RBCC Red Blood Cell Collection

BTK (AGMX1, ATK, BPK) [Confidence: low (only semi-automatic identification from reviews)]
Tyrosine-protein kinase BTK; 2.7.10.2 (Agammaglobulinemia tyrosine kinase; ATK; B-cell progenitor kinase; BPK; Bruton tyrosine kinase)

UniProt Q06187
ID BTK_HUMAN Reviewed; 659 AA.
AC Q06187; Q32ML5;
DT 01-JUN-1994, integrated into UniProtKB/Swiss-Prot.
read moreDT 23-JAN-2007, sequence version 3.
DT 22-JAN-2014, entry version 180.
DE RecName: Full=Tyrosine-protein kinase BTK;
DE EC=2.7.10.2;
DE AltName: Full=Agammaglobulinemia tyrosine kinase;
DE Short=ATK;
DE AltName: Full=B-cell progenitor kinase;
DE Short=BPK;
DE AltName: Full=Bruton tyrosine kinase;
GN Name=BTK; Synonyms=AGMX1, ATK, BPK;
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].
RX PubMed=8380905; DOI=10.1038/361226a0;
RA Vetrie D., Vorechovsky I., Sideras P., Holland J., Davies A.,
RA Flinter F., Hammarstroem L., Kinnon C., Levinsky R.J., Bobrow M.,
RA Smith C.I.E., Bentley D.R.;
RT "The gene involved in X-linked agammaglobulinaemia is a member of the
RT src family of protein-tyrosine kinases.";
RL Nature 361:226-233(1993).
RN [2]
RP ERRATUM.
RA Vetrie D., Vorechovsky I., Sideras P., Holland J., Davies A.,
RA Flinter F., Hammarstroem L., Kinnon C., Levinsky R.J., Bobrow M.,
RA Smith C.I.E., Bentley D.R.;
RL Nature 364:362-362(1993).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC TISSUE=Blood;
RX PubMed=8090769; DOI=10.1073/pnas.91.19.9062;
RA Ohta Y., Haire R.N., Litman R.T., Fu S.M., Nelson R.P., Kratz J.,
RA Kornfeld S.J., la Morena M., Good R.A., Litman G.W.;
RT "Genomic organization and structure of Bruton agammaglobulinemia
RT tyrosine kinase: localization of mutations associated with varied
RT clinical presentations and course in X chromosome-linked
RT agammaglobulinemia.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:9062-9066(1994).
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=7927535; DOI=10.1007/BF01246672;
RA Rohrer J., Parolini O., Belmont J.W., Conley M.E.;
RT "The genomic structure of human BTK, the defective gene in X-linked
RT agammaglobulinemia.";
RL Immunogenetics 40:319-324(1994).
RN [5]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS XLA SER-334; ARG-506;
RP GLN-520; TRP-562 AND LYS-630.
RX PubMed=7880320; DOI=10.1093/hmg/3.10.1743;
RA Hagemann T.L., Chen Y., Rosen F.S., Kwan S.-P.;
RT "Genomic organization of the Btk gene and exon scanning for mutations
RT in patients with X-linked agammaglobulinemia.";
RL Hum. Mol. Genet. 3:1743-1749(1994).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=7626884; DOI=10.1007/BF00364796;
RA Oeltjen J.C., Liu X., Lu J., Allen R.C., Muzny D.M., Belmont J.W.,
RA Gibbs R.A.;
RT "Sixty-nine kilobases of contiguous human genomic sequence containing
RT the alpha-galactosidase A and Bruton's tyrosine kinase loci.";
RL Mamm. Genome 6:334-338(1995).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15772651; DOI=10.1038/nature03440;
RA Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D.,
RA Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A.,
RA Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G.,
RA Jones M.C., Hurles M.E., Andrews T.D., Scott C.E., Searle S.,
RA Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R.,
RA Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L.,
RA Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A.,
RA Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S.,
RA Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R.,
RA Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M.,
RA Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N.,
RA Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D.,
RA Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W.,
RA Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C.,
RA Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C.,
RA Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S.,
RA Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S.,
RA Corby N., Connor R.E., David R., Davies J., Davis C., Davis J.,
RA Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S.,
RA Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I.,
RA Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L.,
RA Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P.,
RA Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S.,
RA Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A.,
RA Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J.,
RA Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J.,
RA Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S.,
RA de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z.,
RA Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C.,
RA Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W.,
RA Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D.,
RA Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H.,
RA McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T.,
RA Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I.,
RA Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N.,
RA Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J.,
RA Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E.,
RA Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S.,
RA Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K.,
RA Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D.,
RA Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R.,
RA Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T.,
RA Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S.,
RA Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L.,
RA Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A.,
RA Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L.,
RA Williams G., Williams L., Williamson A., Williamson H., Wilming L.,
RA Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H.,
RA Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A.,
RA Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F.,
RA Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A.,
RA Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T.,
RA Gibbs R.A., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence of the human X chromosome.";
RL Nature 434:325-337(2005).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
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 [9]
RP NUCLEOTIDE SEQUENCE OF 1-442.
RX PubMed=8425221; DOI=10.1016/0092-8674(93)90667-F;
RA Tsukada S., Saffran D.C., Rawlings D.J., Parolini O., Allen R.C.,
RA Klisak I., Sparkes R.S., Kubagawa H., Mohandas T., Quan S.,
RA Belmont J.W., Cooper M.D., Conley M.E., Witte O.N.;
RT "Deficient expression of a B cell cytoplasmic tyrosine kinase in human
RT X-linked agammaglobulinemia.";
RL Cell 72:279-290(1993).
RN [10]
RP PROTEIN SEQUENCE OF 2-12 AND 323-332, CLEAVAGE OF INITIATOR
RP METHIONINE, ACETYLATION AT ALA-2, AND MASS SPECTROMETRY.
RC TISSUE=Platelet;
RA Bienvenut W.V., Claeys D.;
RL Submitted (NOV-2005) to UniProtKB.
RN [11]
RP PROTEIN SEQUENCE OF 219-235, AND PHOSPHORYLATION AT TYR-223.
RX PubMed=12573241; DOI=10.1016/S1570-9639(02)00524-1;
RA Nore B.F., Mattsson P.T., Antonsson P., Backesjo C.-M., Westlund A.,
RA Lennartsson J., Hansson H., Low P., Ronnstrand L., Smith C.I.E.;
RT "Identification of phosphorylation sites within the SH3 domains of Tec
RT family tyrosine kinases.";
RL Biochim. Biophys. Acta 1645:123-132(2003).
RN [12]
RP INVOLVEMENT IN XLA-IGHD.
RX PubMed=8013627; DOI=10.1016/0014-5793(94)00457-9;
RA Duriez B., Duquesnoy P., Dastot F., Bougneres P., Amselem S.,
RA Goossens M.;
RT "An exon-skipping mutation in the btk gene of a patient with X-linked
RT agammaglobulinemia and isolated growth hormone deficiency.";
RL FEBS Lett. 346:165-170(1994).
RN [13]
RP DOMAIN PH.
RX PubMed=8070576; DOI=10.1016/0014-5793(94)00783-7;
RA Vihinen M., Nilsson L., Smith C.I.;
RT "Tec homology (TH) adjacent to the PH domain.";
RL FEBS Lett. 350:263-265(1994).
RN [14]
RP PHOSPHORYLATION AT TYR-223 AND TYR-551, MUTAGENESIS OF TYR-223, AND
RP ENZYME REGULATION.
RX PubMed=8630736; DOI=10.1016/S1074-7613(00)80417-3;
RA Park H., Wahl M.I., Afar D.E., Turck C.W., Rawlings D.J., Tam C.,
RA Scharenberg A.M., Kinet J.P., Witte O.N.;
RT "Regulation of Btk function by a major autophosphorylation site within
RT the SH3 domain.";
RL Immunity 4:515-525(1996).
RN [15]
RP FUNCTION IN PHOSPHORYLATION OF GTF2I, PHOSPHORYLATION AT TYR-223 AND
RP TYR-551, AND MUTAGENESIS OF GLU-41; PRO-189; TYR-223; TRP-251; ARG-307
RP AND TYR-551.
RX PubMed=9012831; DOI=10.1073/pnas.94.2.604;
RA Yang W., Desiderio S.;
RT "BAP-135, a target for Bruton's tyrosine kinase in response to B cell
RT receptor engagement.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:604-609(1997).
RN [16]
RP MUTAGENESIS OF 251-TRP-TRP-252, AND INTERACTION WITH SH3BP5.
RX PubMed=9571151; DOI=10.1006/bbrc.1998.8420;
RA Matsushita M., Yamadori T., Kato S., Takemoto Y., Inazawa J., Baba Y.,
RA Hashimoto S., Sekine S., Arai S., Kunikata T., Kurimoto M.,
RA Kishimoto T., Tsukada S.;
RT "Identification and characterization of a novel SH3-domain binding
RT protein, Sab, which preferentially associates with Bruton's tyrosine
RT kinase (Btk).";
RL Biochem. Biophys. Res. Commun. 245:337-343(1998).
RN [17]
RP DOMAIN PH, AND SUBCELLULAR LOCATION.
RX PubMed=10196179; DOI=10.1074/jbc.274.16.10983;
RA Varnai P., Rother K.I., Balla T.;
RT "Phosphatidylinositol 3-kinase-dependent membrane association of the
RT Bruton's tyrosine kinase pleckstrin homology domain visualized in
RT single living cells.";
RL J. Biol. Chem. 274:10983-10989(1999).
RN [18]
RP INTERACTION WITH SH3BP5, AND ENZYME REGULATION.
RX PubMed=10339589; DOI=10.1073/pnas.96.11.6341;
RA Yamadori T., Baba Y., Mastushita M., Hashimoto S., Kurosaki M.,
RA Kurosaki T., Kishimoto T., Tsukada S.;
RT "Bruton's tyrosine kinase activity is negatively regulated by Sab, the
RT Btk-SH3 domain-binding protein.";
RL Proc. Natl. Acad. Sci. U.S.A. 96:6341-6346(1999).
RN [19]
RP SUBCELLULAR LOCATION.
RX PubMed=10602036;
RX DOI=10.1002/1521-4141(200001)30:1<145::AID-IMMU145>3.3.CO;2-S;
RA Nore B.F., Vargas L., Mohamed A.J., Branden L.J., Backesjo C.M.,
RA Islam T.C., Mattsson P.T., Hultenby K., Christensson B., Smith C.I.;
RT "Redistribution of Bruton's tyrosine kinase by activation of
RT phosphatidylinositol 3-kinase and Rho-family GTPases.";
RL Eur. J. Immunol. 30:145-154(2000).
RN [20]
RP SUBCELLULAR LOCATION.
RX PubMed=11016936; DOI=10.1074/jbc.M006952200;
RA Mohamed A.J., Vargas L., Nore B.F., Backesjo C.M., Christensson B.,
RA Smith C.I.;
RT "Nucleocytoplasmic shuttling of Bruton's tyrosine kinase.";
RL J. Biol. Chem. 275:40614-40619(2000).
RN [21]
RP PHOSPHORYLATION AT SER-180, AND ENZYME REGULATION.
RX PubMed=11598012; DOI=10.1093/emboj/20.20.5692;
RA Kang S.W., Wahl M.I., Chu J., Kitaura J., Kawakami Y., Kato R.M.,
RA Tabuchi R., Tarakhovsky A., Kawakami T., Turck C.W., Witte O.N.,
RA Rawlings D.J.;
RT "PKCbeta modulates antigen receptor signaling via regulation of Btk
RT membrane localization.";
RL EMBO J. 20:5692-5702(2001).
RN [22]
RP FUNCTION IN PHOSPHORYLATION OF PLCG2.
RX PubMed=11606584; DOI=10.1074/jbc.M107577200;
RA Rodriguez R., Matsuda M., Perisic O., Bravo J., Paul A., Jones N.P.,
RA Light Y., Swann K., Williams R.L., Katan M.;
RT "Tyrosine residues in phospholipase Cgamma 2 essential for the enzyme
RT function in B-cell signaling.";
RL J. Biol. Chem. 276:47982-47992(2001).
RN [23]
RP INTERACTION WITH IBTK, AND ENZYME REGULATION.
RX PubMed=11577348; DOI=10.1038/ni1001-939;
RA Liu W., Quinto I., Chen X., Palmieri C., Rabin R.L., Schwartz O.M.,
RA Nelson D.L., Scala G.;
RT "Direct inhibition of Bruton's tyrosine kinase by IBtk, a Btk-binding
RT protein.";
RL Nat. Immunol. 2:939-946(2001).
RN [24]
RP DOMAIN, INTERACTION WITH CAV1, SUBCELLULAR LOCATION, AND ENZYME
RP REGULATION.
RX PubMed=11751885; DOI=10.1074/jbc.M108537200;
RA Vargas L., Nore B.F., Berglof A., Heinonen J.E., Mattsson P.T.,
RA Smith C.I., Mohamed A.J.;
RT "Functional interaction of caveolin-1 with Bruton's tyrosine kinase
RT and Bmx.";
RL J. Biol. Chem. 277:9351-9357(2002).
RN [25]
RP PHOSPHORYLATION AT TYR-617 AND SER-623, AND MUTAGENESIS OF TYR-617.
RX PubMed=15375214; DOI=10.1073/pnas.0405878101;
RA Guo S., Ferl G.Z., Deora R., Riedinger M., Yin S., Kerwin J.L.,
RA Loo J.A., Witte O.N.;
RT "A phosphorylation site in Bruton's tyrosine kinase selectively
RT regulates B cell calcium signaling efficiency by altering
RT phospholipase C-gamma activation.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:14180-14185(2004).
RN [26]
RP INTERACTION WITH PIN1, PHOSPHORYLATION AT SER-21 AND SER-115, AND
RP ENZYME REGULATION.
RX PubMed=16644721; DOI=10.1074/jbc.M603090200;
RA Yu L., Mohamed A.J., Vargas L., Berglof A., Finn G., Lu K.P.,
RA Smith C.I.;
RT "Regulation of Bruton tyrosine kinase by the peptidylprolyl isomerase
RT Pin1.";
RL J. Biol. Chem. 281:18201-18207(2006).
RN [27]
RP FUNCTION IN THE TLR PATHWAY.
RX PubMed=16517732;
RA Horwood N.J., Page T.H., McDaid J.P., Palmer C.D., Campbell J.,
RA Mahon T., Brennan F.M., Webster D., Foxwell B.M.;
RT "Bruton's tyrosine kinase is required for TLR2 and TLR4-induced TNF,
RT but not IL-6, production.";
RL J. Immunol. 176:3635-3641(2006).
RN [28]
RP INTERACTION WITH GTF2I AND ARID3A, AND FUNCTION.
RX PubMed=16738337; DOI=10.1128/MCB.02009-05;
RA Rajaiya J., Nixon J.C., Ayers N., Desgranges Z.P., Roy A.L.,
RA Webb C.F.;
RT "Induction of immunoglobulin heavy-chain transcription through the
RT transcription factor Bright requires TFII-I.";
RL Mol. Cell. Biol. 26:4758-4768(2006).
RN [29]
RP FUNCTION IN PHOSPHORYLATION OF TIRAP, AND ENZYME REGULATION.
RX PubMed=16415872; DOI=10.1038/ni1299;
RA Mansell A., Smith R., Doyle S.L., Gray P., Fenner J.E., Crack P.J.,
RA Nicholson S.E., Hilton D.J., O'Neill L.A., Hertzog P.J.;
RT "Suppressor of cytokine signaling 1 negatively regulates Toll-like
RT receptor signaling by mediating Mal degradation.";
RL Nat. Immunol. 7:148-155(2006).
RN [30]
RP FUNCTION, INTERACTION WITH TLR8 AND TLR9, ENZYME REGULATION, AND
RP PHOSPHORYLATION AT TYR-223.
RX PubMed=17932028; DOI=10.1074/jbc.M707682200;
RA Doyle S.L., Jefferies C.A., Feighery C., O'Neill L.A.;
RT "Signaling by Toll-like receptors 8 and 9 requires Bruton's tyrosine
RT kinase.";
RL J. Biol. Chem. 282:36953-36960(2007).
RN [31]
RP INTERACTION WITH FASLG.
RX PubMed=19807924; DOI=10.1186/1471-2172-10-53;
RA Voss M., Lettau M., Janssen O.;
RT "Identification of SH3 domain interaction partners of human FasL
RT (CD178) by phage display screening.";
RL BMC Immunol. 10:53-53(2009).
RN [32]
RP REVIEW ON FUNCTION IN REGULATION OF APOPTOSIS.
RX PubMed=9751072; DOI=10.1016/S0006-2952(98)00122-1;
RA Uckun F.M.;
RT "Bruton's tyrosine kinase (BTK) as a dual-function regulator of
RT apoptosis.";
RL Biochem. Pharmacol. 56:683-691(1998).
RN [33]
RP REVIEW ON FUNCTION, AND REVIEW ON ENZYME REGULATION.
RX PubMed=19290921; DOI=10.1111/j.1600-065X.2008.00741.x;
RA Mohamed A.J., Yu L., Backesjo C.M., Vargas L., Faryal R., Aints A.,
RA Christensson B., Berglof A., Vihinen M., Nore B.F., Smith C.I.;
RT "Bruton's tyrosine kinase (Btk): function, regulation, and
RT transformation with special emphasis on the PH domain.";
RL Immunol. Rev. 228:58-73(2009).
RN [34]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-55; THR-191; TYR-361 AND
RP SER-659, AND MASS SPECTROMETRY.
RX PubMed=19369195; DOI=10.1074/mcp.M800588-MCP200;
RA Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G.,
RA Mann M., Daub H.;
RT "Large-scale proteomics analysis of the human kinome.";
RL Mol. Cell. Proteomics 8:1751-1764(2009).
RN [35]
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 [36]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 2-170 IN COMPLEX WITH ZINC.
RX PubMed=9218782; DOI=10.1093/emboj/16.12.3396;
RA Hyvoenen M., Saraste M.;
RT "Structure of the PH domain and Btk motif from Bruton's tyrosine
RT kinase: molecular explanations for X-linked agammaglobulinaemia.";
RL EMBO J. 16:3396-3404(1997).
RN [37]
RP STRUCTURE BY NMR OF 212-275.
RX PubMed=9485443; DOI=10.1021/bi972409f;
RA Hansson H., Mattsson P.T., Allard P., Haapaniemi P., Vihinen M.,
RA Smith C.I.E., Haerd T.;
RT "Solution structure of the SH3 domain from Bruton's tyrosine kinase.";
RL Biochemistry 37:2912-2924(1998).
RN [38]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 1-170 IN COMPLEX WITH
RP INOSITOL-(1,3,4,5)-TETRAKISPHOSPHATE AND ZINC, AND DOMAIN PH.
RX PubMed=10196129; DOI=10.1016/S0969-2126(99)80057-4;
RA Baraldi E., Carugo K.D., Hyvoenen M., Surdo P.L., Riley A.M.,
RA Potter B.V.L., O'Brien R., Ladbury J.E., Saraste M.;
RT "Structure of the PH domain from Bruton's tyrosine kinase in complex
RT with inositol 1,3,4,5-tetrakisphosphate.";
RL Structure 7:449-460(1999).
RN [39]
RP STRUCTURE BY NMR OF 216-273.
RX PubMed=10826882; DOI=10.1023/A:1008376624863;
RA Tzeng S.R., Lou Y.C., Pai M.T., Jain M.L., Cheng J.W.;
RT "Solution structure of the human BTK SH3 domain complexed with a
RT proline-rich peptide from p120cbl.";
RL J. Biomol. NMR 16:303-312(2000).
RN [40]
RP X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 397-659.
RX PubMed=11527964; DOI=10.1074/jbc.M104828200;
RA Mao C., Zhou M., Uckun F.M.;
RT "Crystal structure of Bruton's tyrosine kinase domain suggests a novel
RT pathway for activation and provides insights into the molecular basis
RT of X-linked agammaglobulinemia.";
RL J. Biol. Chem. 276:41435-41443(2001).
RN [41]
RP STRUCTURE BY NMR OF 270-386.
RX PubMed=16969585; DOI=10.1007/s10858-006-9064-3;
RA Huang K.C., Cheng H.T., Pai M.T., Tzeng S.R., Cheng J.W.;
RT "Solution structure and phosphopeptide binding of the SH2 domain from
RT the human Bruton's tyrosine kinase.";
RL J. Biomol. NMR 36:73-78(2006).
RN [42]
RP X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 393-656 IN COMPLEX WITH
RP INHIBITOR.
RA Di Paolo J.A., Huang T., Balazs M., Barbosa J., Barck K.H.,
RA Carano R.A.D., Darrow J., Davies D.R., DeForge L.E., Dennis G. Jr.,
RA Diehl L., Ferrando R.;
RT "A novel, specific Btk inhibitor antagonizes BCR and Fc[gamma]R
RT signaling and suppresses inflammatory arthritis.";
RL Submitted (AUG-2010) to the PDB data bank.
RN [43]
RP X-RAY CRYSTALLOGRAPHY (2.58 ANGSTROMS) OF 2-170 IN COMPLEX WITH
RP INHIBITOR AND ZINC.
RA Murayama K., Kato-Murayama M., Mishima C., Shirouzu M., Yokoyama S.;
RT "Crystal structure of PH domain of Bruton's tyrosine kinase.";
RL Submitted (MAY-2007) to the PDB data bank.
RN [44]
RP X-RAY CRYSTALLOGRAPHY (1.6 ANGSTROMS) OF 382-659 IN COMPLEX WITH
RP INHIBITOR DASATINIB.
RX PubMed=20052711; DOI=10.1002/pro.321;
RA Marcotte D.J., Liu Y.T., Arduini R.M., Hession C.A., Miatkowski K.,
RA Wildes C.P., Cullen P.F., Hong V., Hopkins B.T., Mertsching E.,
RA Jenkins T.J., Romanowski M.J., Baker D.P., Silvian L.F.;
RT "Structures of human Bruton's tyrosine kinase in active and inactive
RT conformations suggest a mechanism of activation for TEC family
RT kinases.";
