder with delayed onset. Antigen-presenting cells (APCs) in Tnfr1
-/- mice displayed greater expression of Il12p40 (IL12B; 161561) than
those in wildtype mice. In vitro, Tnfr1 -/- APCs induced greater
expression of Ifng, but not Il17 (IL17A; 603149), when cultured with
primed T cells than did wildtype APCs. Wheeler et al. (2006) concluded
that EAE in mice lacking Tnfr1 is attenuated in spite of increased Ifng
levels, suggesting that Ifng levels do not necessarily correlate with
EAE severity.

Because their association study suggested a role for TNFR1 in
aging-dependent atherosclerosis (108725), Zhang et al. (2010) grafted
carotid arteries from 18- and 2-month-old wildtype and Tnfr1-/- mice
into congenic apolipoprotein E (APOE; 107741)-deficient (Apoe-/-) mice
and harvested grafts from 1 to 7 weeks postoperatively. Aged wildtype
arteries developed accelerated atherosclerosis associated with enhanced
TNFR1 expression, enhanced macrophage recruitment, reduced smooth muscle
cell proliferation and collagen content, augmented apoptosis, and plaque
hemorrhage. In contrast, aged Tnfr1-/- arteries developed
atherosclerosis that was indistinguishable from that in young Tnfr1-/-
arteries and significantly less than that observed in aged wildtype
arteries. The authors concluded that TNFR1 polymorphisms were associated
with aging-related CAD in humans, and that TNFR1 contributes to
aging-dependent atherosclerosis in mice.

*FIELD* AV
.0001
PERIODIC FEVER, FAMILIAL, AUTOSOMAL DOMINANT
TNFRSF1A, CYS33TYR

In 13 affected members of the prototype Irish/Scottish family with
familial Hibernian fever (142680) reported by Williamson et al. (1982),
McDermott et al. (1999) demonstrated a G-to-A transition in the TNFRSF1A
gene, resulting in the substitution of tyrosine for cysteine at residue
33. In 1 branch of this family, 3 individuals reported to have periodic
fevers did not possess this substitution, but they also did not share
the microsatellite haplotype present in all other affected members, and
the diagnosing physician had not witnessed the attacks of any of these 3
individuals.

.0002
PERIODIC FEVER, FAMILIAL, AUTOSOMAL DOMINANT
TNFRSF1A, THR50MET

In 8 of 8 affected members of an Irish family from the familial
Hibernian fever (142680) linkage study (McDermott et al., 1998),
McDermott et al. (1999) identified a mutation in the TNFRSF1A gene,
leading to the substitution of methionine for threonine at residue 50.
Two additional members of this family who had mild symptoms proved also
to have this mutation. The 1 available member of a French-Canadian
family had the same mutation.

.0003
PERIODIC FEVER, FAMILIAL, AUTOSOMAL DOMINANT
TNFRSF1A, CYS30ARG

In 2 affected members of an Irish-American family with periodic fever
(142680), McDermott et al. (1999) found a mutation in the TNFRSF1A gene
leading to the substitution of arginine for cysteine at residue 30
(relative to the signal peptide cleavage site).

.0004
PERIODIC FEVER, FAMILIAL, AUTOSOMAL DOMINANT
TNFRSF1A, CYS52PHE

In 3 affected members of an Irish/English/German family with periodic
fever (142680), McDermott et al. (1999) identified a G-to-T transversion
in the TNFRSF1A gene, leading to the substitution of phenylalanine for
cysteine at residue 52.

.0005
PERIODIC FEVER, FAMILIAL, AUTOSOMAL DOMINANT
TNFRSF1A, CYS88ARG

In all 7 available members of the Australian family of Scottish ancestry
with periodic fever (142680) studied by Mulley et al. (1998), McDermott
et al. (1999) identified a mutation at nucleotide 349, resulting in the
substitution of arginine for cysteine at residue 88.