RL Protein Sci. 19:429-439(2010).
RN [45]
RP X-RAY CRYSTALLOGRAPHY (2.30 ANGSTROMS) OF 393-659.
RA Di Paolo J., Huang T., Balazs M., Barbosa J., Barck K.H., Bravo B.,
RA Carano R.A.D., Darrow J., Davies D.R., DeForge L.E., Diehl L.,
RA Ferrando R., Gallion S.L., Gianetti A.M., Gribling P., Hurez V.,
RA Hymowitz S.G., Jones R., Kropf J.E., Lee W.P., Maciejewski P.M.,
RA Mitchell S.A., Rong H., Staker B.L., Whitney J.A., Yeh S., Young W.,
RA Yu C., Zhang J., Reif K., Currie K.S.;
RT "A novel, specific BTK inhibitor antagonizes BCR and FcgR signaling
RT and suppresses inflammatory arthritis.";
RL Submitted (SEP-2010) to the PDB data bank.
RN [46]
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS) OF 387-659 IN COMPLEX WITH
RP INHIBITOR.
RX PubMed=21280133; DOI=10.1002/pro.575;
RA Kuglstatter A., Wong A., Tsing S., Lee S.W., Lou Y., Villasenor A.G.,
RA Bradshaw J.M., Shaw D., Barnett J.W., Browner M.F.;
RT "Insights into the conformational flexibility of Bruton's tyrosine
RT kinase from multiple ligand complex structures.";
RL Protein Sci. 20:428-436(2011).
RN [47]
RP REVIEW ON VARIANTS XLA.
RX PubMed=8594569; DOI=10.1093/nar/24.1.160;
RA Vihinen M., Iwata T., Kinnon C., Kwan S.-P., Ochs H.D.,
RA Vorechovsky I., Smith C.I.E.;
RT "BTKbase, mutation database for X-linked agammaglobulinemia (XLA).";
RL Nucleic Acids Res. 24:160-165(1996).
RN [48]
RP REVIEW ON VARIANTS XLA.
RX PubMed=9016530; DOI=10.1093/nar/25.1.166;
RA Vihinen M., Belohradsky B.H., Haire R.N., Holinski-Feder E.,
RA Kwan S.-P., Lappalainen I., Lehvaeslaiho H., Lester T., Meindl A.,
RA Ochs H.D., Ollila J., Vorechovsky I., Weiss M., Smith C.I.E.;
RT "BTKbase, mutation database for X-linked agammaglobulinemia (XLA).";
RL Nucleic Acids Res. 25:166-171(1997).
RN [49]
RP VARIANTS XLA TRP-288; GLY-307; ASP-607 AND
RP SER-VAL-PHE-SER-SER-THR-ARG-103 INS.
RX PubMed=8162056; DOI=10.1093/hmg/3.1.79;
RA Bradley L.A.D., Sweatman A.K., Lovering R.C., Jones A.M., Morgan G.,
RA Levinsky R.J., Kinnon C.;
RT "Mutation detection in the X-linked agammaglobulinemia gene, BTK,
RT using single strand conformation polymorphism analysis.";
RL Hum. Mol. Genet. 3:79-83(1994).
RN [50]
RP VARIANTS XLA HIS-28 AND TRP-288.
RX PubMed=8162018; DOI=10.1093/hmg/3.1.161;
RA de Weers M., Mensink R.G.J., Kraakman M.E.M., Schuurman R.K.B.,
RA Hendriks R.W.;
RT "Mutation analysis of the Bruton's tyrosine kinase gene in X-linked
RT agammaglobulinemia: identification of a mutation which affects the
RT same codon as is altered in immunodeficient xid mice.";
RL Hum. Mol. Genet. 3:161-166(1994).
RN [51]
RP VARIANTS XLA ASP-113; CYS-361; GLN-520; PRO-542; TRP-562; LYS-630 AND
RP PRO-652.
RX PubMed=7849697; DOI=10.1093/hmg/3.10.1751;
RA Conley M.E., Fitch-Hilgenberg M.E., Cleveland J.L., Parolini O.,
RA Rohrer J.;
RT "Screening of genomic DNA to identify mutations in the gene for
RT Bruton's tyrosine kinase.";
RL Hum. Mol. Genet. 3:1751-1756(1994).
RN [52]
RP VARIANTS XLA HIS-28; PRO-33; PRO-408; GLY-589; ASP-613 AND
RP 260-GLN--GLU-280 DEL.
RX PubMed=7849721; DOI=10.1093/hmg/3.10.1899;
RA Zhu Q., Zhang M., Winkelstein J., Chen S.-H., Ochs H.D.;
RT "Unique mutations of Bruton's tyrosine kinase in fourteen unrelated X-
RT linked agammaglobulinemia families.";
RL Hum. Mol. Genet. 3:1899-1900(1994).
RN [53]
RP VARIANTS XLA GLU-430; GLN-520; GLN-525; PRO-562; VAL-582; GLY-589;
RP GLU-594 AND ASP-613.
RX PubMed=7809124; DOI=10.1073/pnas.91.26.12803;
RA Vihinen M., Vetrie D., Maniar H.S., Ochs H.D., Zhu Q., Vorechovsky I.,
RA Webster A.D.B., Notarangelo L.D., Nilsson L., Sowadski J.M.,
RA Smith C.I.E.;
RT "Structural basis for chromosome X-linked agammaglobulinemia: a
RT tyrosine kinase disease.";
RL Proc. Natl. Acad. Sci. U.S.A. 91:12803-12807(1994).
RN [54]
RP VARIANT XLA PHE-64, AND CHARACTERIZATION OF OTHER XLA VARIANTS.
RX PubMed=7849006; DOI=10.1021/bi00005a002;
RA Vihinen M., Zvelebil J.J.M., Zhu Q., Brooimans R.A., Ochs H.D.,
RA Zegers B.J.M., Nilsson L., Waterfield M.D., Smith C.I.E.;
RT "Structural basis for pleckstrin homology domain mutations in X-linked
RT agammaglobulinemia.";
RL Biochemistry 34:1475-1481(1995).
RN [55]
RP VARIANTS XLA SER-25; TRP-288; MET-370; VAL-509; PRO-525; LYS-526;
RP TRP-562; VAL-582 AND ARG-594.
RX PubMed=7711734;
RA Vorechovsky I., Vihinen M., de Saint Basile G., Honsova S.,
RA Hammarstroem L., Mueller S., Nilsson L., Fischer A., Smith C.I.E.;
RT "DNA-based mutation analysis of Bruton's tyrosine kinase gene in
RT patients with X-linked agammaglobulinaemia.";
RL Hum. Mol. Genet. 4:51-58(1995).
RN [56]
RP VARIANTS XLA LYS-567; LEU-587 AND HIS-641.
RX PubMed=7633420; DOI=10.1093/hmg/4.4.693;
RA Jin H., Webster A.D.B., Vihinen M., Sideras P., Vorechovsky I.,
RA Hammarstroem L., Bernatowska-Matuszkiewicz E., Smith C.I.E.,
RA Bobrow M., Vetrie D.;
RT "Identification of Btk mutations in 20 unrelated patients with X-
RT linked agammaglobulinaemia (XLA).";
RL Hum. Mol. Genet. 4:693-700(1995).
RN [57]
RP VARIANTS XLA PRO-33; GLY-302 DEL; GLN-520 AND CYS-641.
RX PubMed=7633429; DOI=10.1093/hmg/4.4.755;
RA Gaspar H.B., Bradley L.A.D., Katz F., Lovering R.C., Roifman C.M.,
RA Morgan G., Levinsky R.J., Kinnon C.;
RT "Mutation analysis in Bruton's tyrosine kinase, the X-linked
RT agammaglobulinaemia gene, including identification of an insertional
RT hotspot.";
RL Hum. Mol. Genet. 4:755-757(1995).
RN [58]
RP VARIANTS XLA ASN-429 AND ARG-477.
RX PubMed=8634718; DOI=10.1093/hmg/4.12.2403;
RA Vorechovsky I., Luo L., de Saint Basile G., Hammarstroem L.,
RA Webster A.D.B., Smith C.I.E.;
RT "Improved oligonucleotide primer set for molecular diagnosis of X-
RT linked agammaglobulinaemia: predominance of amino acid substitutions
RT in the catalytic domain of Bruton's tyrosine kinase.";
RL Hum. Mol. Genet. 4:2403-2405(1995).
RN [59]
RP VARIANTS XLA GLU-302 AND ASP-476.
RX PubMed=7627183; DOI=10.1002/humu.1380050405;
RA Hagemann T.L., Rosen F.S., Kwan S.-P.;
RT "Characterization of germline mutations of the gene encoding Bruton's
RT tyrosine kinase in families with X-linked agammaglobulinemia.";
RL Hum. Mutat. 5:296-302(1995).
RN [60]
RP VARIANT XLA PHE-358.
RX PubMed=7897635;
RA Ohashi Y., Tsuchiya S., Konno T.;
RT "A new point mutation involving a highly conserved leucine in the Btk
RT SH2 domain in a family with X linked agammaglobulinaemia.";
RL J. Med. Genet. 32:77-79(1995).
RN [61]
RP VARIANT XLA PRO-295.
RX PubMed=8723128;
RX DOI=10.1002/(SICI)1096-8628(19960503)63:1<318::AID-AJMG53>3.0.CO;2-N;
RA Schuster V., Seidenspinner S., Kreth H.W.;
RT "Detection of a novel mutation in the SRC homology domain 2 (SH2) of
RT Bruton's tyrosine kinase and direct female carrier evaluation in a
RT family with X-linked agammaglobulinemia.";
RL Am. J. Med. Genet. 63:318-322(1996).
RN [62]
RP VARIANTS XLA ARG-12; PRO-28; GLU-302; TRP-502; HIS-521; TYR-633 AND
RP SER-644.
RX PubMed=8695804;
RA Hashimoto S., Tsukada S., Matsushita M., Miyawaki T., Niida Y.,
RA Yachie A., Kobayashi S., Iwata T., Hayakawa H., Matsuoka H., Tsuge I.,
RA Yamadori T., Kunikata T., Arai S., Yoshizaki K., Taniguchi N.,
RA Kishimoto T.;
RT "Identification of Bruton's tyrosine kinase (Btk) gene mutations and
RT characterization of the derived proteins in 35 X-linked
RT agammaglobulinemia families: a nationwide study of Btk deficiency in
RT Japan.";
RL Blood 88:561-573(1996).
RN [63]
RP VARIANTS XLA TRP-288; LYS-544 AND PRO-592.
RX PubMed=8834236; DOI=10.1007/s004390050066;
RA Kobayashi S., Iwata T., Saito M., Iwasaki R., Matsumoto H.,
RA Naritaka S., Kono Y., Hayashi Y.;
RT "Mutations of the Btk gene in 12 unrelated families with X-linked
RT agammaglobulinemia in Japan.";
RL Hum. Genet. 97:424-430(1996).
RN [64]
RP VARIANTS XLA SER-154 AND ARG-155.
RX PubMed=9280283; DOI=10.1016/S0014-5793(97)00912-5;
RA Vihinen M., Nore B., Mattsson P.T., Backesj C.-M., Nars M.,
RA Koutaniemi S., Watanabe C., Lester T., Jones A.M., Ochs H.D.,
RA Smith C.I.E.;
RT "Missense mutations affecting a conserved cysteine pair in the TH
RT domain of Btk.";
RL FEBS Lett. 413:205-210(1997).
RN [65]
RP VARIANTS XLA.
RX PubMed=9260159;
RA Saha B.K., Curtis S.K., Vogler L.B., Vihinen M.;
RT "Molecular and structural characterization of five novel mutations in
RT the Bruton's tyrosine kinase gene from patients with X-linked
RT agammaglobulinemia.";
RL Mol. Med. 3:477-485(1997).
RN [66]
RP VARIANTS XLA GLN-288; THR-307; ARG-430; ASP-445; GLY-525; PHE-535;
RP LEU-563 AND PRO-622.
RX PubMed=9545398; DOI=10.1086/301828;
RA Conley M.E., Mathias D., Treadaway J., Minegishi Y., Rohrer J.;
RT "Mutations in btk in patients with presumed X-linked
RT agammaglobulinemia.";
RL Am. J. Hum. Genet. 62:1034-1043(1998).
RN [67]
RP VARIANTS XLA GLU-19; HIS-28; ASN-61; PRO-117; HIS-127; ARG-155;
RP PRO-295; PHE-369; GLY-372; ARG-414; TYR-506; GLY-521; GLN-525;
RP SER-559; TRP-562; GLU-594; THR-619; GLY-626 AND HIS-641.
RX PubMed=9445504;
RA Holinski-Feder E., Weiss M., Brandau O., Jedele K.B., Nore B.,
RA Baeckesjoe C.-M., Vihinen M., Hubbard S.R., Belohradsky B.H.,
RA Smith C.I.E., Meindl A.;
RT "Mutation screening of the BTK gene in 56 families with X-linked
RT agammaglobulinemia (XLA): 47 unique mutations without correlation to
RT clinical course.";
RL Pediatrics 101:276-284(1998).
RN [68]
RP VARIANTS XLA.
RX PubMed=10220140;
RX DOI=10.1002/(SICI)1098-1004(1999)13:4<280::AID-HUMU3>3.0.CO;2-L;
RA Vihinen M., Kwan S.-P., Lester T., Ochs H.D., Resnick I., Vaeliaho J.,
RA Conley M.E., Smith C.I.E.;
RT "Mutations of the human BTK gene coding for Bruton tyrosine kinase in
RT X-linked agammaglobulinemia.";
RL Hum. Mutat. 13:280-285(1999).
RN [69]
RP VARIANT XLA PRO-562.
RX PubMed=10678660;
RX DOI=10.1002/(SICI)1096-8628(20000131)90:3<229::AID-AJMG8>3.0.CO;2-Q;
RA Curtis S.K., Hebert M.D., Saha B.K.;
RT "Twin carriers of X-linked agammaglobulinemia (XLA) due to germline
RT mutation in the Btk gene.";
RL Am. J. Med. Genet. 90:229-232(2000).
RN [70]
RP VARIANTS XLA SER-39; PRO-512; GLN-512; GLY-544; TYR-578 AND LYS-589.
RX PubMed=10612838;
RX DOI=10.1002/(SICI)1098-1004(200001)15:1<117::AID-HUMU26>3.0.CO;2-H;
RA Orlandi P., Ritis K., Moschese V., Angelini F., Arvanitidis K.,
RA Speletas M., Sideras P., Plebani A., Rossi P.;
RT "Identification of nine novel mutations in the Bruton's tyrosine
RT kinase gene in X-linked agammaglobulinaemia patients.";
RL Hum. Mutat. 15:117-117(2000).
RN [71]
RP VARIANTS [LARGE SCALE ANALYSIS] LYS-82 AND LYS-190.
RX PubMed=17344846; DOI=10.1038/nature05610;
RA Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C.,
RA Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S.,
RA O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S.,
RA Bhamra G., Buck G., Choudhury B., Clements J., Cole J., Dicks E.,
RA Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J.,
RA Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K.,
RA Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T.,
RA West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P.,
RA Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E.,
RA DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E.,
RA Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T.,
RA Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R.;
RT "Patterns of somatic mutation in human cancer genomes.";
RL Nature 446:153-158(2007).
CC -!- FUNCTION: Non-receptor tyrosine kinase indispensable for B
CC lymphocyte development, differentiation and signaling. Binding of
CC antigen to the B-cell antigen receptor (BCR) triggers signaling
CC that ultimately leads to B-cell activation. After BCR engagement
CC and activation at the plasma membrane, phosphorylates PLCG2 at
CC several sites, igniting the downstream signaling pathway through
CC calcium mobilization, followed by activation of the protein kinase
CC C (PKC) family members. PLCG2 phosphorylation is performed in
CC close cooperation with the adapter protein B-cell linker protein
CC BLNK. BTK acts as a platform to bring together a diverse array of
CC signaling proteins and is implicated in cytokine receptor
CC signaling pathways. Plays an important role in the function of
CC immune cells of innate as well as adaptive immunity, as a
CC component of the Toll-like receptors (TLR) pathway. The TLR
CC pathway acts as a primary surveillance system for the detection of
CC pathogens and are crucial to the activation of host defense.
CC Especially, is a critical molecule in regulating TLR9 activation
CC in splenic B-cells. Within the TLR pathway, induces tyrosine
CC phosphorylation of TIRAP which leads to TIRAP degradation. BTK
CC plays also a critical role in transcription regulation. Induces
CC the activity of NF-kappa-B, which is involved in regulating the
CC expression of hundreds of genes. BTK is involved on the signaling
CC pathway linking TLR8 and TLR9 to NF-kappa-B. Transiently
CC phosphorylates transcription factor GTF2I on tyrosine residues in
CC response to BCR. GTF2I then translocates to the nucleus to bind
CC regulatory enhancer elements to modulate gene expression. ARID3A
CC and NFAT are other transcriptional target of BTK. BTK is required
CC for the formation of functional ARID3A DNA-binding complexes.
CC There is however no evidence that BTK itself binds directly to
CC DNA. BTK has a dual role in the regulation of apoptosis.
CC -!- CATALYTIC ACTIVITY: ATP + a [protein]-L-tyrosine = ADP + a
CC [protein]-L-tyrosine phosphate.
CC -!- COFACTOR: Binds 1 zinc ion per subunit.
CC -!- ENZYME REGULATION: Activated by phosphorylation. In primary B
CC lymphocytes, is almost always non-phosphorylated and is thus
CC catalytically inactive. Stimulation of TLR8 and TLR9 causes BTK
CC activation. As a negative feedback mechanism to fine-tune BCR
CC signaling, activated PRKCB down-modulates BTK function via direct
CC phosphorylation of BTK at Ser-180, resulting in translocation of
CC BTK back to the cytoplasmic fraction. PIN1, SH3BP5, and IBTK were
CC also identified as BTK activity inhibitors. Interaction with CAV1
CC leads to dramatic down-regulation of the kinase activity of BTK.
CC LFM-13A is a specific inhibitor of BTK. Dasatinib, a cancer drug
CC acting as a tyrosine kinase inhibitor, also blocks BTK activity.
CC -!- SUBUNIT: Binds GTF2I through the PH domain. Interacts with SH3BP5
CC via the SH3 domain. Interacts with IBTK via its PH domain.
CC Interacts with ARID3A, CAV1, FASLG, PIN1, TLR8 and TLR9.
CC -!- INTERACTION:
CC Self; NbExp=2; IntAct=EBI-624835, EBI-624835;
CC Q99856:ARID3A; NbExp=3; IntAct=EBI-624835, EBI-5458244;
CC Q8WV28:BLNK; NbExp=2; IntAct=EBI-624835, EBI-2623522;
CC P78347:GTF2I; NbExp=6; IntAct=EBI-624835, EBI-359622;
CC P08238:HSP90AB1; NbExp=2; IntAct=EBI-624835, EBI-352572;
CC P21145:MAL; NbExp=5; IntAct=EBI-624835, EBI-3932027;
CC Q04759:PRKCQ; NbExp=2; IntAct=EBI-624835, EBI-374762;
CC O60239:SH3BP5; NbExp=4; IntAct=EBI-624835, EBI-624860;
CC -!- SUBCELLULAR LOCATION: Cytoplasm. Cell membrane; Peripheral
CC membrane protein. Nucleus. Note=In steady state, BTK is
CC predominantly cytosolic. Following B-cell receptor (BCR)
CC engagement by antigen, translocates to the plasma membrane through
CC its PH domain. Plasma membrane localization is a critical step in
CC the activation of BTK. A fraction of BTK also shuttles between the
CC nucleus and the cytoplasm, and nuclear export is mediated by the
CC nuclear export receptor CRM1.
CC -!- TISSUE SPECIFICITY: Predominantly expressed in B-lymphocytes.
CC -!- DOMAIN: The PH domain mediates the binding to inositol
CC polyphosphate and phosphoinositides, leading to its targeting to
CC the plasma membrane. It is extended in the BTK kinase family by a
CC region designated the TH (Tec homology) domain, which consists of
CC about 80 residues preceding the SH3 domain.
CC -!- PTM: Following B-cell receptor (BCR) engagement, translocates to
CC the plasma membrane where it gets phosphorylated at Tyr-551 by LYN
CC and SYK. Phosphorylation at Tyr-551 is followed by
CC autophosphorylation of Tyr-223 which may create a docking site for
CC a SH2 containing protein. Phosphorylation at Ser-180 by PRKCB,
CC leads in translocation of BTK back to the cytoplasmic fraction.
CC Phosphorylation at Ser-21 and Ser-115 creates a binding site for
CC PIN1 at these Ser-Pro motifs, and promotes it's recruitment.
CC -!- DISEASE: X-linked agammaglobulinemia (XLA) [MIM:300755]: Humoral
CC immunodeficiency disease which results in developmental defects in
CC the maturation pathway of B-cells. Affected boys have normal
CC levels of pre-B-cells in their bone marrow but virtually no
CC circulating mature B-lymphocytes. This results in a lack of
CC immunoglobulins of all classes and leads to recurrent bacterial
CC infections like otitis, conjunctivitis, dermatitis, sinusitis in
CC the first few years of life, or even some patients present
CC overwhelming sepsis or meningitis, resulting in death in a few
CC hours. Treatment in most cases is by infusion of intravenous
CC immunoglobulin. Note=The disease is caused by mutations affecting
CC the gene represented in this entry.
CC -!- DISEASE: X-linked hypogammaglobulinemia and isolated growth
CC hormone deficiency (XLA-IGHD) [MIM:307200]: In rare cases XLA is
CC inherited together with isolated growth hormone deficiency (IGHD).
CC Note=The disease may be caused by mutations affecting the gene
CC represented in this entry.
CC -!- SIMILARITY: Belongs to the protein kinase superfamily. Tyr protein
CC kinase family. TEC subfamily.
CC -!- SIMILARITY: Contains 1 Btk-type zinc finger.
CC -!- SIMILARITY: Contains 1 PH domain.
CC -!- SIMILARITY: Contains 1 protein kinase domain.
CC -!- SIMILARITY: Contains 1 SH2 domain.
CC -!- SIMILARITY: Contains 1 SH3 domain.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology
CC and Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/BTKID851chXq22.html";
CC -!- WEB RESOURCE: Name=BTKbase; Note=BTK mutation db;
CC URL="http://bioinf.uta.fi/BTKbase/";
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/BTK";
CC -----------------------------------------------------------------------
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DR EMBL; X58957; CAA41728.1; -; mRNA.
DR EMBL; U10087; AAB60639.1; -; Genomic_DNA.
DR EMBL; U10084; AAB60639.1; JOINED; Genomic_DNA.
DR EMBL; U10085; AAB60639.1; JOINED; Genomic_DNA.
DR EMBL; U10086; AAB60639.1; JOINED; Genomic_DNA.
DR EMBL; L31572; AAA61479.1; -; Genomic_DNA.
DR EMBL; L31557; AAA61479.1; JOINED; Genomic_DNA.
DR EMBL; L31558; AAA61479.1; JOINED; Genomic_DNA.
DR EMBL; L31559; AAA61479.1; JOINED; Genomic_DNA.
DR EMBL; L31561; AAA61479.1; JOINED; Genomic_DNA.
DR EMBL; L31563; AAA61479.1; JOINED; Genomic_DNA.
DR EMBL; L31564; AAA61479.1; JOINED; Genomic_DNA.
DR EMBL; L31565; AAA61479.1; JOINED; Genomic_DNA.
DR EMBL; L31566; AAA61479.1; JOINED; Genomic_DNA.
DR EMBL; L31567; AAA61479.1; JOINED; Genomic_DNA.
DR EMBL; L31568; AAA61479.1; JOINED; Genomic_DNA.
DR EMBL; L31569; AAA61479.1; JOINED; Genomic_DNA.
DR EMBL; L31570; AAA61479.1; JOINED; Genomic_DNA.
DR EMBL; L31571; AAA61479.1; JOINED; Genomic_DNA.
DR EMBL; U13433; AAC51347.1; -; Genomic_DNA.
DR EMBL; U13410; AAC51347.1; JOINED; Genomic_DNA.
DR EMBL; U13412; AAC51347.1; JOINED; Genomic_DNA.
DR EMBL; U13413; AAC51347.1; JOINED; Genomic_DNA.
DR EMBL; U13414; AAC51347.1; JOINED; Genomic_DNA.
DR EMBL; U13415; AAC51347.1; JOINED; Genomic_DNA.
DR EMBL; U13416; AAC51347.1; JOINED; Genomic_DNA.
DR EMBL; U13417; AAC51347.1; JOINED; Genomic_DNA.
DR EMBL; U13422; AAC51347.1; JOINED; Genomic_DNA.
DR EMBL; U13423; AAC51347.1; JOINED; Genomic_DNA.
DR EMBL; U13424; AAC51347.1; JOINED; Genomic_DNA.
DR EMBL; U13425; AAC51347.1; JOINED; Genomic_DNA.
DR EMBL; U13427; AAC51347.1; JOINED; Genomic_DNA.
DR EMBL; U13428; AAC51347.1; JOINED; Genomic_DNA.
DR EMBL; U13429; AAC51347.1; JOINED; Genomic_DNA.
DR EMBL; U13430; AAC51347.1; JOINED; Genomic_DNA.
DR EMBL; U13431; AAC51347.1; JOINED; Genomic_DNA.
DR EMBL; U13432; AAC51347.1; JOINED; Genomic_DNA.
DR EMBL; U78027; AAB64205.1; -; Genomic_DNA.
DR EMBL; AL035422; CAB55876.1; -; Genomic_DNA.
DR EMBL; BC109079; AAI09080.1; -; mRNA.
DR EMBL; BC109080; AAI09081.1; -; mRNA.
DR PIR; I37212; A45184.
DR RefSeq; NP_000052.1; NM_000061.2.
DR UniGene; Hs.159494; -.
DR PDB; 1AWW; NMR; -; A=212-275.
DR PDB; 1AWX; NMR; -; A=212-275.
DR PDB; 1B55; X-ray; 2.40 A; A/B=2-170.
DR PDB; 1BTK; X-ray; 1.60 A; A/B=2-170.
DR PDB; 1BWN; X-ray; 2.10 A; A/B=2-170.
DR PDB; 1K2P; X-ray; 2.10 A; A/B=397-659.
DR PDB; 1QLY; NMR; -; A=216-273.
DR PDB; 2GE9; NMR; -; A=270-386.
DR PDB; 2Z0P; X-ray; 2.58 A; A/B/C/D=2-170.
DR PDB; 3GEN; X-ray; 1.60 A; A=382-659.
DR PDB; 3K54; X-ray; 1.94 A; A=382-659.
DR PDB; 3OCS; X-ray; 1.80 A; A=393-657.
DR PDB; 3OCT; X-ray; 1.95 A; A=393-656.
DR PDB; 3P08; X-ray; 2.30 A; A/B=393-659.
DR PDB; 3PIX; X-ray; 1.85 A; A=387-659.
DR PDB; 3PIY; X-ray; 2.55 A; A=387-659.
DR PDB; 3PIZ; X-ray; 2.21 A; A=387-659.
DR PDB; 3PJ1; X-ray; 2.00 A; A=387-659.
DR PDB; 3PJ2; X-ray; 1.75 A; A=387-659.
DR PDB; 3PJ3; X-ray; 1.85 A; A=387-659.
DR PDBsum; 1AWW; -.
DR PDBsum; 1AWX; -.
DR PDBsum; 1B55; -.
DR PDBsum; 1BTK; -.
DR PDBsum; 1BWN; -.
DR PDBsum; 1K2P; -.
DR PDBsum; 1QLY; -.
DR PDBsum; 2GE9; -.
DR PDBsum; 2Z0P; -.
DR PDBsum; 3GEN; -.
DR PDBsum; 3K54; -.
DR PDBsum; 3OCS; -.
DR PDBsum; 3OCT; -.
DR PDBsum; 3P08; -.
DR PDBsum; 3PIX; -.
DR PDBsum; 3PIY; -.
DR PDBsum; 3PIZ; -.
DR PDBsum; 3PJ1; -.
DR PDBsum; 3PJ2; -.
DR PDBsum; 3PJ3; -.
DR ProteinModelPortal; Q06187; -.
DR SMR; Q06187; 2-170, 216-387, 395-657.
DR DIP; DIP-34071N; -.
DR IntAct; Q06187; 41.
DR MINT; MINT-110243; -.
DR STRING; 9606.ENSP00000308176; -.
DR BindingDB; Q06187; -.
DR ChEMBL; CHEMBL5251; -.
DR GuidetoPHARMACOLOGY; 1948; -.
DR PhosphoSite; Q06187; -.
DR DMDM; 547759; -.
DR PaxDb; Q06187; -.
DR PRIDE; Q06187; -.
DR DNASU; 695; -.
DR Ensembl; ENST00000308731; ENSP00000308176; ENSG00000010671.
DR Ensembl; ENST00000593575; ENSP00000469726; ENSG00000268897.
DR GeneID; 695; -.
DR KEGG; hsa:695; -.
DR UCSC; uc004ehg.2; human.
DR CTD; 695; -.
DR GeneCards; GC0XM100604; -.
DR HGNC; HGNC:1133; BTK.
DR HPA; CAB016689; -.
DR HPA; HPA001198; -.
DR HPA; HPA002028; -.
DR MIM; 300300; gene.
DR MIM; 300755; phenotype.
DR MIM; 307200; phenotype.
DR neXtProt; NX_Q06187; -.
DR Orphanet; 632; Short stature due to isolated growth hormone deficiency with X-linked hypogammaglobulinemia.
DR Orphanet; 47; X-linked agammaglobulinemia.
DR PharmGKB; PA25454; -.
DR eggNOG; COG0515; -.
DR HOGENOM; HOG000233859; -.
DR HOVERGEN; HBG008761; -.
DR InParanoid; Q06187; -.
DR KO; K07370; -.
DR OMA; SCRHYNI; -.
DR PhylomeDB; Q06187; -.
DR BRENDA; 2.7.10.2; 2681.
DR Reactome; REACT_6900; Immune System.
DR SignaLink; Q06187; -.
DR EvolutionaryTrace; Q06187; -.
DR GeneWiki; Bruton%27s_tyrosine_kinase; -.
DR GenomeRNAi; 695; -.
DR NextBio; 2850; -.
DR PRO; PR:Q06187; -.
DR ArrayExpress; Q06187; -.
DR Bgee; Q06187; -.
DR CleanEx; HS_BTK; -.
DR Genevestigator; Q06187; -.
DR GO; GO:0031410; C:cytoplasmic vesicle; IEA:Ensembl.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0045121; C:membrane raft; IDA:HGNC.
DR GO; GO:0005634; C:nucleus; TAS:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; TAS:HGNC.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004715; F:non-membrane spanning protein tyrosine kinase activity; TAS:UniProtKB.
DR GO; GO:0005547; F:phosphatidylinositol-3,4,5-trisphosphate binding; IDA:UniProtKB.
DR GO; GO:0002250; P:adaptive immune response; TAS:UniProtKB.
DR GO; GO:0097190; P:apoptotic signaling pathway; TAS:ProtInc.
DR GO; GO:0042113; P:B cell activation; TAS:UniProtKB.
DR GO; GO:0050853; P:B cell receptor signaling pathway; TAS:UniProtKB.
DR GO; GO:0019722; P:calcium-mediated signaling; TAS:HGNC.
DR GO; GO:0048469; P:cell maturation; IEA:Ensembl.
DR GO; GO:0038095; P:Fc-epsilon receptor signaling pathway; TAS:Reactome.
DR GO; GO:0007249; P:I-kappaB kinase/NF-kappaB cascade; IEA:Ensembl.
DR GO; GO:0045087; P:innate immune response; TAS:UniProtKB.
DR GO; GO:0007498; P:mesoderm development; TAS:ProtInc.
DR GO; GO:0002755; P:MyD88-dependent toll-like receptor signaling pathway; TAS:Reactome.
DR GO; GO:0045579; P:positive regulation of B cell differentiation; TAS:UniProtKB.
DR GO; GO:0051092; P:positive regulation of NF-kappaB transcription factor activity; TAS:UniProtKB.
DR GO; GO:0002902; P:regulation of B cell apoptotic process; TAS:UniProtKB.
DR GO; GO:0002721; P:regulation of B cell cytokine production; TAS:UniProtKB.
DR GO; GO:0034134; P:toll-like receptor 2 signaling pathway; TAS:Reactome.
DR GO; GO:0034142; P:toll-like receptor 4 signaling pathway; TAS:Reactome.
DR GO; GO:0038123; P:toll-like receptor TLR1:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0038124; P:toll-like receptor TLR6:TLR2 signaling pathway; TAS:Reactome.
DR GO; GO:0006351; P:transcription, DNA-dependent; IEA:UniProtKB-KW.
DR Gene3D; 2.30.29.30; -; 1.
DR Gene3D; 3.30.505.10; -; 1.
DR InterPro; IPR011009; Kinase-like_dom.
DR InterPro; IPR011993; PH_like_dom.
DR InterPro; IPR001849; Pleckstrin_homology.
DR InterPro; IPR000719; Prot_kinase_dom.
DR InterPro; IPR017441; Protein_kinase_ATP_BS.
DR InterPro; IPR001245; Ser-Thr/Tyr_kinase_cat_dom.
DR InterPro; IPR000980; SH2.
DR InterPro; IPR001452; SH3_domain.
DR InterPro; IPR008266; Tyr_kinase_AS.
DR InterPro; IPR020635; Tyr_kinase_cat_dom.
DR InterPro; IPR001562; Znf_Btk_motif.
DR Pfam; PF00779; BTK; 1.
DR Pfam; PF00169; PH; 1.
DR Pfam; PF07714; Pkinase_Tyr; 1.
DR Pfam; PF00017; SH2; 1.
DR Pfam; PF00018; SH3_1; 1.
DR PRINTS; PR00401; SH2DOMAIN.
DR PRINTS; PR00452; SH3DOMAIN.
DR PRINTS; PR00402; TECBTKDOMAIN.
DR PRINTS; PR00109; TYRKINASE.
DR SMART; SM00107; BTK; 1.
DR SMART; SM00233; PH; 1.
DR SMART; SM00252; SH2; 1.
DR SMART; SM00326; SH3; 1.
DR SMART; SM00219; TyrKc; 1.
DR SUPFAM; SSF50044; SSF50044; 1.
DR SUPFAM; SSF56112; SSF56112; 1.
DR PROSITE; PS50003; PH_DOMAIN; 1.
DR PROSITE; PS00107; PROTEIN_KINASE_ATP; 1.
DR PROSITE; PS50011; PROTEIN_KINASE_DOM; 1.
DR PROSITE; PS00109; PROTEIN_KINASE_TYR; 1.
DR PROSITE; PS50001; SH2; 1.
DR PROSITE; PS50002; SH3; 1.
DR PROSITE; PS51113; ZF_BTK; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Adaptive immunity; Apoptosis; ATP-binding;
KW Cell membrane; Complete proteome; Cytoplasm;
KW Direct protein sequencing; Disease mutation; Immunity;
KW Innate immunity; Kinase; Lipid-binding; Membrane; Metal-binding;
KW Nucleotide-binding; Nucleus; Phosphoprotein; Polymorphism;
KW Reference proteome; SH2 domain; SH3 domain; Transcription;
KW Transcription regulation; Transferase; Tyrosine-protein kinase; Zinc;
KW Zinc-finger.
FT INIT_MET 1 1 Removed.
FT CHAIN 2 659 Tyrosine-protein kinase BTK.
FT /FTId=PRO_0000088065.
FT DOMAIN 3 133 PH.
FT DOMAIN 214 274 SH3.
FT DOMAIN 281 377 SH2.
FT DOMAIN 402 655 Protein kinase.
FT ZN_FING 135 171 Btk-type.
FT NP_BIND 408 416 ATP (By similarity).
FT REGION 12 24 Inositol-(1,3,4,5)-tetrakisphosphate 1-
FT binding.
FT REGION 474 479 Inhibitor-binding.
FT MOTIF 581 588 CAV1-binding.
FT ACT_SITE 521 521 Proton acceptor (By similarity).
FT METAL 143 143 Zinc.
FT METAL 154 154 Zinc.
FT METAL 155 155 Zinc.
FT METAL 165 165 Zinc.
FT BINDING 26 26 Inositol-(1,3,4,5)-tetrakisphosphate.
FT BINDING 28 28 Inositol-(1,3,4,5)-tetrakisphosphate.
FT BINDING 39 39 Inositol-(1,3,4,5)-tetrakisphosphate.
FT BINDING 53 53 Inositol-(1,3,4,5)-tetrakisphosphate; via
FT carbonyl oxygen.
FT BINDING 430 430 ATP (By similarity).
FT BINDING 445 445 Inhibitor.
FT BINDING 461 461 Inhibitor.
FT BINDING 477 477 Inhibitor.
FT BINDING 538 538 Inhibitor.
FT BINDING 539 539 Inhibitor; via amide nitrogen.
FT BINDING 542 542 Inhibitor; via carbonyl oxygen.
FT MOD_RES 2 2 N-acetylalanine.
FT MOD_RES 21 21 Phosphoserine.
FT MOD_RES 40 40 Phosphotyrosine (By similarity).
FT MOD_RES 55 55 Phosphoserine.
FT MOD_RES 115 115 Phosphoserine.
FT MOD_RES 180 180 Phosphoserine; by PKC/PRKCB.
FT MOD_RES 191 191 Phosphothreonine.
FT MOD_RES 223 223 Phosphotyrosine; by autocatalysis.
FT MOD_RES 344 344 Phosphotyrosine (By similarity).
FT MOD_RES 361 361 Phosphotyrosine.
FT MOD_RES 551 551 Phosphotyrosine; by LYN and SYK.
FT MOD_RES 617 617 Phosphotyrosine.
FT MOD_RES 623 623 Phosphoserine.
FT MOD_RES 659 659 Phosphoserine.
FT VARIANT 11 11 L -> P (in XLA).
FT /FTId=VAR_006216.
FT VARIANT 12 12 K -> R (in XLA).
FT /FTId=VAR_006217.
FT VARIANT 14 14 S -> F (in XLA).
FT /FTId=VAR_006218.
FT VARIANT 19 19 K -> E (in XLA).
FT /FTId=VAR_008291.
FT VARIANT 25 25 F -> S (in XLA).
FT /FTId=VAR_006219.
FT VARIANT 27 27 K -> R (in XLA).
FT /FTId=VAR_008292.
FT VARIANT 28 28 R -> C (in XLA; no effect on
FT phosphorylation of GTF2I).
FT /FTId=VAR_008293.
FT VARIANT 28 28 R -> H (in XLA; moderate).
FT /FTId=VAR_006220.
FT VARIANT 28 28 R -> P (in XLA).
FT /FTId=VAR_006221.
FT VARIANT 33 33 T -> P (in XLA; severe).
FT /FTId=VAR_006222.
FT VARIANT 39 39 Y -> S (in XLA).
FT /FTId=VAR_008960.
FT VARIANT 40 40 Y -> C (in XLA).
FT /FTId=VAR_008294.
FT VARIANT 40 40 Y -> N (in XLA).
FT /FTId=VAR_008295.
FT VARIANT 61 61 I -> N (in XLA).
FT /FTId=VAR_008296.
FT VARIANT 64 64 V -> D (in XLA).
FT /FTId=VAR_008297.
FT VARIANT 64 64 V -> F (in XLA).
FT /FTId=VAR_006223.
FT VARIANT 82 82 R -> K (in dbSNP:rs56035945).
FT /FTId=VAR_041676.
FT VARIANT 103 103 Q -> QSVFSSTR (in XLA).
FT /FTId=VAR_006224.
FT VARIANT 113 113 V -> D (in XLA).
FT /FTId=VAR_006225.
FT VARIANT 115 115 S -> F (in XLA).
FT /FTId=VAR_008298.
FT VARIANT 117 117 T -> P (in XLA).
FT /FTId=VAR_008299.
FT VARIANT 127 127 Q -> H (in XLA).
FT /FTId=VAR_008300.
FT VARIANT 154 154 C -> S (in XLA).
FT /FTId=VAR_008301.
FT VARIANT 155 155 C -> G (in XLA).
FT /FTId=VAR_008302.
FT VARIANT 155 155 C -> R (in XLA).
FT /FTId=VAR_008303.
FT VARIANT 184 184 T -> P (in XLA).
FT /FTId=VAR_008304.
FT VARIANT 190 190 P -> K (in a lung large cell carcinoma
FT sample; somatic mutation; requires 2
FT nucleotide substitutions).
FT /FTId=VAR_041677.
FT VARIANT 260 280 Missing (in XLA; severe).
FT /FTId=VAR_006226.
FT VARIANT 288 288 R -> Q (in XLA).
FT /FTId=VAR_008305.
FT VARIANT 288 288 R -> W (in XLA).
FT /FTId=VAR_006227.
FT VARIANT 295 295 L -> P (in XLA).
FT /FTId=VAR_006228.
FT VARIANT 302 302 G -> E (in XLA).
FT /FTId=VAR_006230.
FT VARIANT 302 302 G -> R (in XLA).
FT /FTId=VAR_008306.
FT VARIANT 302 302 Missing (in XLA).
FT /FTId=VAR_006229.
FT VARIANT 307 307 R -> G (in XLA; loss of activity).
FT /FTId=VAR_006231.
FT VARIANT 307 307 R -> T (in XLA).
FT /FTId=VAR_008307.
FT VARIANT 308 308 D -> E (in XLA).
FT /FTId=VAR_008308.
FT VARIANT 319 319 V -> A (in XLA; moderate).
FT /FTId=VAR_008309.
FT VARIANT 334 334 Y -> S (in XLA).
FT /FTId=VAR_006232.
FT VARIANT 358 358 L -> F (in XLA).
FT /FTId=VAR_006233.
FT VARIANT 361 361 Y -> C (in XLA; mild; dbSNP:rs28935478).
FT /FTId=VAR_006234.
FT VARIANT 362 362 H -> Q (in XLA).
FT /FTId=VAR_006235.
FT VARIANT 364 364 H -> P (in XLA).
FT /FTId=VAR_006236.
FT VARIANT 365 365 N -> Y (in XLA).
FT /FTId=VAR_006237.
FT VARIANT 366 366 S -> F (in XLA).
FT /FTId=VAR_008310.
FT VARIANT 369 369 L -> F (in XLA).
FT /FTId=VAR_008311.
FT VARIANT 370 370 I -> M (in XLA).
FT /FTId=VAR_006238.
FT VARIANT 372 372 R -> G (in XLA).
FT /FTId=VAR_008312.
FT VARIANT 408 408 L -> P (in XLA; moderate).
FT /FTId=VAR_006239.
FT VARIANT 414 414 G -> R (in XLA).
FT /FTId=VAR_008313.
FT VARIANT 418 418 Y -> H (in XLA).
FT /FTId=VAR_006240.
FT VARIANT 429 429 I -> N (in XLA).
FT /FTId=VAR_006241.
FT VARIANT 430 430 K -> E (in XLA; loss of phosphorylation
FT of GTF2I).
FT /FTId=VAR_006242.
FT VARIANT 430 430 K -> R (in XLA).
FT /FTId=VAR_008314.
FT VARIANT 445 445 E -> D (in XLA).
FT /FTId=VAR_008315.
FT VARIANT 462 462 G -> D (in XLA).
FT /FTId=VAR_008316.
FT VARIANT 462 462 G -> V (in XLA).
FT /FTId=VAR_008317.
FT VARIANT 476 476 Y -> D (in XLA).
FT /FTId=VAR_006243.
FT VARIANT 477 477 M -> R (in XLA).
FT /FTId=VAR_006244.
FT VARIANT 502 502 C -> F (in XLA).
FT /FTId=VAR_006245.
FT VARIANT 502 502 C -> W (in XLA).
FT /FTId=VAR_006246.
FT VARIANT 506 506 C -> R (in XLA).
FT /FTId=VAR_006247.
FT VARIANT 506 506 C -> Y (in XLA).
FT /FTId=VAR_006248.
FT VARIANT 508 508 A -> D (in XLA).
FT /FTId=VAR_008318.
FT VARIANT 509 509 M -> I (in XLA).
FT /FTId=VAR_008319.
FT VARIANT 509 509 M -> V (in XLA).
FT /FTId=VAR_006249.
FT VARIANT 512 512 L -> P (in XLA).
FT /FTId=VAR_008961.
FT VARIANT 512 512 L -> Q (in XLA).
FT /FTId=VAR_008962.
FT VARIANT 518 518 L -> R (in XLA).
FT /FTId=VAR_008320.
FT VARIANT 520 520 R -> Q (in XLA; severe; prevents
FT activation due to absence of contact
FT between the catalytic loop and the
FT regulatory phosphorylated residue).
FT /FTId=VAR_006251.
FT VARIANT 521 521 D -> G (in XLA).
FT /FTId=VAR_008321.
FT VARIANT 521 521 D -> H (in XLA; severe).
FT /FTId=VAR_006252.
FT VARIANT 521 521 D -> N (in XLA; severe).
FT /FTId=VAR_006253.
FT VARIANT 523 523 A -> E (in XLA).
FT /FTId=VAR_008322.
FT VARIANT 525 525 R -> G (in XLA).
FT /FTId=VAR_008323.
FT VARIANT 525 525 R -> P (in XLA).
FT /FTId=VAR_006254.
FT VARIANT 525 525 R -> Q (in XLA; severe; disturbs ATP-
FT binding).
FT /FTId=VAR_006255.
FT VARIANT 526 526 N -> K (in XLA).
FT /FTId=VAR_006256.
FT VARIANT 535 535 V -> F (in XLA).
FT /FTId=VAR_008324.
FT VARIANT 542 542 L -> P (in XLA; growth hormone
FT deficiency).
FT /FTId=VAR_006257.
FT VARIANT 544 544 R -> G (in XLA).
FT /FTId=VAR_008963.
FT VARIANT 544 544 R -> K (in XLA).
FT /FTId=VAR_006258.
FT VARIANT 559 559 F -> S (in XLA).
FT /FTId=VAR_008325.
FT VARIANT 562 562 R -> P (in XLA; dbSNP:rs28935176).
FT /FTId=VAR_006259.
FT VARIANT 562 562 R -> W (in XLA).
FT /FTId=VAR_006260.
FT VARIANT 563 563 W -> L (in XLA).
FT /FTId=VAR_008326.
FT VARIANT 567 567 E -> K (in XLA; severe).
FT /FTId=VAR_006261.
FT VARIANT 578 578 S -> Y (in XLA).
FT /FTId=VAR_008964.
FT VARIANT 581 581 W -> R (in XLA).
FT /FTId=VAR_006262.
FT VARIANT 582 582 A -> V (in XLA).
FT /FTId=VAR_006263.
FT VARIANT 583 583 F -> S (in XLA).
FT /FTId=VAR_008327.
FT VARIANT 587 587 M -> L (in XLA; mild).
FT /FTId=VAR_006264.
FT VARIANT 589 589 E -> D (in XLA).
FT /FTId=VAR_008328.
FT VARIANT 589 589 E -> G (in XLA; moderate; interferes with
FT substrate binding).
FT /FTId=VAR_006265.
FT VARIANT 589 589 E -> K (in XLA).
FT /FTId=VAR_008965.
FT VARIANT 592 592 S -> P (in XLA).
FT /FTId=VAR_006267.
FT VARIANT 594 594 G -> E (in XLA; mild; interferes with
FT substrate binding).
FT /FTId=VAR_006268.
FT VARIANT 594 594 G -> R (in XLA).
FT /FTId=VAR_006269.
FT VARIANT 598 598 Y -> C (in XLA).
FT /FTId=VAR_006270.
FT VARIANT 607 607 A -> D (in XLA; mild).
FT /FTId=VAR_006271.
FT VARIANT 613 613 G -> D (in XLA; mild; interferes with
FT substrate binding and/or domain
FT interactions).
FT /FTId=VAR_006272.
FT VARIANT 619 619 P -> A (in XLA).
FT /FTId=VAR_008330.
FT VARIANT 619 619 P -> S (in XLA).
FT /FTId=VAR_006273.
FT VARIANT 619 619 P -> T (in XLA).
FT /FTId=VAR_008331.
FT VARIANT 622 622 A -> P (in XLA).
FT /FTId=VAR_008332.
FT VARIANT 626 626 V -> G (in XLA).
FT /FTId=VAR_008333.
FT VARIANT 630 630 M -> I (polymorphism, 35%).
FT /FTId=VAR_006274.
FT VARIANT 630 630 M -> K (in XLA).
FT /FTId=VAR_006275.
FT VARIANT 630 630 M -> T (in XLA).
FT /FTId=VAR_008334.
FT VARIANT 633 633 C -> Y (in XLA).
FT /FTId=VAR_006276.
FT VARIANT 641 641 R -> C (in XLA).
FT /FTId=VAR_006277.
FT VARIANT 641 641 R -> H (in XLA; severe).
FT /FTId=VAR_006278.
FT VARIANT 644 644 F -> L (in XLA).
FT /FTId=VAR_008335.
FT VARIANT 644 644 F -> S (in XLA).
FT /FTId=VAR_006279.
FT VARIANT 647 647 L -> P (in XLA).
FT /FTId=VAR_006280.
FT VARIANT 652 652 L -> P (in XLA).
FT /FTId=VAR_006281.
FT MUTAGEN 41 41 E->K: No effect on phosphorylation of
FT GTF2I.
FT MUTAGEN 189 189 P->A: No effect on phosphorylation of
FT GTF2I.
FT MUTAGEN 223 223 Y->F: Loss of phosphorylation of GTF2I.
FT MUTAGEN 251 252 WW->LL: Large decrease in binding by
FT SH3BP5.
FT MUTAGEN 251 251 W->L: No effect on phosphorylation of
FT GTF2I.
FT MUTAGEN 307 307 R->K: Loss of phosphorylation of GTF2I.
FT MUTAGEN 551 551 Y->F: Loss of phosphorylation of GTF2I.
FT MUTAGEN 617 617 Y->E: Defective in mediating calcium
FT response.
FT STRAND 6 13
FT STRAND 18 20
FT STRAND 25 32
FT STRAND 34 43
FT TURN 44 47
FT STRAND 48 57
FT HELIX 58 60
FT STRAND 61 66
FT HELIX 75 77
FT HELIX 93 96
FT STRAND 100 106
FT STRAND 111 116
FT HELIX 118 132
FT STRAND 140 142
FT STRAND 149 152
FT TURN 153 155
FT STRAND 165 167
FT TURN 212 215
FT STRAND 218 223
FT STRAND 228 232
FT STRAND 240 242
FT STRAND 248 252
FT TURN 257 259
FT STRAND 261 265
FT TURN 266 268
FT STRAND 279 282
FT HELIX 288 298
FT STRAND 303 308
FT STRAND 310 312
FT STRAND 315 326
FT STRAND 330 335
FT STRAND 337 339
FT TURN 340 342
FT STRAND 343 347
FT STRAND 350 354
FT HELIX 355 363
FT STRAND 373 376
FT HELIX 393 395
FT HELIX 399 401
FT STRAND 402 409
FT TURN 411 413
FT STRAND 414 421
FT TURN 422 424
FT STRAND 425 432
FT HELIX 439 450
FT STRAND 460 464
FT STRAND 466 474
FT HELIX 482 487
FT HELIX 489 491
FT HELIX 495 514
FT HELIX 524 526
FT STRAND 527 529
FT STRAND 535 537
FT HELIX 542 545
FT HELIX 549 552
FT TURN 554 556
FT HELIX 561 563
FT HELIX 566 571
FT HELIX 576 591
FT TURN 592 594
FT TURN 597 600
FT HELIX 603 611
FT HELIX 624 632
FT HELIX 638 640
FT HELIX 644 657
SQ SEQUENCE 659 AA; 76281 MW; DF06B5D1FEC257CC CRC64;
MAAVILESIF LKRSQQKKKT SPLNFKKRLF LLTVHKLSYY EYDFERGRRG SKKGSIDVEK
ITCVETVVPE KNPPPERQIP RRGEESSEME QISIIERFPY PFQVVYDEGP LYVFSPTEEL
RKRWIHQLKN VIRYNSDLVQ KYHPCFWIDG QYLCCSQTAK NAMGCQILEN RNGSLKPGSS
HRKTKKPLPP TPEEDQILKK PLPPEPAAAP VSTSELKKVV ALYDYMPMNA NDLQLRKGDE
YFILEESNLP WWRARDKNGQ EGYIPSNYVT EAEDSIEMYE WYSKHMTRSQ AEQLLKQEGK
EGGFIVRDSS KAGKYTVSVF AKSTGDPQGV IRHYVVCSTP QSQYYLAEKH LFSTIPELIN
YHQHNSAGLI SRLKYPVSQQ NKNAPSTAGL GYGSWEIDPK DLTFLKELGT GQFGVVKYGK
WRGQYDVAIK MIKEGSMSED EFIEEAKVMM NLSHEKLVQL YGVCTKQRPI FIITEYMANG
CLLNYLREMR HRFQTQQLLE MCKDVCEAME YLESKQFLHR DLAARNCLVN DQGVVKVSDF
GLSRYVLDDE YTSSVGSKFP VRWSPPEVLM YSKFSSKSDI WAFGVLMWEI YSLGKMPYER
FTNSETAEHI AQGLRLYRPH LASEKVYTIM YSCWHEKADE RPTFKILLSN ILDVMDEES
//