.0006
PERIODIC FEVER, FAMILIAL, AUTOSOMAL DOMINANT
TNFRSF1A, CYS88TYR

In all 4 affected members of a Finnish family with periodic fever
(142680) studied by Karenko et al. (1992), McDermott et al. (1999)
demonstrated a G-to-A transition at nucleotide 350, resulting in the
substitution of tyrosine for cysteine at residue 88.

.0007
PERIODIC FEVER, FAMILIAL, AUTOSOMAL DOMINANT
TNFRSF1A, ARG92PRO

In a 2-generation Dutch family with periodic fever (142680), Aganna et
al. (2001) demonstrated a G-to-C transversion in exon 4 of the TNFRSF1A
gene, resulting in the substitution of proline for arginine at residue
92 (R92P). The mutation was present in the affected father and in all of
his 4 children (the affected proposita, a mildly affected son, and 2
unaffected children) but was not found in 120 control chromosomes from
unaffected Dutch individuals. Low soluble plasma levels of TNFRSF1A
segregated with the mutation in all the children, including those who
were unaffected. The authors raised the possibility that low levels of
soluble TNFRSF1A in combination with particular environmental insults
may be necessary to produce the full-blown phenotype.

.0008
PERIODIC FEVER, FAMILIAL, AUTOSOMAL DOMINANT
TNFRSF1A, CYS30SER

Dode et al. (2000) observed the cys30-to-ser (C30S) mutation in a French
family with periodic fever (142680); Aksentijevich et al. (2001) found
the same mutation in an Irish American family with 3 affected members.
The cys30-to-arg mutation (191190.0003) in the same codon had been
previously reported.

.0009
PERIODIC FEVER, FAMILIAL, AUTOSOMAL DOMINANT
TNFRSF1A, CYS33GLY

Aksentijevich et al. (2001) found the cys33-to-gly mutation in a father
and daughter with periodic fever (142680) originally from Puerto Rico.
They had histories of recurrent fever, abdominal pain, and arthralgia
since birth and had been treated with corticosteroids for many years.
The father had developed progressive hepatic amyloidosis, eventually
necessitating liver transplantation. The cys33-to-tyr mutation
(191190.0001) in the same codon had been previously reported.

.0010
PERIODIC FEVER, FAMILIAL, AUTOSOMAL DOMINANT
TNFRSF1A, 3-BP DEL, NT211

In a 3-generation northern Irish family with periodic fever (142680),
Aganna et al. (2003) identified a 3-bp deletion at nucleotide 211 in
exon 3 of the TNFRSF1A gene. The mutation was associated with AA
amyloidosis in 3 family members. The authors stated that this was the
first amino acid deletion to be identified in this disorder.

.0011
PERIODIC FEVER, FAMILIAL, AUTOSOMAL DOMINANT
TNFRSF1A, CYS70SER

In a 2-generation Japanese family with periodic fever (142680), Aganna
et al. (2003) identified a 295T-A transversion in exon 3 of the TNFRSF1A
gene, resulting in a cys70-to-ser (C70S) substitution. The authors
stated that this was the first report of TNF receptor-associated
periodic fever in a patient from the Far East.

.0012
PERIODIC FEVER, FAMILIAL, AUTOSOMAL DOMINANT
TNFRSF1A, CYS55ALA

In a patient with periodic fever syndrome (142680), Wildemann et al.
(2007) identified a heterozygous cys55-to-ala (C55A) substitution in
exon 2 of the TNFRSF1A gene. The patient had experienced recurrent
attacks of fever, myalgias, and painful migratory rashes since
childhood. At age 38, he developed brainstem and cerebellar symptoms
from a T-cell predominant inflammatory infiltrate without evidence of
demyelination. The findings were consistent with CNS involvement in
TRAPS. Treatment with a TNF-alpha antagonist resulted in marked clinical
improvement with mild residual symptoms.