MIM 300300
*RECORD*
*FIELD* NO
300300
*FIELD* TI
*300300 BRUTON AGAMMAGLOBULINEMIA TYROSINE KINASE; BTK
;;AGAMMAGLOBULINEMIA TYROSINE KINASE; ATK;;
read moreB-CELL PROGENITOR KINASE; BPK
*FIELD* TX

DESCRIPTION

BTK is a key regulator of B-cell development. Mutations in the BTK gene
result in X-linked agammaglobulinemia (XLA; 300755), an immunodeficiency
characterized by failure to produce mature B lymphocytes and associated
with a failure of Ig heavy chain rearrangement (Rawlings and Witte,
1994).

CLONING

Using a positional cloning strategy to identify genes within the XLA
locus on the X chromosome, followed by screening a cDNA library derived
from a Burkitt lymphoma cell line, Vetrie et al. (1993) isolated BTK,
which they called ATK. The ORF of ATK encodes a 659-amino acid
polypeptide. Two alternative initiation codons within the same ORF would
result in peptide chains of 571 and 497 amino acids, respectively, if
used. ATK shares a high degree of similarity with members of the SRC
(190090) family of protooncogenes that encode protein-tyrosine kinases.
Northern blot analysis of RNAs derived from lymphoid lineages
demonstrated that the 2.6-kb ATK mRNA was expressed in a B-cell line and
in B cells of 2 patients with chronic lymphocytic leukemia, but not in T
cells or a T-cell line.

Desiderio (1993) compared the structure of ATK and LTK (151520) with
SRC.

Tsukada et al. (1993) independently described BTK as a cytoplasmic
tyrosine kinase that they termed BPK. BPK was expressed in all cells of
the B lineage and in myeloid cells. Tsukada et al. (1993) concluded that
BPK is not a member of the SRC family based on the following
differences: (1) the kinase catalytic domain contains the sequence
DLAARN, which is similar to ABL (189980), FPS (190030), and CSK
(124095), but different from the SRC family (DLRAAN); (2) BPK lacks the
consensus myristoylation signal (glycine at position 2 and lysine or
arginine at position 7); (3) BPK lacks the equivalent of tyrosine 527 in
SRC in the C-terminal domain following the kinase sequences, which is
important in regulation of kinase activity; and (4) the N-terminal
region of BPK is unusually long.

GENE STRUCTURE

Rohrer et al. (1994) determined the genomic organization of the BTK
gene. BTK contains 19 exons and spans 37 kb. The region 5-prime to the
first untranslated exon lacks TATAA or CAAT boxes, but it contains 3
retinoic acid-binding sites.

MAPPING

By in situ hybridization, Vetrie et al. (1993) mapped the BTK gene to
chromosome Xq21.3-q22. Oeltjen et al. (1995) concluded that the 3-prime
end of the GLA gene (300644) is 9 kb from the 5-prime end of the BTK
gene, and they found 2 additional genes in the region immediately
5-prime to BTK.

GENE FUNCTION

Tsukada et al. (1993) found that BPK mRNA, protein expression, and
kinase activity were all reduced or absent in XLA pre-B and B cell
lines.

Although evidence from the study of XLA indicated that BTK plays a
crucial role in B-lymphocyte differentiation and activation, its precise
mechanism of action remained unknown, primarily because the proteins
that it interacts with had not been identified until the work of Cheng
et al. (1994). They showed that BTK interacted with SRC homology 3
domains of FYN (137025), LYN (165120), and HCK (142370). All of these
are protein-tyrosine kinases that are activated upon stimulation of B-
and T-cell receptors. These interactions were mediated by two 10-amino
acid motifs in BTK. An analogous site with the same specificity was also
identified in ITK (186973), the T-cell-specific homolog of BTK. The
findings of Cheng et al. (1994) extended the range of interactions
mediated by SRC homology 3 domains and provided an indication of a link
between BTK and previously established signaling pathways in B
lymphocytes.

Uckun et al. (1996) noted that a number of human diseases including
immune deficiencies apparently stem from inherited or acquired
deficiencies of checkpoints that regulate the rate of apoptosis in
lymphoid cells. Uckun et al. (1996) reported that DT-40 lymphoma B cells
rendered BTK deficient through targeted disruption of the BTK gene did
not undergo radiation-induced apoptosis. They further demonstrated that
the tyrosine kinase domain of BTK was necessary for triggering
radiation-induced apoptosis.

Ng et al. (2004) tested the specificity of recombinant antibodies from
single peripheral B cells isolated from patients with XLA and found that
XLA B cells were selected to express a unique antibody repertoire using
distinct VH and D genes favoring hydrophobic reading frames normally
counterselected in healthy donor B cells. Patient B cells appeared to
undergo extensive secondary recombination on both IgK (see 147200) and
IgL (see 147220) loci and had a slightly increased proportion of cells
expressing antinuclear antibodies. Ng et al. (2004) concluded that
almost half of the antibodies expressed by XLA B cells are polyreactive
and that BTK is essential for removal of autoreactive B cells.

Hantschel et al. (2007) identified the BTK tyrosine kinase and TEC
kinase (600583) as major binders of the tyrosine kinase inhibitor
dasatinib, which is used for treatment of BCR/ABL (see 151410)-positive
CML (608232). Dasatinib did not bind ITK. In a CML cell line, they
determined that a thr474-to-ile (T474I) substitution in the BTK gene
conferred resistance to dasatinib. They suggested that, like the
structurally homologous thr315 residue in the ABL gene (see
189980.0001), the BTK thr474 residue is the gatekeeper residue critical
for dasatinib binding. Analysis of mast cells derived from Btk-deficient
mice suggested that inhibition of Btk by dasatinib may be responsible
for the observed reduction in histamine release upon dasatinib
treatment. Dasatinib inhibited histamine release in primary human
basophils and secretion of proinflammatory cytokines in immune cells.
The findings suggested that dasatinib may have immunosuppressive side
effects.

Using ELISA, microarray analysis, RT-PCR, and flow cytometry, Hasan et
al. (2007) demonstrated that Btk -/- mouse B cells responded more
efficiently to CpG-DNA stimulation by producing higher levels of
proinflammatory cytokines and Il27 (608273), but lower levels of the
inhibitory cytokine Il10 (124092). Tlr9 (605474) protein and mRNA
expression was enhanced in Btk -/- cells, especially after Tlr9
stimulation. Whereas Btk -/- and wildtype transitional stage-1 (T1) B
cells failed to proliferate and died after CpG stimulation, T2 cells,
expressing higher levels of Tlr9, proliferated and matured. Hasan et al.
(2007) concluded that BTK regulates both TLR9 activation and expression
in B lymphocytes and is necessary for inhibitory cytokine expression.

BIOCHEMICAL FEATURES

Vihinen et al. (1994) used a 3-dimensional model for the BTK kinase
domain, based on the core structure of cAMP-dependent protein kinase, to
interpret the structural basis for disease in 8 independent point
mutations in patients with XLA. Because arg525 of BTK had been thought
to substitute functionally for a critical lysine residue in
protein-serine kinases, they studied the arg525-to-gln mutation and
found that it abrogated the tyrosine kinase activity of BTK. All of the
8 mutations, including lys430-to-glu (300300.0002), were located on one
face of the BTK kinase domain, indicating structural clustering of
functionally important residues.

Mao et al. (2001) determined the x-ray crystal structure of the BTK
kinase domain in its unphosphorylated state to 2.1-angstrom resolution.
The structure suggested that the trans-phosphorylation of tyr551 can
lead to BTK activation by triggering an exchange of hydrogen-bonded
pairs from glu445/arg544 to glu445/lys430 and subsequent relocation of
helix alpha-C of the N-terminal lobe. The model also indicated that
mutations in the C-terminal lobe of the kinase domain, such as R562W
(300300.0042), are directly or indirectly involved in peptide substrate
binding. Other disease-associated mutations in this domain (e.g., E589G;
300300.0044) alter interactions with neighboring residues.

MOLECULAR GENETICS

Using probes derived for the Southern analysis of DNA from 33 unrelated
families and 150 normal X chromosomes, Vetrie et al. (1993) detected
restriction pattern abnormalities in 8 families. Five of them had
deletions that were shown to be entirely intragenic to BTK, confirming
involvement of BTK in XLA. Two single-base missense mutations were
identified in XLA patients. The failure of pre-B cells in the bone
marrow of XLA males to develop into mature, circulating B cells could be
the result of the product of the mutant ATK gene failing to fulfill its
role in B-cell signaling. Vetrie et al. (1993) noted that inactivation
of the mouse Lck gene (153390), another member of the SRC family of
tyrosine kinases, results in a thymocyte differentiation defect.

Vorechovsky et al. (1993) pointed out that common variable
immunodeficiency (CVID) is sometimes clinically and immunologically
indistinguishable from XLA if it starts early in childhood and occurs
sporadically in males with a decreased number of B cells. Using a cDNA
clone that represented the full-length ATK cDNA, Vorechovsky et al.
(1993) did Southern blot analysis of 39 Swedish male patients diagnosed
with CVID or possible CVID. One man in his late 40s, who had had
recurrent respiratory infections from infancy, lacked immunoglobulins of
all isotypes, and had less than 1% B cells among peripheral blood
mononuclear cells, had an abnormality of the ATK gene. The abnormality
was missing in his mother but had been inherited by both of his
daughters.

Vorechovsky et al. (1993) failed to find the arg28-to-cys mutation,
which is found in xid in mice (see ANIMAL MODEL), in 13 unrelated
patients with XLA and 2 patients with the syndrome of XLA and growth
hormone deficiency (307200). They pointed to the milder phenotype of the
xid mouse compared to XLA cases and suggested that if this particular
mutation occurs in the human BTK gene, it might result in a milder
phenotype with normal or only moderately reduced B cells and more
selective immunoglobulin deficiency in boys, which may or may not
increase susceptibility to infections.

Parolini et al. (1993) identified a family in which a healthy father
transmitted the XLA defect to 2 of his daughters, indicating gonadal or
somatic mosaicism. To assess the frequency of this phenomenon, Conley et
al. (1998) evaluated 11 sisters of 7 women who were carriers of XLA and
whose mutation occurred on the paternal haplotype. None of the 11
sisters were carriers of the mutations seen in their nephews.

Duriez et al. (1994) found an exon-skipping mutation in the BTK gene
which appeared to account for the syndrome of X-linked
agammaglobulinemia and isolated growth hormone deficiency in a sporadic
case (see 300300.0004).

Ohta et al. (1994) reported the DNA sequence of the 18 coding exons of
BTK and their flanking regions. Correlations were made between the
nature of mutations and the organization of the BTK gene. They found
several examples of the same mutation occurring in unrelated patients,
and one of these mutations occurred at the same codon that is
substituted in the xid mouse. However, in xid, the mutation occurs at
the first position in the conserved arginine codon, C214-to-T, and
results in an arg28-to-cys amino acid change, whereas in human cases it
occurs in the second nucleotide, G215-to-A, and results in an
arg28-to-his amino acid change (300300.0005). The observations suggested
that a limited number of deleterious changes in BTK produce clinically
recognizable XLA. XLA patients have been classified in 2 general groups:
those presenting at an early age with particularly severe infections and
those with less severe disease in which production of immunoglobulin is
sustained at low-to-normal levels well into the first decade of life. In
the latter cases, an oncogenetic change may occur in which the defective
tyrosine kinase no longer can sustain the B-cell population, and a
progressive reduction in immunoglobulin production occurs. Ohta et al.
(1994) described the arg525-to-gln mutation (300300.0001) in patients
whose disorder might have been classified as common variable
immunodeficiency disease. These patients had low levels of circulating B
cells at an early age with mildly decreased IgM and variable IgG levels,
although all were IgA deficient.

Kornfeld et al. (1995) described the case of a 16-year-old boy who had
recurrent upper respiratory tract infections at 13 months of age and was
diagnosed as having transient hypogammaglobulinemia of infancy on the
basis of low immunoglobulin levels, normal diphtheria and tetanus
antibody responses, normal anterior and posterior cervical nodes, normal
tonsillar tissue, and normal numbers of B cells in the blood. IgA levels
returned to normal at 15 months of age and remained within normal limits
over the next 12 months, and IgG and IgM levels remained relatively
unchanged. At age 10, he began receiving intravenous gammaglobulin,
which resulted in cessation of infections. The clinical picture was
thought to be that of common variable immunodeficiency disease. However,
gene studies revealed the deletion of exon 16 of the BTK gene resulting
from a splice junction defect. The patient represents an example of the
extreme variation that can occur in the XLA phenotype.

Hagemann et al. (1995) described 6 mutations in the BTK gene as the
cause of XLA; 5 were novel. The mutations included 2 nonsense and 2
missense mutations, a single base deletion at an intron acceptor splice
site, and a 16-bp insertion.

Kobayashi et al. (1996) reported abnormalities in the BTK gene in 12
unrelated Japanese families with X-linked agammaglobulinemia. Gene
rearrangement in the kinase domain was found in 2 patients by Southern
blotting. Seven point mutations, 2 small deletions, and 1 small
insertion were detected by SSCP analysis and sequencing. Phenotypic
heterogeneity was observed in affected family members with the same
mutation. The authors concluded that analyzing BTK gene alterations with
SSCP is valuable for the diagnosis of XLA patients and for carrier
detection; however, the correlation between gene abnormalities and
clinical features remains unclear.

Among 26 unrelated patients with XLA, Vorechovsky et al. (1997) found 24
different mutations of the BTK gene. Most resulted in the premature
termination of translation. Mutations were detected in most BTK exons
with a predominance of frameshift and nonsense mutations in the 5-prime
end of the gene and missense mutations in its 3-prime part,
corresponding to the catalytic domain of the enzyme.

Conley et al. (1998) analyzed 101 families in which affected males were
diagnosed as having XLA. Mutations in the BTK gene were identified in 38
of 40 families with more than 1 affected family member and in 56 of 61
families with sporadic disease. Excluding the patients in whom the
marked decrease in B cell numbers characteristic of XLA could not be
confirmed by immunofluorescence studies, mutations in BTK were
identified in 43 of 46 patients with presumed sporadic XLA. Two of the 3
remaining patients had defects in other genes required for normal B cell
development, namely the mu heavy chain gene (IGHM1; 147020), as reported
by Yel et al. (1996) or the lambda-5/14.1 surrogate light chain gene
(IGLL1; 146770), as reported by Minegishi et al. (1998). Both of these
patients were compound heterozygotes and there were no clinical features
that would distinguish them from patients with typical XLA. An
Epstein-Barr virus-transformed cell line from a third patient had normal
BTK cDNA by SSCP, normal BTK message by Northern blot, and normal BTK
protein by Western blot. Therefore, it is unlikely that this patient had
XLA. Ten mutations were found in more than one family; 1 of these
occurred in 3 families. Of the 83 unique mutations included in the study
of Conley et al. (1998), 43 had been described previously by their
laboratory, 5 had been reported by other groups, and 35 had not been
previously described.

In a study of 12 Korean patients with X-linked agammaglobulinemia, Jo et
al. (2001) identified 7 mutations in the BTK gene, including a point
mutation in intron 1 (300300.0055). Luciferase analysis showed reduced
transcriptional activity in the intron-1 mutant compared with the
wildtype. EMSA and functional analysis indicated that a nuclear protein
had the ability to bind to the intron-1 mutant oligonucleotides. Jo et
al. (2001) proposed that several regulatory elements mediate the
transcriptional regulation of BTK and that the first intron is important
in BTK promoter activity.

Sakamoto et al. (2001) suggested maternal germinal mosaicism to explain
the finding of 2 sibs with XLA who had a single base deletion (563C) in
exon 6 of the BTK gene and whose mother had no evidence of the mutation.
Cytoplasmic expression of BTK protein in monocytes was not detected in
either patient; normal cytoplasmic expression of BTK protein was found
in monocytes of the mother.

Martin et al. (2001) identified a 2-bp deletion in the BTK gene
(300300.0054) in a patient with X-linked agammaglobulinemia who
developed classic type I diabetes (see 222100) at the age of 14 years.
Autoantibodies associated with type I diabetes were undetectable, a
result consistent with the diagnosis of X-linked agammaglobulinemia. The
patient's HLA type was the one that is associated with the highest
genetic risk of type I diabetes. The data implied that autoantibodies
are not required for either the initiation or the progression of type I
diabetes. Martin et al. (2001) concluded that type I diabetes can
develop in the absence of both autoantibodies and B cells. This aspect
of its pathogenesis places type I diabetes in marked contrast to
spontaneous autoimmune diabetes in NOD mice, which has been claimed to
be B cell-dependent. The findings suggested that immunotherapy directed
specifically toward B cells or autoantibodies may not be effective in
preventing the destruction of beta cells.

Wattanasirichaigoon et al. (2006) reported 7 different mutations in the
BTK gene among 7 patients with XLA; 4 of the mutations were novel. Six
patients were Thai, and 1 patient was Burmese.

About 60% of DCLRE1C (605988) and IGHM (147020) gene defects involve
gross deletions, compared with about 6% of BTK gene defects. Van Zelm et
al. (2008) compared gross deletion breakpoints involving DCLRE1C, IGHM,
and BTK to identify mechanisms underlying these differences in gross
deletion frequencies. Their analysis suggested that gross deletions
involve transposable elements or large homologous regions rather than
recombination motifs. Van Zelm et al. (2008) hypothesized that the
transposable element content of a gene is related to its gross deletion
frequency.

- BTK Mutation Database

Vihinen et al. (1996) described a database of BTK mutations (BTKbase)
listing entries from 189 unrelated families showing 148 unique molecular
events. Information was included regarding the phenotype. Mutations in
all 5 domains of the BTK had been observed to cause XLA, the most common
class of changes being missense mutations. The mutations appeared almost
uniformly throughout the molecule and frequently affected CpG sites
forming arginine residues. Vihinen et al. (1999) reported that BTKbase
listed 544 mutation entries from 471 unrelated families showing 341
unique molecular events. In addition to mutations, a number of variants
or polymorphisms had been found. Most mutations led to truncation of the
enzyme, and about one-third of point mutations affected CpG sites.

ANIMAL MODEL

Presumably the X-linked B-lymphocyte defect of mice, studied by
Marshall-Clarke et al. (1979), is homologous. This defect is
characteristic of the CBA-N strain of mice (Scher et al., 1975).
Defective mice lack the subpopulation of B lymphocytes responsive to
certain T-independent antigens of which trinitrophenylated (TNP)-Ficoll
is the prototype. Their responses to T-dependent antigens may also be
impaired and they are unable to respond to the hapten phosphorylcholine
(PC). They lack those B cells that form colonies when cultured in vitro.

Cohen et al. (1985) isolated a cDNA probe recognizing a family of genes,
called XLR, on the mouse X chromosome, at least some members of which
are closely linked to the X-linked immunodeficiency (xid) trait.

Linkage studies involving 1,114 progeny backcross revealed
colocalization of the xid mutation in mice with the Btk gene (Thomas et
al., 1993). The xid mutation was associated in mice with a missense
mutation that altered the highly conserved arginine near the N terminus
of the Btk protein. Because this region of the protein lies outside any
obvious kinase domain, the xid mutation may define another aspect of
tyrosine kinase. Rawlings et al. (1993) likewise mapped the xid and the
Btk gene to the same region and demonstrated the same missense mutation,
an arg28-to-cys change.

Drabek et al. (1997) generated transgenic mice in which expression of
the human BTK gene was driven by the murine class II major
histocompatibility complex Ea gene locus control region, which provides
gene expression from the pre-B cell stage onwards. When these transgenic
mice were mated onto a Btk(-) background, correction of the xid B cell
defects was observed: B cells differentiated to mature low IgM/high IgD
stages, peritoneal CD5(+) B cells were present, and serum immunoglobulin
levels and in vivo responses to antigens were in the normal ranges. A
comparable rescue by transgenic Btk expression was also observed in
heterozygous Btk +/- female mice in those B-lineage cells that were
Btk-deficient as a result of X-chromosome inactivation.

Kawakami et al. (2006) found that dendritic cells of Btk-null mice
exhibited a more mature phenotype and a stronger in vitro and in vivo T
cell-stimulatory ability than wildtype cells. Increased IgE responses
were induced by adoptive transfer of Btk-null dendritic cells into
wildtype mice. Consistent with the stronger T cell-stimulatory ability
of Btk-null dendritic cells, Btk-null mice exhibited enhanced
inflammation in T helper cell 2-driven asthma and T helper cell 1-driven
contact sensitivity experiments. The negative regulatory functions of
Btk in dendritic cells appeared to be mediated mainly through autocrine
secretion of IL10 (124092) and subsequent activation of Stat3 (102582).

Using Tec (600583) -/- Btk -/- double-knockout mice, Shinohara et al.
(2008) showed that these tyrosine kinases were crucial in Rankl
(TNFSF11; 602642)-induced osteoclastogenesis. In response to Rankl
stimulation, Btk and Tec formed a signaling complex required for
osteoclastogenesis with adaptor molecules such as Blnk (604515), which
also recruited Syk (600085), linking Rank (TNFRSF11A; 603499) and ITAM
(see 608740) signals to phosphorylate Plc-gamma (see 172420). Tec kinase
inhibition reduced osteoclastic bone resorption in models of
osteoporosis and inflammation-induced bone destruction. Shinohara et al.
(2008) concluded that their studies provided a link between
immunodeficiency and abnormal bone homeostasis owing to defects in
signaling molecules shared by B cells and osteoclasts.

*FIELD* AV
.0001
AGAMMAGLOBULINEMIA, X-LINKED
BTK, ARG525GLN

In a patient with X-linked agammaglobulinemia (300755), Vetrie et al.
(1993) identified a G-to-A transition at nucleotide 1706, resulting in a
change of arginine-525 to glutamine. This conserved amino acid
substitution was predicted to have a highly detrimental effect on the
catalytic function of the putative protein-tyrosine kinase. Loss of the
conserved arg525 could prevent substrate recognition because this
residue is thought to be important in the substrate-specific domain.
Ohta et al. (1994) also described the arg525-to-gln mutation in a family
in which the diagnosis of common variable immunodeficiency disease had
been made.

.0002
AGAMMAGLOBULINEMIA, X-LINKED
BTK, LYS430GLU

In a patient with X-linked agammaglobulinemia (300755), Vetrie et al.
(1993) identified an A-to-G transition at position 1420, resulting in a
substitution of glutamic acid for lysine-430. Substitution of lys430
(equivalent to lys295 of v-src) within the ATP-binding site would
completely abolish kinase activity.