.0013
MULTIPLE SCLEROSIS, SUSCEPTIBILITY TO, 5
TNFRSF1A, IVS6, A-G (dbSNP rs1800693)

Gregory et al. (2012) investigated the contribution of the
single-nucleotide polymorphism (SNP) dbSNP rs1800693 to susceptibility
to multiple sclerosis associated with the TNFRSF1A region (MS5; 614810).
The SNP dbSNP rs1800693 is proximal to the TNFRSF1A exon 6/intron 6
boundary, and the G risk allele resulted in skipping of exon 6 in
minigene splicing assays. In primary human immune cells, the presence of
the risk allele correlated with increased expression of transcripts
lacking exon 6. TNFR1 exon 6 skipping results in a frameshift and a
premature stop codon, which translates into a protein comprising only
the amino-terminal 183 amino acids of TNFR1 followed by a novel 45 amino
acid sequence, as confirmed by tandem mass spectrometry. This mutant
protein, delta-6-TNFR1, lacks the extracellular carboxy-terminal portion
of the fourth cysteine-rich domain of the select protein, the
transmembrane domain, and the intracellular region that is essential for
appropriate subcellular localization. The mutant protein demonstrated a
more diffuse intracellular distribution than the normal localization to
the Golgi apparatus. Gregory et al. (2012) found no significant
spontaneous NF-kappa-B (see 164011) signaling or TNFR1-mediated
apoptosis upon delta-6-TNFR1 expression. However, the mutant protein
could potentially retain some intracellular activity by accumulating in
the endoplasmic reticulum and evoking a stress response. Gregory et al.
(2012) concluded that the combined genetic and functional analyses
strongly implicated dbSNP rs1800693 as the causal SNP in the
MS-associated TNFRSF1A region. Because the delta-6-TNFR1 protein is
soluble and capable of TNF antagonism, Gregory et al. (2012) concluded
that their evidence was consistent with the reported worsening of MS
upon anti-TNF therapy.

*FIELD* RF
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A. J.; Henrickson, M.; Pons-Estel, B.; O'Shea, J. J.; Kastner, D.
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21. Kumpfel, T.; Hoffmann, L.-A.; Pellkofer, H.; Pollmann, W.; Feneberg,
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22. Li, S.; Zhang, L.; Yao, Q.; Li, L.; Dong, N.; Rong, J.; Gao, W.;
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28. Milatovich, A.; Song, K.; Heller, R. A.; Francke, U.: Tumor necrosis
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29. Mulley, J.; Saar, K.; Hewitt, G.; Ruschendorf, F.; Phillips, H.;
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30. Nophar, Y.; Kemper, O.; Brakebusch, C.; Engelmann, H.; Zwang,
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31. Pearson, J. S.; Giogha, C.; Ong, S. Y.; Kennedy, C. L.; Kelly,
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antagonizes death receptor signalling during bacterial gut infection. Nature 501:
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32. Poirier, O.; Nicaud, V.; Gariepy, J.; Courbon, D.; Elbaz, A.;
Morrison, C.; Kee, F.; Evans, A.; Arveiler, D.; Ducimetiere, P.; Amarenco,
P.; Cambien, F.: Polymorphism R92Q of the tumour necrosis factor
receptor 1 gene is associated with myocardial infarction and carotid
intima-media thickness: the ECTIM, AXA, EVA and GENIC studies. Europ.
J. Hum. Genet. 12: 213-219, 2004.

33. Qian, Y.; Dekaris, I.; Yamagami, S.; Dana, R.: Topical soluble
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34. Rothe, J.; Lesslauer, W.; Lotscher, H.; Lang, Y.; Koebel, P.;
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37. Smith, C. A.; Davis, T.; Anderson, D.; Solam, L.; Beckmann, M.
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39. Stein, C. M.; Zalwango, S.; Chiunda, A. B.; Millard, C.; Leontiev,
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Elston, R. C.; Mugerwa, R. D.; Whalen, C. C.; Iyengar, S. K.: Linkage
and association analysis of candidate genes for TB and TNF-alpha cytokine
expression: evidence for association with IFNGR1, IL-10, and TNF receptor
1 genes. Hum. Genet. 121: 663-673, 2007.