.0003
HYPOAGAMMAGLOBULINEMIA, X-LINKED
BTK, TYR361CYS

Like most other cytoplasmic tyrosine kinases, the Bruton tyrosine kinase
contains a unique amino terminal region, SH3 and SH2 domains (short for
SRC homology 3 and 2, respectively), and a carboxy-terminal kinase
domain. In a patient with atypical X-linked agammaglobulinemia (300755),
Saffran et al. (1994) found a point mutation in the SH2 domain of BTK in
a B-cell line. SH2 domains are critical mediators of binding with
phosphotyrosine-containing proteins in the cell. The mutation was
located in what crystal-structure studies of the SRC SH2 domain predict
is a critical hydrophobic binding pocket. The consequence of this
mutation is predicted to be decreased stability of the BTK protein,
possibly resulting from the inability of BTK to interact with important
substrates. The patient was a 23-year-old man who was the oldest of 3
brothers previously described as having atypical X-linked
agammaglobulinemia by Conley and Puck (1988). A diagnosis of
hypogammaglobulinemia was made when the proband was 6 years old and his
brothers were 5 and 2 years old. Without therapy, the patient's serum
IgG concentration was 590 mg per deciliter. All 3 brothers had 0.3 to 2%
B cells in the peripheral circulation, whereas patients with typical
Bruton agammaglobulinemia have a mean of 0.1% and normal subjects have 5
to 15% B cells. Although the patient complied poorly with therapy, he
had not had serious infections. The single point mutation found in the
SH2 domain of the coding sequence changed amino acid residue 361 from
tyrosine to cysteine as a result of a TAC-to-TGC transition. Buckley
(1994), who provided a diagram of the structure of the BTK protein,
suggested that some of the other less severe antibody-deficiency
syndromes in humans could be caused by mutations in the non-kinase
portions of the BTK gene. In addition, she pointed with interest to the
fact that BTK is also expressed in cells of the myeloid lineage and that
it is well known that intermittent neutropenia occurs in boys with
X-linked agammaglobulinemia, particularly at the height of an acute
infection (Buckley and Rowlands, 1973). She raised the possibility that
BTK is only one of the signaling molecules in myeloid maturation and
that neutropenia may develop in X-linked agammaglobulinemia only when
white cell production is rapid.

In a patient with mild X-linked agammaglobulinemia, Conley et al. (1994)
identified an A-to-G transition in exon 12, resulting in a substitution
of cysteine for tyrosine-361.

.0004
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE III
BTK, IVS17DS, G-A, +5

In a sporadic case of the syndrome of X-linked agammaglobulinemia and
isolated growth hormone deficiency (307200), Duriez et al. (1994)
analyzed the BTK gene by RT-PCR, sequencing of cDNA and genomic DNA, and
in vitro splicing assays to demonstrate an intronic point mutation,
1882+5G-A, located in the tyrosine kinase domain. This exon-skipping
event resulted in a frameshift leading to a premature stop codon 14
amino acids downstream and in the loss of the last 61 residues of the
carboxy-terminal end of the protein. The possibility that a mutant form
of BTK may give rise to XLA alone in most cases but that some mutant
forms can generate both XLA and IGHD suggests that the BTK gene is
expressed in the pituitary gland. To test this hypothesis, Duriez et al.
(1994) carried out 30 cycles of RT-PCR on mRNA from pituitaries, and the
product was sequenced. This led to the detection of a specific BTK
amplification product of expected size and sequence. The finding tempted
Duriez et al. (1994) to speculate that the protein tyrosine kinase
encoded by the BTK gene plays a role in the biosynthesis or secretion of
growth hormone and that some mutant forms of the BTK protein can impair
both the production of growth hormone and the development of B lineage
cells. They stated that 'characterisation of additional BTK gene
mutations in the rare patients inheriting both XLA and IGHD is eagerly
awaited.'

.0005
AGAMMAGLOBULINEMIA, X-LINKED
BTK, ARG28HIS

Ohta et al. (1994) described cases of X-linked agammaglobulinemia
(300755) with a G-to-A transition at nucleotide 215 resulting in an
arg28-to-his (R28H) amino acid replacement. The same amino acid change
occurs as the cause of xid in the mouse but the mutation is a C-to-T
transition at nucleotide 214. The arg28-to-his mutation was described in
a case of XLA by de Weers et al. (1994).

Wood et al. (2001) found the R28H mutation in a 25-year-old man with a
selective antipolysaccharide antibody deficiency whose IgG levels had
fallen slightly below the normal range since the age of 23 years but who
had remained well on antibiotic prophylaxis for 12 years. The authors
suggested that male patients with antipolysaccharide antibody deficiency
should be evaluated for B-cell lymphopenia and BTK mutations.

.0006
AGAMMAGLOBULINEMIA, X-LINKED
BTK, MET1THR

There is little concordance of phenotype with genotype in XLA (300755)
and defects in BTK cause immunodeficiencies that range from mild
impairment to complete inability to produce antibodies. The factors
modifying the phenotype of XLA are not understood. Bykowsky et al.
(1996) described 2 brothers with a T-to-C transition of nucleotide 134
that resulted in change of the translation initiation ATG (met) to ACG
(thr). The brothers had different clinical and laboratory phenotypes.
The proband lacked immunoglobulins and B cells and had recurrent
infections, whereas his older affected brother had normal levels of IgG
and IgM and very few infections. Both had undetectable levels of BTK
kinase activity in circulating mononuclear cells. Complete sequencing of
the BTK gene transcripts in both brothers revealed no additional
mutations to account for the discordant phenotypes.

.0007
HYPOGAMMAGLOBULINEMIA, X-LINKED
BTK, ALA-ASP, 1952C-A

Jones et al. (1996) described 3 brothers affected by immunodeficiency
characterized by low B cell numbers and hypogammaglobulinemia (300755),
but normal T cell numbers and function. One brother presented at the age
of 2 years with pneumococcal pneumonia and empyema requiring
thoracotomy. He had a history of recurrent chest infections and severe
otitis media. He developed pneumococcal meningitis at 5 years, at which
time the diagnosis of hypogammaglobulinemia was first made. The second
brother presented at the age of 2 years with a cervical abscess,
followed several months later by an episode of pneumococcal meningitis.
At 3 years he developed pneumococcal pericarditis requiring
pericardiectomy. This occurred concurrently with his elder brother's
pneumococcal meningitis, and as a result both boys were investigated and
found to have hypogammaglobulinemia. Both boys received routine
immunizations as well as Pneumovax. The third brother was identified by
screening at the age of 8 weeks because of immunodeficiency in the older
brothers. None of the brothers had received regular immunoglobulin
replacement treatment. Analysis of cDNA prepared from the 3 affected
brothers identified a single nucleotide alteration (C-to-A) at
nucleotide 1952 (1952C-A). This resulted in a nonpolar-to-polar amino
acid substitution (alanine to aspartic acid) in the kinase domain near
the C-terminal end of the BTK protein.

.0008
AGAMMAGLOBULINEMIA, X-LINKED
BTK, ARG13TER

In 2 patients with X-linked agammaglobulinemia (300755), Conley et al.
(1994) identified a C-to-T transition at a CpG dinucleotide in exon 2,
resulting in a stop codon at position 13 and a truncated protein.

.0009
AGAMMAGLOBULINEMIA, X-LINKED
BTK, GLN15TER

In a patient with X-linked agammaglobulinemia (300755), Conley et al.
(1994) identified a C-to-T transition at a CpG dinucleotide in exon 2,
resulting in a stop codon at position 15 and a truncated protein.

.0010
AGAMMAGLOBULINEMIA, X-LINKED
BTK, THR33PRO

In 2 patients with severe X-linked agammaglobulinemia (300755), Zhu et
al. (1994) identified an A-to-C transition at position 229, resulting in
a substitution of proline for threonine-33. This mutation was found in
the pleckstrin homology domain.

.0011
AGAMMAGLOBULINEMIA, X-LINKED
BTK, 4-BP DEL, CODON 76, GAAA

In a patient with X-linked agammaglobulinemia (300755), Conley et al.
(1994) identified a 4-bp (GAAA) deletion at codons 76 and 77 in exon 3,
resulting in a frameshift and a premature stop codon at position 120.

.0012
AGAMMAGLOBULINEMIA, X-LINKED
BTK, 2-BP DEL, IVS2DS, +3AA

In a patient with X-linked agammaglobulinemia (300755), Hagemann et al.
(1994) identified a 2-bp deletion at the 5-prime end of intron 2. Two
adenines were deleted from positions +3 and +4 of the consensus sequence
GTAAGT at the donor splice site. Although the deletion does not break
the GT/AG boundary rule, the resulting donor splice site does not match
the consensus sequence, and the mutation would most likely result in
exon 2 skipping. This would remove the 5-prime end of the coding
sequence, including the translation start site and the PH domain.

.0013
AGAMMAGLOBULINEMIA, X-LINKED
BTK, IVS4AS, G-C, -1

In a patient with X-linked agammaglobulinemia (300755), Hagemann et al.
(1994) identified a G-to-C substitution, which is the first nucleotide
of the acceptor splice site of intron 4, that breaks the GT/AG
exon-intron boundary rule. The skipping of exon 5 would cause a
frameshift.

.0014
AGAMMAGLOBULINEMIA, X-LINKED
BTK, 21-BP INS, NT442

In a patient with X-linked agammaglobulinemia (300755), Bradley et al.
(1994) identified a 21-bp insertion at position 442 in the 5-prime
terminal region, resulting in an in-frame insertion of 7 amino acids
(ser-val-phe-ser-ser-thr-arg) between amino acids 103 and 104 in the
protein. Hagemann et al. (1994) found that the inserted sequence matched
the 3-prime acceptor sequence of intron 4 except for an A-to-G
transition at position -2 from the 3-prime end. This base substitution
breaks the GT/AG boundary rule. An alternative splice site 22-bp
upstream of the normal 3-prime intron boundary matches the AG acceptor
consensus sequence and would explain the 21-bp inserted sequence from
the patient's cDNA.

.0015
AGAMMAGLOBULINEMIA, X-LINKED
BTK, VAL113ASP

In a patient with severe X-linked agammaglobulinemia (300755), Conley et
al. (1994) identified a T-to-A transition in exon 5, resulting in a
substitution of aspartic acid for valine-113 in the pleckstrin homology
domain. This patient was below the fifth percentile in height, but when
evaluated for growth hormone deficiency, was found to have normal growth
hormone production. It is possible that other genetic or environmental
factors, in concert with absent or defective Btk, cause growth hormone
deficiency.

.0016
AGAMMAGLOBULINEMIA, X-LINKED
BTK, 1-BP DEL, CODON 130, A

In a patient with X-linked agammaglobulinemia (300755), Conley et al.
(1994) identified a 1-bp (A) deletion at codon 130 in exon 5, resulting
in a frameshift.

.0017
AGAMMAGLOBULINEMIA, X-LINKED
BTK, 1-BP INS, CODON 186, A

In a patient with X-linked agammaglobulinemia (300755), Conley et al.
(1994) identified a 1-bp (A) insertion at codon 186 in exon 7, resulting
in a frameshift.

.0018
AGAMMAGLOBULINEMIA, X-LINKED
BTK, 8-BP INS, NT721

In a patient with X-linked agammaglobulinemia (300755), de Weers et al.
(1994) identified an 8-bp (CTACATAG) insertion at position A721 in the
N-terminal region, resulting in a frameshift and a truncated protein.

.0019
AGAMMAGLOBULINEMIA, X-LINKED
BTK, 1-BP DEL, CODON 218, A

In a patient with X-linked agammaglobulinemia (300755), Conley et al.
(1994) identified a 1-bp (A) deletion at codon 218 in exon 8, resulting
in a frameshift.

.0020
AGAMMAGLOBULINEMIA, X-LINKED
BTK, GLU240TER

In a patient with severe X-linked agammaglobulinemia (300755), Zhu et
al. (1994) identified a G-to-T transition, resulting in a stop codon at
position 240 and a truncated protein. This mutation was found in the SH3
domain.

.0021
AGAMMAGLOBULINEMIA, X-LINKED
BTK, TRP252TER

In a patient with X-linked agammaglobulinemia (300755), Conley et al.
(1994) identified a G-to-A transition in exon 8, resulting in a stop
codon at position 252 and a truncated protein. This mutation was found
in the SH3 domain.

.0022
AGAMMAGLOBULINEMIA, X-LINKED
BTK, ARG255TER

In a patient with X-linked agammaglobulinemia (300755), Bradley et al.
(1994) identified a C-to-T transition at position 895, resulting in a
stop codon at position 255 and a severely truncated protein lacking the
remaining 404 amino acids, which include the SH2 and kinase domains.
This patient and his brother have no detectable B-cells, confirming that
the absence of the functional domains of Btk results in a classic XLA
phenotype.

.0023
AGAMMAGLOBULINEMIA, X-LINKED
BTK, IVS9DS, G-A, +1

In 2 patients with severe X-linked agammaglobulinemia (300755), Zhu et
al. (1994) identified a G-to-A substitution at nucleotide 909, which is
the first nucleotide of the donor splice site of intron 9. The mutation
causes a deletion of 21 amino acids between residues gln260 and glu280
due to skipping of exon 9. This mutation was found in the SH3 domain.

.0024
AGAMMAGLOBULINEMIA, X-LINKED
BTK, 1-BP DEL/3-BP INS, CODON 261

In a patient with X-linked agammaglobulinemia (300755), Conley et al.
(1994) identified a 1-bp (G) deletion associated with a 3-bp (TTA)
insertion at codon 261 in exon 9, resulting in a frameshift. This
mutation was found in the SH3 domain.

.0025
AGAMMAGLOBULINEMIA, X-LINKED
BTK, ARG288TRP

In a patient with severe X-linked agammaglobulinemia (300755), de Weers
et al. (1994) identified a C-to-T transition at position 993, resulting
in a substitution of tryptophan for arginine-288. This mutation was
found in the SH2-like domain where arg288 is highly conserved and
crucial for the interaction with the aromatic ring of phosphotyrosine.
Therefore, the replacement of arg288 by a nonpolar tryptophan would
entirely abrogate the formation of the high-affinity complex with
phosphotyrosine.

.0026
AGAMMAGLOBULINEMIA, X-LINKED
BTK, ARG307GLY

In a patient with severe X-linked agammaglobulinemia (300755), Bradley
et al. (1994) identified an A-to-G transition at position 1051,
resulting in a substitution of glycine for arginine-307. This mutation
was found in the SH2-like domain where arg307 is involved in the binding
interactions at the base of the phosphotyrosine binding pocket. The
change to a neutral glycine residue is highly likely to disrupt the
binding potential of this region. This patient has less than 1% B cells
and undetectable immunoglobulin levels, indicating that the replacement
of this highly conserved arginine residue completely abolishes the
functioning of Btk.

.0027
AGAMMAGLOBULINEMIA, X-LINKED
BTK, TYR334SER

In a patient with X-linked agammaglobulinemia (300755), Hagemann et al.
(1994) identified an A-to-C transition at position 1133 in exon 12,
resulting in a substitution of serine for tyrosine-334. This mutation
was found in the SH2-like domain where tyr334 is most likely responsible
for the substrate recognition.

.0028
AGAMMAGLOBULINEMIA, X-LINKED
BTK, 1-BP DEL, IVS11DS, +1G

In a patient with X-linked agammaglobulinemia (300755), Conley et al.
(1994) identified a 1-bp (G) deletion that occurred in a run of 3 Gs in
the last codon (325) of exon 11 and the first nucleotide of intron 11.
This mutation was found in the SH2 domain.

.0029
AGAMMAGLOBULINEMIA, X-LINKED
BTK, IVS12AS, A-T, -2

In 3 patients with moderate to severe X-linked agammaglobulinemia
(300755), Zhu et al. (1994) identified an A-to-T substitution at
nucleotide 1235, which is the second nucleotide of the acceptor splice
site of intron 12. The mutation causes a deletion of 12-bp between
residues 1235-1247, a frameshift at codon 372, and a stop codon at
position 398. This mutation was found in the SH2 domain.

.0030
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE III
BTK, TYR375TER

In a patient with X-linked agammaglobulinemia and growth hormone
deficiency (307200), Conley et al. (1994) identified a T-to-G transition
in exon 13, resulting in a stop codon at position 375 associated with an
absence of Btk transcript. This mutation was found in the SH2 domain.

.0031
AGAMMAGLOBULINEMIA, X-LINKED
BTK, 16-BP INS, NT1263

In 4 patients with moderate X-linked agammaglobulinemia (300755), Zhu et
al. (1994) identified the 16-bp insertion (duplication) at position 1263
of the cDNA, resulting in a frameshift and a premature stop codon in
position 404. This mutation was found in the SH2 domain.

.0032
AGAMMAGLOBULINEMIA, X-LINKED
BTK, LEU408PRO

In 2 patients with moderate X-linked agammaglobulinemia (300755), Zhu et
al. (1994) identified a T-to-C transition at position 1355, resulting in
a substitution of proline for leucine-408. This mutation was found in
the SH1 domain.

.0033
AGAMMAGLOBULINEMIA, X-LINKED
BTK, TYR425TER

In a patient with severe X-linked agammaglobulinemia (300755), de Weers
et al. (1994) identified a C-to-A transition at position 1407, resulting
in a stop codon at position 425 and a truncated protein. This mutation
was found in the ATP-binding site.

.0034
AGAMMAGLOBULINEMIA, X-LINKED
BTK, CYS502TER

In a patient with severe X-linked agammaglobulinemia (300755), Zhu et
al. (1994) identified a C-to-A transition at position 1638, resulting in
a stop codon at position 502 and a truncated protein. This mutation was
found in the SH1 domain.

.0035
AGAMMAGLOBULINEMIA, X-LINKED
BTK, CYS506ARG

In a patient with X-linked agammaglobulinemia (300755), Hagemann et al.
(1994) identified a T-to-C transition at position 1648 in exon 15,
resulting in a substitution of arginine for cysteine-506 in the middle
of the kinase domain. Whether this residue is directly involved in
catalytic activity or substrate recognition is not clear.

.0036
AGAMMAGLOBULINEMIA, X-LINKED
BTK, ARG520TER

In 2 patients with moderate to severe X-linked agammaglobulinemia
(300755), Zhu et al. (1994) and Hagemann et al. (1994) identified a
C-to-T transition at position 1690, resulting in a stop codon at
position 520 (in the middle of the kinase domain) and a truncated
protein.

.0037
AGAMMAGLOBULINEMIA, X-LINKED
BTK, ARG520GLN

In patients with severe X-linked agammaglobulinemia (300755), Zhu et al.
(1994) and Hagemann et al. (1994) identified a G-to-A transition at
position 1691, resulting in a substitution of glutamine for
arginine-520. Arg-520 is a highly conserved residue among all protein
kinases. This mutation was found in the SH1 domain.

.0038
AGAMMAGLOBULINEMIA, X-LINKED
BTK, 1-BP DEL, 1720A

In a patient with X-linked agammaglobulinemia (300755), Hagemann et al.
(1994) identified a 1-bp deletion (A1720) at codon 530 in exon 16, which
is in the substrate specific portion of the SH1 domain. This deletion
results in a frameshift that generates a stop codon at nucleotide
position 1796-1798 and eliminates the C-terminal portion of the
catalytic domain.

.0039
AGAMMAGLOBULINEMIA, X-LINKED
BTK, 4-BP DEL, CODON 527, GTTT

In a patient with X-linked agammaglobulinemia (300755), Conley et al.
(1994) identified a 4-bp (GTTT) deletion at codons 527 and 528 in exon
16, resulting in a frameshift. The patient was the mother of a boy who
died suddenly of bacterial sepsis at 11 months of age. The absence of
germinal follicles in lymph nodes at autopsy examination of this child
suggested the diagnosis of XLA despite the lack of family history of
immunodeficiency. The mother was shown to be a carrier of XLA. Analysis
of X-chromosome inactivation patterns and DNA demonstrated a pattern
consistent with one normal allele and one abnormal allele on SSCP
analysis of exon 16. This mutation was found in the kinase domain.

.0040
ISOLATED GROWTH HORMONE DEFICIENCY, TYPE III
BTK, LEU542PRO

In a patient with X-linked agammaglobulinemia and growth hormone
deficiency (307200), Conley et al. (1994) identified a T-to-C transition
in exon 16, resulting in a substitution of proline for leucine-542 in
the substrate binding region. The patient had not experienced major
infections and responded well to growth hormone replacement. This
mutation was found in the kinase domain.