40. Tang, W.; Lu, Y.; Tian, Q.-Y.; Zhang, Y.; Guo, F.-J.; Liu, G.-Y.;
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10 others: The growth factor progranulin binds to TNF receptors
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41. Tartaglia, L. A.; Ayres, T. M.; Wong, G. H. W.; Goeddel, D. V.
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42. Tchernitchko, D.; Chiminqgi, M.; Galacteros, F.; Prehu, C.; Segbena,
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43. Vielhauer, V.; Stavrakis, G.; Mayadas, T. N.: Renal cell-expressed
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44. Wheeler, R. D.; Zehntner, S. P.; Kelly, L. M.; Bourbonniere, L.;
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45. Wildemann, B.; Rudofsky, G., Jr.; Kress, B.; Jarius, S.; Konig,
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Genet. 19: 2754-2766, 2010.

*FIELD* CN
Ada Hamosh - updated: 12/12/2013
Ada Hamosh - updated: 12/11/2013
George E. Tiller - updated: 9/4/2013
Ada Hamosh - updated: 3/21/2013
Ada Hamosh - updated: 9/4/2012
Ada Hamosh - updated: 7/8/2011
Ada Hamosh - updated: 9/9/2009
Cassandra L. Kniffin - updated: 5/18/2009
Cassandra L. Kniffin - updated: 1/7/2008
Paul J. Converse - updated: 8/21/2007
Paul J. Converse - updated: 2/15/2007
Paul J. Converse - updated: 1/10/2006
Paul J. Converse - updated: 10/31/2005
Marla J. F. O'Neill - updated: 5/20/2005
Victor A. McKusick - updated: 4/26/2005
Cassandra L. Kniffin - updated: 11/11/2004
Stylianos E. Antonarakis - updated: 5/25/2004
Marla J. F. O'Neill - updated: 5/3/2004
Marla J. F. O'Neill - updated: 4/30/2004
Patricia A. Hartz - updated: 3/4/2004
Victor A. McKusick - updated: 8/30/2001
Michael B. Petersen - updated: 4/26/2001
Jane Kelly - updated: 2/15/2001
Paul J. Converse - updated: 6/29/2000
Stylianos E. Antonarakis - updated: 4/5/1999
Victor A. McKusick - updated: 4/5/1999
Patti M. Sherman - updated: 2/26/1999
Patti M. Sherman - updated: 11/9/1998
Moyra Smith - updated: 8/27/1996

*FIELD* CD
Victor A. McKusick: 2/1/1989

*FIELD* ED
alopez: 12/12/2013
alopez: 12/11/2013
carol: 10/25/2013
alopez: 9/4/2013
carol: 6/4/2013
alopez: 4/2/2013
terry: 3/21/2013
alopez: 9/6/2012
terry: 9/4/2012
terry: 8/17/2012
terry: 7/27/2012
terry: 7/20/2011
alopez: 7/11/2011
terry: 7/8/2011
alopez: 9/14/2009
terry: 9/9/2009
wwang: 8/17/2009
ckniffin: 8/6/2009
wwang: 5/21/2009
ckniffin: 5/18/2009
ckniffin: 3/26/2009
wwang: 1/31/2008
ckniffin: 1/7/2008
mgross: 8/22/2007
terry: 8/21/2007
mgross: 2/15/2007
carol: 3/10/2006
mgross: 1/10/2006
alopez: 10/31/2005
wwang: 10/27/2005
wwang: 5/23/2005
terry: 5/20/2005
tkritzer: 4/29/2005
terry: 4/26/2005
tkritzer: 11/17/2004
ckniffin: 11/11/2004
mgross: 5/25/2004
carol: 5/6/2004
terry: 5/3/2004
terry: 4/30/2004
mgross: 3/11/2004
terry: 3/4/2004
cwells: 11/6/2003
carol: 2/6/2003
terry: 2/6/2003
mcapotos: 12/21/2001
mcapotos: 12/19/2001
cwells: 9/20/2001
cwells: 9/13/2001
terry: 8/30/2001
carol: 4/26/2001
mcapotos: 2/16/2001
mcapotos: 2/15/2001
carol: 6/29/2000
carol: 6/1/2000
mgross: 4/5/1999
carol: 4/5/1999
carol: 3/2/1999
psherman: 2/26/1999
psherman: 12/18/1998
carol: 11/10/1998
psherman: 11/9/1998
dkim: 7/30/1998
terry: 6/1/1998
mark: 9/11/1996
mark: 8/27/1996
jason: 7/18/1994
carol: 2/5/1993
carol: 5/22/1992
supermim: 3/16/1992
carol: 2/23/1992
carol: 2/19/1992