.0041
AGAMMAGLOBULINEMIA, X-LINKED
BTK, IVS16DS, G-T, +1

In a patient with X-linked agammaglobulinemia (300755), Conley et al.
(1994) identified a G-to-T substitution at codon 544, which is the first
nucleotide of the donor splice site of intron 16. The mutation preserved
a potential splice donor site and the GT sequence was moved 5-prime by 1
basepair. Use of this splice site would result in a frameshift and a
premature stop codon. This mutation was found in the kinase domain.

.0042
AGAMMAGLOBULINEMIA, X-LINKED
BTK, ARG562TRP

In a patient with mild X-linked agammaglobulinemia (300755), Conley et
al. (1994) and Hagemann et al. (1994) identified a C-to-T transition in
exon 17, resulting in a substitution of tryptophan for arginine-562.
This mutation was found in the kinase domain. Whether this residue is
directly involved in catalytic activity or substrate recognition is not
clear.

.0043
AGAMMAGLOBULINEMIA, X-LINKED
BTK, TYR581ARG

In a patient with mild X-linked agammaglobulinemia (300755), Conley et
al. (1994) identified a T-to-C transition in exon 17, resulting in a
substitution of arginine for tyrosine-581. The wildtype tryptophan at
this site is conserved in most serine/threonine kinases as well as in
most tyrosine kinases. This mutation was found in the kinase domain.

.0044
AGAMMAGLOBULINEMIA, X-LINKED
BTK, GLU589GLY

In 3 patients with moderate X-linked agammaglobulinemia (300755), Zhu et
al. (1994) identified an A-to-G transition at position 1898, resulting
in a substitution of glycine for glutamic acid-589. This mutation was
found in the SH1 domain.

.0045
AGAMMAGLOBULINEMIA, X-LINKED
BTK, TYR591TER

In a patient with X-linked agammaglobulinemia (300755), Conley et al.
(1994) identified a C-to-A transition in exon 17, resulting in a stop
codon at position 591 and a truncated protein. This mutation was found
in the kinase domain.

.0046
AGAMMAGLOBULINEMIA, X-LINKED
BTK, ALA607ASP

In 2 patients with mild X-linked agammaglobulinemia (300755), Bradley et
al. (1994) identified a C-to-A transition at position 1952, resulting in
a substitution of aspartic acid for alanine-607 near the 3-prime end of
the gene.

.0047
AGAMMAGLOBULINEMIA, X-LINKED
BTK, GLY613ASP

In 2 patients with mild X-linked agammaglobulinemia (300755), Zhu et al.
(1994) identified a G-to-A transition at position 1970, resulting in a
substitution of aspartic acid for glycine-613. This mutation was found
in the SH1 domain.

.0048
AGAMMAGLOBULINEMIA, X-LINKED
BTK, MET630LYS

In a patient with mild X-linked agammaglobulinemia (300755), Conley et
al. (1994) and Hagemann et al. (1994) identified a T-to-A transition in
exon 18, resulting in a substitution of lysine for methionine-630. This
mutation was found in the kinase domain. Whether this residue is
directly involved in catalytic activity or substrate recognition is not
clear.

.0049
AGAMMAGLOBULINEMIA, X-LINKED
BTK, GLU636TER

In a patient with X-linked agammaglobulinemia (300755), Bradley et al.
(1994) identified a G-to-T transition at nucleotide 2038, resulting in a
stop codon at position 636 and a loss of the 24 terminal amino acids
from the protein, including several highly conserved residues. As there
are 3 affected boys in this family who have no detectable B-cells or
immunoglobulin, it is likely that the last 24 amino acids of this
protein are critical for its correct expression and/or function in
B-cell development.

.0050
AGAMMAGLOBULINEMIA, X-LINKED
BTK, 6-BP INS, NT2041

In a patient with X-linked agammaglobulinemia (300755), de Weers et al.
(1994) identified a 6-bp (TTTTAG) insertion at position A2041 in the
C-terminal region, resulting in a frameshift and a truncated protein.

.0051
AGAMMAGLOBULINEMIA, X-LINKED
BTK, LEU652PRO

In a patient with mild X-linked agammaglobulinemia (300755), Conley et
al. (1994) identified a T-to-C transition in exon 19, resulting in a
substitution of proline for leucine-652. This leucine defines the
3-prime border of the conserved kinase domain in many tyrosine kinases.

.0052
AGAMMAGLOBULINEMIA, X-LINKED
BTK, 26-BP INS, NT2019

In a patient with severe X-linked agammaglobulinemia (300755), Zhu et
al. (1994) identified a 26-bp insertion (duplication) at position 2019,
resulting in a frameshift and a premature stop codon in position 653.
This mutation was found in the SH1 domain.

.0053
AGAMMAGLOBULINEMIA, X-LINKED
BTK, ARG562PRO

Curtis et al. (2000) identified a missense mutation, 1817G-C (arg562 to
pro; R562P), in exon 17 of the BTK gene in cousins with XLA (300755).
The same mutation was present in both mothers (twin sisters) of the
cousins, identifying them as carriers. However, the mutation was absent
in all other relatives including the grandmother of the cousins (mother
of the twin sisters). This suggested that the mutation had originated in
the germline of one of the grandparents or in the zygote.

.0054
AGAMMAGLOBULINEMIA, X-LINKED
BTK, 2-BP DEL, 54TG

In a patient with X-linked agammaglobulinemia (300755) who developed
classic type I diabetes at the age of 14 years, Martin et al. (2001)
identified a 2-bp deletion (TG) at nucleotides 54-55 in exon 8 of the
BTK gene, resulting in a frameshift at codon 214 in the TH domain and a
premature stop codon at position 223 in the SH3 domain of the BTK
protein.

.0055
AGAMMAGLOBULINEMIA, X-LINKED
BTK, IVS1DS, G-A, +5

In a Korean family with X-linked agammaglobulinemia (300755), Jo et al.
(2001) identified a point mutation in intron 1 of the BTK gene, a G-to-A
transversion at position +5.

.0056
AGAMMAGLOBULINEMIA, X-LINKED
BTK, 6.1-KB DEL

Jo et al. (2003) identified BTK mutations in 6 patients with presumed
XLA (300755) from unrelated Korean families. Of the 6 mutations, 4 were
novel, including a 6.1-kb deletion including BTK exons 11-18. The large
deletion, identified by long-distance PCR, revealed Alu-Alu mediated
recombination that extended from an Alu sequence in intron 10 to another
Alu sequence in intron 18, spanning a distance of 6.1 kb.

*FIELD* SA
Berning et al. (1980); van der Meer et al. (1986); Vorechovsky et
al. (1993)
*FIELD* RF
1. Berning, A. K.; Eicher, E. M.; Paul, W. E.; Scher, I.: Mapping
of the X-linked immune deficiency mutation (xid) of CBA/N mice. J.
Immun. 124: 1875-1877, 1980.

2. Bradley, L. A. D.; Sweatman, A. K.; Lovering, R. C.; Jones, A.
M.; Morgan, G.; Levinsky, R. J.; Kinnon, C.: Mutation detection in
the X-linked agammaglobulinemia gene, BTK, using single strand conformation
polymorphism analysis. Hum. Molec. Genet. 3: 79-83, 1994.

3. Buckley, R. H.: Assessing inheritance of agammaglobulinemia. (Editorial) New
Eng. J. Med. 330: 1526-1528, 1994.

4. Buckley, R. H.; Rowlands, D. T., Jr.: Agammaglobulinemia, neutropenia,
fever, and abdominal pain. J. Allergy Clin. Immun. 51: 308-318,
1973.

5. Bykowsky, M. J.; Haire, R. N.; Ohta, Y.; Tang, H.; Sung, S.-S.
J.; Veksler, E. S.; Greene, J. M.; Fu, S. M.; Litman, G. W.; Sullivan,
K. E.: Discordant phenotype in siblings with X-linked agammaglobulinemia. Am.
J. Hum. Genet. 58: 477-483, 1996.

6. Cheng, G.; Ye, Z.-S.; Baltimore, D.: Binding of Bruton's tyrosine
kinase to Fyn, Lyn, or Hck through a Src homology 3 domain-mediated
interaction. Proc. Nat. Acad. Sci. 91: 8152-8155, 1994.

7. Cohen, D. I.; Steinberg, A. D.; Paul, W. E.; Davis, M. M.: Expression
of an X-linked gene family (XLR) in late-stage B cells and its alteration
by the xid mutation.. Nature 314: 372-374, 1985.

8. Conley, M. E.; Fitch-Hilgenberg, M. E.; Cleveland, J. L.; Parolini,
O.; Rohrer, J.: Screening of genomic DNA to identify mutations in
the gene for Bruton's tyrosine kinase. Hum. Molec. Genet. 3: 1751-1756,
1994.

9. Conley, M. E.; Mathias, D.; Treadaway, J.; Minegishi, Y.; Rohrer,
J.: Mutations in Btk in patients with presumed X-linked agammaglobulinemia. Am.
J. Hum. Genet. 62: 1034-1043, 1998.

10. Conley, M. E.; Puck, J. M.: Carrier detection in typical and
atypical X-linked agammaglobulinemia. J. Pediat. 112: 688-694, 1988.

11. Curtis, S. K.; Hebert, M. D.; Saha, B. K.: Twin carriers of X-linked
agammaglobulinemia (XLA) due to germline mutation in the Btk gene. Am.
J. Med. Genet. 90: 229-232, 2000.

12. Desiderio, S.: Becoming B cells. (Abstract) Nature 361: 202,
1993.

13. de Weers, M.; Mensink, R. G. J.; Kraakman, M. E. M.; Schuurman,
R. K. B.; Hendriks, R. W.: Mutation analysis of the Bruton's tyrosine
kinase gene in X-linked agammaglobulinemia: identification of a mutation
which affects the same codon as is altered in immunodeficient xid
mice. Hum. Molec. Genet. 3: 161-166, 1994.

14. Drabek, D.; Raguz, S.; De Wit, T. P. M.; Dingjan, G. M.; Savelkoul,
H. F. J.; Grosveld, F.; Hendriks, R. W.: Correction of the X-linked
immunodeficiency phenotype by transgenic expression of human Bruton
tyrosine kinase under the control of the class II major histocompatibility
complex Ea locus control region. Proc. Nat. Acad. Sci. 94: 610-615,
1997.

15. Duriez, B.; Duquesnoy, P.; Dastot, F.; Bougneres, P.; Amselem,
S.; Goossens, M.: An exon-skipping mutation in the btk gene of a
patient with X-linked agammaglobulinemia and isolated growth hormone
deficiency. FEBS Lett. 346: 165-170, 1994.

16. Hagemann, T. L.; Chen, Y.; Rosen, F. S.; Kwan, S.-P.: Genomic
organization of the Btk gene and exon scanning for mutations in patients
with X-linked agammaglobulinemia. Hum. Molec. Genet. 3: 1743-1749,
1994.

17. Hagemann, T. L.; Rosen, F. S.; Kwan, S.-P.: Characterization
of germline mutations of the gene encoding Bruton's tyrosine kinase
in families with X-linked agammaglobulinemia. Hum. Mutat. 5: 296-302,
1995.

18. Hantschel, O.; Rix, U.; Schmidt, U.; Burckstummer, T.; Kneidinger,
M.; Schutze, G.; Colinge, J.; Bennett, K. L.; Ellmeier, W.; Valent,
P.; Superti-Furga, G.: The Btk tyrosine kinase is a major target
of the Bcr-Abl inhibitor dasatinib. Proc. Nat. Acad. Sci. 104: 13283-13288,
2007.

19. Hasan, M.; Lopez-Herrera, G.; Blomberg, K. E. M.; Lindvall, J.
M.; Berglof, A.; Smith, C. I. E.; Vargas, L.: Defective Toll-like
receptor 9-mediated cytokine production in B cells from Bruton's tyrosine
kinase-deficient mice. Immunology 123: 239-249, 2007.

20. Jo, E.-K.; Kanegane, H.; Nonoyama, S.; Tsukada, S.; Lee, J.-H.;
Lim, K.; Shong, M.; Song, C.-H.; Kim, H.-J.; Park, J.-K.; Miyawaki,
T.: Characterization of mutations, including a novel regulatory defect
in the first intron, in Bruton's tyrosine kinase gene from seven Korean
X-linked agammaglobulinemia families. J. Immun. 167: 4038-4045,
2001.

21. Jo, E.-K.; Wang, Y.; Kanegane, H.; Futatani, T.; Song, C.-H.;
Park, J.-K.; Kim, J. S.; Kim, D. S.; Ahn, K.-M.; Lee, S.-I.; Park,
H. J.; Hahn, Y. S.; Lee, J.-H.; Miyawaki, T.: Identification of mutations
in the Bruton's tyrosine kinase gene, including a novel genomic rearrangements
(sic) resulting in large deletion, in Korean X-linked agammaglobulinemia
patients. J. Hum. Genet. 48: 322-326, 2003.

22. Jones, A.; Bradley, L.; Alterman, L.; Tarlow, M.; Thompson, R.;
Kinnon, C.; Morgan, G.: X linked agammaglobulinaemia with a 'leaky'
phenotype. Arch. Dis. Child. 74: 548-549, 1996.

23. Kawakami, Y.; Inagaki, N.; Salek-Ardakani, S.; Kitaura, J.; Tanaka,
H.; Nagao, K.; Kawakami, Y.; Xiao, W.; Nagai, H.; Croft, M.; Kawakami,
T.: Regulation of dendritic cell maturation and function by Bruton's
tyrosine kinase via IL-10 and Stat3. Proc. Nat. Acad. Sci. 103:
153-158, 2006.

24. Kobayashi, S.; Iwata, T.; Saito, M.; Iwasaki, R.; Matsumoto, H.;
Naritaka, S.; Kono, Y.; Hayashi, Y.: Mutations of the Btk gene in
12 unrelated families with X-linked agammaglobulinemia in Japan. Hum.
Genet. 97: 424-430, 1996.

25. Kornfeld, S. J.; Kratz, J.; Haire, R. N.; Litman, G. W.; Good,
R. A.: X-linked agammaglobulinemia presenting as transient hypogammaglobulinemia
of infancy. J. Allergy Clin. Immun. 95: 915-917, 1995.

26. Mao, C.; Zhou, M.; Uckun, F. M.: Crystal structure of Bruton's
tyrosine kinase domain suggests a novel pathway for activation and
provides insights into the molecular basis of X-linked agammaglobulinemia. J.
Biol. Chem. 276: 41435-41443, 2001.

27. Marshall-Clarke, S.; Cooke, A.; Hutchings, P. R.: Deficient production
of anti-red cell autoantibodies by mice with an X-linked B-lymphocyte
defect. Europ. J. Immun. 9: 820-823, 1979.

28. Martin, S.; Wolf-Eichbaum, D.; Duinkerken, G.; Scherbaum, W. A.;
Kolb, H.; Noordzij, J. G.; Roep, B. O.: Development of type 1 diabetes
despite severe hereditary B-cell deficiency. New Eng. J. Med. 345:
1036-1040, 2001.

29. Minegishi, Y.; Coustan-Smith, E.; Wang, Y.-H.; Cooper, M. D.;
Campana, D.; Conley, M. E.: Mutations in the human lambda-5/14.1
gene result in B cell deficiency and agammaglobulinemia. J. Exp.
Med. 187: 71-77, 1998.

30. Ng, Y.-S.; Wardemann, H.; Chelnis, J.; Cunningham-Rundles, C.;
Meffre, E.: Bruton's tyrosine kinase is essential for human B cell
tolerance. J. Exp. Med. 200: 927-934, 2004.

31. Oeltjen, J. C.; Liu, X.; Lu, J.; Allen, R. C.; Muzny, D.; Belmont,
J. W.; Gibbs, R. A.: Sixty-nine kilobases of contiguous human genomic
sequence containing the alpha-galactosidase A and Bruton's tyrosine
kinase loci. Mammalian Genome 6: 334-338, 1995.

32. Ohta, Y.; Haire, R. N.; Litman, R. T.; Fu, S. M.; Nelson, R. P.;
Kratz, J.; Kornfeld, S. J.; de la Morena, M.; Good, R. A.; Litman,
G. W.: Genomic organization and structure of Bruton agammaglobulinemia
tyrosine kinase: localization of mutations associated with varied
clinical presentations and course in X chromosome-linked agammaglobulinemia. Proc.
Nat. Acad. Sci. 91: 9062-9066, 1994.

33. Parolini, O.; Hejtmancik, J. F.; Allen, R. C.; Belmont, J. W.;
Lassiter, G. L.; Henry, M. J.; Barker, D. F.; Conley, M. E.: Linkage
analysis and physical mapping near the gene for X-linked agammaglobulinemia
at Xq22. Genomics 15: 342-349, 1993.

34. Rawlings, D. J.; Saffran, D. C.; Tsukada, S.; Largaespada, D.
A.; Grimaldi, J. C.; Cohen, L.; Mohr, R. N.; Bazan, J. F.; Howard,
M.; Copeland, N. G.; Jenkins, N. A.; Witte, O. N.: Mutation of unique
region of Bruton's tyrosine kinase in immunodeficient xid mice. Science 261:
358-361, 1993.

35. Rawlings, D. J.; Witte, O. N.: Bruton's tyrosine kinase is a
key regulator in B-cell development. Immun. Rev. 138: 105-119, 1994.

36. Rohrer, J.; Parolini, O.; Belmont, J. W.; Conley, M. E.: The
genomic structure of human BTK, the defective gene in X-linked agammaglobulinemia. Immunogenetics 40:
319-324, 1994. Note: Erratum: Immunogenetics 42: 76 only, 1995.

37. Saffran, D. C.; Parolini, O.; Fitch-Hilgenberg, M. E.; Rawlings,
D. J.; Afar, D. E. H.; Witte, O. N.; Conley, M. E.: A point mutation
in the SH2 domain of Bruton's tyrosine kinase in atypical X-linked
agammaglobulinemia. New Eng. J. Med. 330: 1488-1491, 1994.

38. Sakamoto, M.; Kanegane, H.; Fujii, H.; Tsukada, S.; Miyawaki,
T.; Shinomiya, N.: Maternal germinal mosaicism of X-linked agammaglobulinemia. Am.
J. Med. Genet. 99: 234-237, 2001.

39. Scher, I.; Steinberg, A. D.; Berning, A. K.; Paul, W. E.: X-linked
B-lymphocyte immune defect in CBA-N mice. II. Studies of the mechanisms
underlying the immune defect. J. Exp. Med. 142: 637-650, 1975.

40. Shinohara, M.; Koga, T.; Okamoto, K.; Sakaguchi, S.; Arai, K.;
Yasuda, H.; Takai, T.; Kodama, T.; Morio, T.; Geha, R. S.; Kitamura,
D.; Kurosaki, T.; Ellmeier, W.; Takayanagi, H.: Tyrosine kinases
Btk and Tec regulate osteoclast differentiation by linking RANK and
ITAM signals. Cell 132: 794-806, 2008.

41. Thomas, J. D.; Sideras, P.; Smith, C. I. E.; Vorechovsky, I.;
Chapman, V.; Paul, W. E.: Colocalization of X-linked agammaglobulinemia
and X-linked immunodeficiency genes. Science 261: 355-358, 1993.

42. Tsukada, S.; Saffran, D. C.; Rawlings, D. J.; Parolini, O.; Allen,
R. C.; Klisak, I.; Sparkes, R. S.; Kubagawa, H.; Mohandas, T.; Quan,
S.; Belmont, J. W.; Cooper, M. D.; Conley, M. E.; Witte, O. N.: Deficient
expression of a B cell cytoplasmic tyrosine kinase in human X-linked
agammaglobulinemia. Cell 72: 279-290, 1993.

43. Uckun, F. M.; Waddick, K. G.; Mahajan, S.; Jun, X.; Takata, M.;
Bolen, J.; Kurosaki, T.: BTK as a mediator of radiation-induced apoptosis
in DT-40 lymphoma B cells. Science 273: 1096-1099, 1996.