MIM 614810
*RECORD*
*FIELD* NO
614810
*FIELD* TI
#614810 MULTIPLE SCLEROSIS, SUSCEPTIBILITY TO, 5; MS5
*FIELD* TX
A number sign (#) is used with this entry because genetic variation in
read morethe TNFRSF1A gene (191190) influences susceptibility to multiple
sclerosis.

For a discussion of genetic heterogeneity of multiple sclerosis (MS),
see MS1 (126200).

MAPPING

Xu et al. (2001) investigated 27 microsatellite markers from 8
chromosomal regions syntenic to loci of importance for experimental
autoimmune diseases in the rat in 74 Swedish MS families. They observed
possible linkage with markers in the 12p13-p12 region (highest NPL score
of 1.16).

In a metaanalysis of genomewide association studies including 2,624
patients with MS and 7,220 controls, followed by replication in an
independent set of 2,215 patients MS and 2,116 controls, De Jager et al.
(2009) identified a locus for MS susceptibility on chromosome 12p13 in
the TNFRSF1A gene (191190) (dbSNP rs1800693; combined p = 1.59 x
10(-11)).

MOLECULAR GENETICS

Gregory et al. (2012) investigated the dbSNP rs1800693 SNP in the
TNFRSF1A gene (191190.0013) that was discovered through GWAS to be
associated with MS but not with other autoimmune conditions such as
rheumatoid arthritis (180300), psoriasis (177900), or Crohn disease
(266600). By analyzing MS GWAS data in conjunction with the 1000 Genomes
Project data, Gregory et al. (2012) provided genetic evidence that
strongly implicated dbSNP rs1800693 as the causal variant in the
TNFRSF1A region. Gregory et al. (2012) further substantiated this
through functional studies showing that the MS risk allele directs
expression of a novel, soluble form of TNFR1 (encoded by TNFRSF1A) that
can block tumor necrosis factor (TNF; 191160). Importantly, TNF-blocking
drugs can promote onset or exacerbation of MS, but they have proven
highly efficacious in the treatment of autoimmune diseases for which
there is no association with dbSNP rs1800693. This indicates that the
clinical experience with these drugs parallels the disease association
of dbSNP rs1800693, and that the MS-associated TNRF1 variant mimics the
effect of TNF-blocking drugs.

*FIELD* RF
1. De Jager, P. L.; Jia, X.; Wang, J.; de Bakker, P. I. W.; Ottoboni,
L.; Aggarwal, N. T.; Picco, L.; Raychaudhuri, S.; Tran, D.; Aubin,
C.; Briskin, R.; Romano, S.; and 22 others: Meta-analysis of genome
scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple
sclerosis susceptibility loci. Nature Genet. 41: 776-782, 2009.

2. Gregory, A. P.; Dendrou, C. A.; Attfield, K. E.; Haghikia, A.;
Xifara, D. K.; Butter, F.; Poschmann, G.; Kaur, G.; Lambert, L.; Leach,
O. A.; Promel, S.; Punwani, D.; and 9 others: TNF receptor 1 genetic
risk mirrors outcome of anti-TNF therapy in multiple sclerosis. Nature 488:
508-511, 2012.

3. Xu, C.; Dai, Y.; Lorentzen, J. C.; Dahlman, I.; Olsson, T.; Hillert,
J.: Linkage analysis in multiple sclerosis of chromosomal regions
syntenic to experimental autoimmune disease loci. Europ. J. Hum.
Genet. 9: 458-463, 2001.

*FIELD* CD
Ada Hamosh: 9/6/2012

*FIELD* ED
alopez: 09/06/2012