44. van der Meer, J. W. M.; Mouton, R. P.; Daha, M. R.; Schuurman,
R. K. B.: Campylobacter jejuni bacteraemia as a cause of recurrent
fever in a patient with hypogammaglobulinaemia. J. Infect. 12: 235-239,
1986.

45. van Zelm, M. C.; Geertsema, C.; Nieuwenhuis, N.; de Ridder, D.;
Conley, M. E.; Schiff, C.; Tezcan, I.; Bernatowska, E.; Hartwig, N.
G.; Sanders, E. A. M.; Litzman, J.; Kondratenko, I.; van Dongen, J.
J. M.; van der Burg, M.: Gross deletions involving IGHM, BTK, or
Artemis: a model for genomic lesions mediated by transposable elements. Am.
J. Hum. Genet. 82: 320-332, 2008.

46. Vetrie, D.; Vorechovsky, I.; Sideras, P.; Holland, J.; Davies,
A.; Flinter, F.; Hammarstrom, L.; Kinnon, C.; Levinsky, R.; Bobrow,
M.; Smith, C. I. E.; Bentley, D. R.: The gene involved in X-linked
agammaglobulinaemia is a member of the src family of protein-tyrosine
kinases. Nature 361: 226-233, 1993. Note: Erratum: Nature 364: 362
only, 1993.

47. Vihinen, M.; Iwata, T.; Kinnon, C.; Kwan, S.-P.; Ochs, H. D.;
Vorechovsky, I.; Smith, C. I. E.: BTKbase, mutation database for
X-linked agammaglobulinemia (XLA). Nucleic Acids Res. 24: 160-165,
1996.

48. Vihinen, M.; Kwan, S.-P.; Lester, T.; Ochs, H. D.; Resnick, I.;
Valiaho, J.; Conley, M. E.; Smith, C. I. E.: Mutations of the human
BTK gene coding for Bruton tyrosine kinase in X-linked agammaglobulinemia. Hum.
Mutat. 13: 280-285, 1999.

49. Vihinen, M.; Vetrie, D.; Maniar, H. S.; Ochs, H. D.; Zhu, Q.;
Vorechovsky, I.; Webster, A. D. B.; Notarangelo, L. D.; Nilsson, L.;
Sowadski, J. M.; Smith, C. I. E.: Structural basis for chromosome
X-linked agammaglobulinemia: a tyrosine kinase disease. Proc. Nat.
Acad. Sci. 91: 12803-12807, 1994.

50. Vorechovsky, I.; Luo, L.; Hertz, J. M.; Froland, S. S.; Klemola,
T.; Fiorini, M.; Quinti, I.; Paganelli, R.; Ozsahin, H.; Hammarstrom,
L.; Webster, A. D. B.; Smith, C. I. E.: Mutation pattern in the Bruton's
tyrosine kinase gene in 26 unrelated patients with X-linked agammaglobulinemia. Hum.
Mutat. 9: 418-425, 1997.

51. Vorechovsky, I.; Zhou, J.-N.; Hammarstrom, L.; Smith, C. I. E.;
Thomas, J. D.; Paul, W. E.; Notarangelo, L. D.; Bernatowska-Matuszkiewicz,
E.: Absence of xid mutation in X-linked agammaglobulinaemia. (Letter) Lancet 342:
552, 1993.

52. Vorechovsky, I.; Zhou, J.-N.; Vetrie, D.; Bentley, D.; Bjorkander,
J.; Hammarstrom, L.; Smith, C. I. E.: Molecular diagnosis of X-linked
agammaglobulinaemia. (Letter) Lancet 341: 1153, 1993. Note: Erratum:
Lancet 361: 1394 only, 2003.

53. Wattanasirichaigoon, D.; Benjaponpitak, S.; Techasaensiri, C.;
Kamchaisatian, W.; Vichyanond, P.; Janwityanujit, S.; Choubtum, L.;
Sirinavin, S.: Four novel and three recurrent mutations of the BTK
gene and pathogenic effects of putative splice mutations. J. Hum.
Genet. 51: 1006-1014, 2006.

54. Wood, P. M. D.; Mayne, A.; Joyce, H.; Smith, C. I. E.; Granoff,
D. M.; Kumararatne, D. S.: A mutation in Bruton's tyrosine kinase
as a cause of selective anti-polysaccharide antibody deficiency. J.
Pediat. 139: 148-151, 2001.

55. Yel, L.; Minegishi, Y.; Coustan-Smith, E.; Buckley, R. H.; Trubel,
H.; Pachman, L. M.; Kitchingman, G. R.; Campana, D.; Rohrer, J.; Conley,
M. E.: Mutations in the mu heavy-chain gene in patients with agammaglobulinemia. New
Eng. J. Med. 335: 1486-1493, 1996.

56. Zhu, Q.; Zhang, M.; Winkelstein, J.; Chen, S.-H.; Ochs, H. D.
: Unique mutations of Bruton's tyrosine kinase in fourteen unrelated
X-linked agammaglobulinemia families. Hum. Molec. Genet. 3: 1899-1900,
1994.

*FIELD* CN
Patricia A. Hartz - updated: 2/2/2009
Paul J. Converse - updated: 11/21/2008
Cassandra L. Kniffin - updated: 10/13/2008
Patricia A. Hartz - updated: 5/2/2008
Cassandra L. Kniffin - updated: 3/21/2007
Paul J. Converse - updated: 4/11/2006
Patricia A. Hartz - updated: 3/27/2006
Victor A. McKusick - updated: 1/15/2004
Paul J. Converse - updated: 1/25/2002
Paul J. Converse - updated: 1/9/2002
Victor A. McKusick - updated: 10/30/2001
Deborah L. Stone - updated: 10/19/2001
Victor A. McKusick - updated: 3/13/2001
Victor A. McKusick - updated: 2/23/2000
Victor A. McKusick - updated: 9/23/1999
Victor A. McKusick - updated: 5/14/1999
Victor A. McKusick - updated: 5/15/1998
Victor A. McKusick - updated: 6/18/1997
Victor A. McKusick - updated: 2/12/1997
Moyra Smith - updated: 8/29/1996
Moyra Smith - updated: 3/13/1996

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

*FIELD* ED
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carol: 7/6/1996
joanna: 3/22/1996
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mark: 10/24/1995
terry: 8/10/1995
davew: 8/25/1994
jason: 7/15/1994
mimadm: 5/12/1994
warfield: 3/21/1994

MIM 300755
*RECORD*
*FIELD* NO
300755
*FIELD* TI
#300755 AGAMMAGLOBULINEMIA, X-LINKED; XLA
;;BRUTON-TYPE AGAMMAGLOBULINEMIA;;
AGAMMAGLOBULINEMIA, X-LINKED, TYPE 1; AGMX1;;
read moreIMMUNODEFICIENCY 1; IMD1
HYPOGAMMAGLOBULINEMIA, X-LINKED, INCLUDED
*FIELD* TX
A number sign (#) is used with this entry because X-linked
agammaglobulinemia (XLA, AGMX1) is caused by mutation in the gene
encoding Bruton tyrosine kinase (BTK; 300300).

DESCRIPTION

X-linked agammaglobulinemia is an immunodeficiency characterized by
failure to produce mature B lymphocytes and associated with a failure of
Ig heavy chain rearrangement. The defect in this disorder resides in
BTK, also known as BPK or ATK, a key regulator in B-cell development
(Rawlings and Witte, 1994). The X-linked form accounts for approximately
85 to 90% of cases of the disorder. Also see 300310. The remaining 15%
of cases constitute a heterogeneous group of autosomal disorders (Lopez
Granados et al., 2002; Ferrari et al., 2007). See agammaglobulinemia-1
(AGM1; 601495) for a discussion of genetic heterogeneity of the
autosomal forms of agammaglobulinemia.

CLINICAL FEATURES

X-linked agammaglobulinemia, the first genetic immunodeficiency to be
specifically identified, was described by Bruton (1952). Patients are
unusually prone to bacterial infection but not to viral infection. A
clinical picture resembling rheumatoid arthritis develops in many.
Before antibiotics, death occurred in the first decade. In the more
usual X-linked form of the disease, plasma cells are lacking. A rarer
form of agammaglobulinemia (Hitzig and Willi, 1961), which is inherited
as an autosomal recessive (601457), shows marked depression of the
circulating lymphocytes, and lymphocytes are absent from the lymphoid
tissue. The alymphocytotic type (also see 300400) is even more virulent
than the Bruton form, leading to death in the first 18 months after
birth from severe thrush, chronic diarrhea, and recurrent pulmonary
infections.

Seligmann et al. (1968) proposed a classification of immunologic
deficiencies. Ament et al. (1973) pointed out that gastrointestinal
infestation with Giardia lamblia is frequent in this and other forms of
immunodeficiency. Infection with Campylobacter jejuni and Salmonella spp
is also frequent (Melamed et al., 1983). Giardiasis may lead to
malabsorption, while C. jejuni infection may result in recurrent fever
(van der Meer et al., 1986; Kerstens et al., 1992).

Geha et al. (1973) showed that males with proven X-linked
agammaglobulinemias lacked bone marrow-derived (B) lymphocytes from the
circulating blood, whereas progenitor and thymus (T) cells were normal.
See 301000 and 308230 for other X-linked deficiencies of
immunoglobulins.

Although patients have recurrent bacterial infections, they generally
have a normal response to viral infection, presumably because
cell-mediated immunity is intact. A notable exception is the usually
fatal echovirus-induced meningoencephalitis, which is often associated
with the 'dermatomyositis-like' syndrome first described by Janeway et
al. (1956). Mease et al. (1981) successfully treated a 32-year-old man
who developed signs of myopathy and encephalopathy over a period of 3
months. Echo 11 virus was recovered from muscle and spinal fluid. In
vitro lymphocyte transformation was temporarily markedly depressed by
the infection. High doses of immune globulin given intravenously cured
the man of this usually fatal complication.

Rosen et al. (1984) reviewed primary immunodeficiencies, giving a
classification according to whether the immunodeficiency was
predominantly one of antibody formation, was predominantly one of
cell-mediated immunity, or was associated with other defects as in
ataxia-telangiectasia.

Lederman and Winkelstein (1985) collected data from 96 patients cared
for in 26 North American medical centers and representing a total
experience of almost 1,200 patient-years.

Boys with agammaglobulinemia lack circulating B cells. Landreth et al.
(1985) described 4 boys with agammaglobulinemia who lacked pre-B
lymphocytes. In classic agammaglobulinemia, pre-B cells are present in
normal numbers in the bone marrow but appear to be either blocked or
aborted in their ability to mature, express surface immunoglobulins, or
produce antibody. In the boys who lacked pre-B cells, clinical
presentation with recurrent infections was delayed until the second or
third year. None of the 4 boys had a history of recurrent infection or
similar disease in maternal first cousins or uncles. Two of the patients
were brothers. The mode of inheritance is unclear. The immune defect
resembled that of the thymoma-agammaglobulinemia syndrome, but thymoma
was not present in any of the 4.

Thorsteinsson et al. (1990) described studies in 3 brothers with IMD1,
the first of whom was diagnosed in 1963 at the age of 9 years and died
at the age of 23.

Van der Meer et al. (1993) reported the cases of 3 unrelated men with
XLA who developed colorectal cancer at the ages of 26, 29, and 36 years.
Van der Meer et al. (1993) suggested that there is an increased risk of
colorectal cancer in these individuals and that it may be related to
intestinal infections.

Ochs and Smith (1996) provided a comprehensive review of the clinical
and molecular aspects of X-linked agammaglobulinemia.

Smith and Witte (1999) provided a comprehensive review of XLA. XLA is
characterized by an increased susceptibility mainly to extracellular
bacterial infections; however, enteroviral infections frequently run a
severe course and often resist therapy (Lederman and Winkelstein, 1985;
McKinney et al., 1987; Ochs and Smith, 1996). Rudge et al. (1996)
described a patient with XLA who had an enteroviral infection,
presumably contracted at 8 years of age. Autopsy performed at 17 years
of age, after several years of progressive dementia, showed severe
thinning of the cerebral cortex, reduced subcortical and deep white
matter, and marked dilatation of the lateral ventricles.

Wood et al. (2001) described a 25-year-old man with a selective
antipolysaccharide antibody deficiency who was found to have a
previously described mutation (300300.0005) in the BTK gene. From the
age of 23 years, his IgG level had fallen slightly below the normal
range, but he had remained well on antibiotic prophylaxis for 12 years.
The authors suggested that male patients with antipolysaccharide
antibody deficiency should be evaluated for B-cell lymphopenia and Btk
mutations.

BIOCHEMICAL FEATURES

Edwards et al. (1978) showed reduced ecto-5-prime-nucleotidase (129190)
activity in peripheral blood lymphocytes. This is an ectoenzyme that
regulates the uptake of AMP into lymphocytes by converting the
nontransportable nucleotide to its readily transported nucleoside,
adenosine.

INHERITANCE

Lau et al. (1988) discussed the calculation of genetic risks in XLA,
including allowance for nonallelic genetic heterogeneity.

Hendriks et al. (1989) described a family in which each of 2 sisters had
a son with XLA. The 2 sisters with affected sons and another sister all
showed exclusive inactivation of the paternal X chromosome in B
lymphocytes, indicating that the gene for XLA came from their father,
who, however, had no agammaglobulinemia. He was presumed to be an X
chromosomal mosaic. RFLP segregation analyses in other XLA pedigrees
suggested that this may be a frequent situation.

Sakamoto et al. (2001) suggested maternal germinal mosaicism to explain
the finding of 2 sibs with XLA who had a single base deletion (563C) in
exon 6 of the BTK gene and whose mother had no evidence of the mutation.
Cytoplasmic expression of BTK protein in monocytes was not detected in
either patient; normal cytoplasmic expression of BTK protein was found
in monocytes of the mother.

MAPPING

Race and Sanger (1975) thought that the agammaglobulinemia locus was
possibly linked to Xg; the lod scores were positive but low at a
recombination fraction of 30%.

In 12 families, including an extensively affected Dutch kindred of 8
generations, Mensink et al. (1984) studied linkage with Xg (314700) and
the 12E7 polymorphism that is closely linked to Xg. They concluded that
XLA and Xg are at least 20 cM apart. Cohen et al. (1985) isolated a cDNA
probe recognizing a family of genes, called Xlr (see 300113), on the
mouse X chromosome, at least some members of which are closely linked to
the xid trait. In accompanying studies, Cohen et al. (1985) presented
data which, combined with the RFLP analysis closely linking the Xlr gene
family to the xid mutation, suggest that the xid defect resides in a
member of this family. From a study of the comparative mapping of the
human and mouse X chromosomes, Buckle et al. (1985) predicted that the
XLA locus of man may be on Xq between PGK1 (311800) and GLA (300644),
i.e., in the segment Xq13-Xq22. This remarkable prediction was borne out
by the findings of Kwan et al. (1986).

By RFLP studies in 11 families, they showed that XLA is linked to 2
markers, DXS3 and DXS17, both localized in region Xq21.3-q22 (lod = 3.65
at theta = 0.04 and lod = 2.17 at theta = 0.0, respectively). In a
single 8-generation Dutch kindred, Mensink et al. (1986) found a maximum
lod score of 3.30 at a recombination fraction of 0.06 for linkage of XLA
and marker p19-2 (DXS3). In another pedigree, similar linkage to DXS3
was excluded (lod = -3.14 at theta 0.06). This suggested the existence
of a second form of X-linked agammaglobulinemia; data obtained by
Mensink et al. (1986) from all pedigrees suggested localization of a
second XLA gene in the Xp22 band as defined by marker p99-6 (DXS41); see
300310. This is a possible parallel to the historic demonstration of
heterogeneity in elliptocytosis (611804) by the linkage principle.
Mensink et al. (1986) predicted that more detailed molecular studies
'will ultimately reveal phenotypic differences, reflecting different XLA
gene loci, one of them probably coding for a recombinase involved in
immunoglobulin heavy-chain rearrangements (Schwaber et al., 1983) and
the other(s) being involved in later stages of precursor B cell
differentiation (Levitt et al., 1984). 'With a multipoint linkage
analysis in 9 families with XLA, Ott et al. (1986) concluded that there
was 'clear evidence for heterogeneity of XLA.' The finding of possible
linkage to Xg by Race and Sanger (1975) may have been related to their
having a mixture of 'Xp' and 'Xq' families. Malcolm et al. (1989)
presented further evidence, based on linkage data, for the existence of
2 loci.

Mensink et al. (1987) mapped XLA to Xq21.3-q22. No recombination was
found between XLA and DXS17 (lod = greater than 6 at theta = 0); no
recombinants were found between XLA and DXS17 in this study or in the
study by Kwan et al. (1986)--with the exception of the remarkable Z
pedigree which may have carried a different form of agammaglobulinemia.
Malcolm et al. (1987) demonstrated close linkage to DNA markers in the
Xq21.3-q22 region in studies of 15 families. Guioli et al. (1989) found
close linkage of IMD1 and DXS178. No recombinants were observed, giving
a maximum lod score of 5.92 at theta = 0. Kwan et al. (1990)
demonstrated another marker closely linked to XLA, DXS178.

DIAGNOSIS

Fearon et al. (1987) used a strategy similar to that of Conley et al.
(1986) to show that the defect in XLA is intrinsic to B cells as well as
to detect the carrier state. According to their strategy, recombinant
DNA probes simultaneously detect RFLPs and patterns of methylation of
X-chromosome genes. (Different DNA methylation patterns reflect whether
the X chromosome is active or inactive and these differences in
methylation can be monitored by restriction endonucleases that have the
capacity to recognize methylated cytosine residues.) Random
X-inactivation patterns were observed in isolated peripheral blood
granulocytes, T lymphocytes, and B lymphocytes of women who were not
carriers. In contrast, 1 of the 2 X chromosomes was preferentially
active in the B cells, but not the T cells or granulocytes, of 3
carriers of the disorder. Fearon et al. (1987) used X-chromosome
inactivation analysis to demonstrate that the X chromosome with the
wildtype allele at the agammaglobulinemia locus was the active one in
all the B cells. Allen et al. (1994) tested carrier status by study of B
lymphocytes and T lymphocytes separated by means of antibodies to the
B-cell specific antigen CD19 (107265). B lymphocytes were isolated from
the mononuclear cell fraction of 20 cc of blood by using anti-CD19
immunomagnetic beads. Quantitative PCR at the androgen-receptor locus
was then used to examine patterns of X inactivation in CD19-positive B
cells. The trinucleotide repeat at the androgen receptor locus (AR;
313700) is within approximately 100 bp of 2 HpaII restriction-enzyme
sites that are methylated on the inactive X chromosome but unmethylated
on the active X chromosome. Obligate carriers of XLA demonstrated more
than 95% skewing of X inactivation in CD19-positive cells but not in
CD19-negative cells. Allen et al. (1994) suggested that refinements in
techniques for primary carrier testing and genetic mapping of XLA make
possible an ordered approach to prenatal diagnosis and genetic
counseling.

Schuurman et al. (1988) demonstrated the usefulness of linked RFLP
markers in identifying the carrier state and in the early diagnosis of
XLA in a newborn son.

Journet et al. (1992) demonstrated that the pregnant mother of a boy
with XLA but no family history of immune disease was a carrier by
demonstrating with a methylation-sensitive probe that the X-inactivation
pattern was skewed in the woman's B cells but random in her
polymorphonuclear cells. Using RFLP probes flanking the XLA locus on
each side, they excluded the diagnosis of XLA in the fetus on the basis
of a chorionic villus sample (risk of error less than 0.003). Subsequent
studies of the baby confirmed normality.

PATHOGENESIS

Pearl et al. (1978) showed that precursor B lymphocytes containing IgM
heavy chains can be demonstrated in the bone marrow in XLA. This
suggested that an arrest in the differentiation of precursor B
lymphocytes into B lymphocytes may be involved. Schwaber et al. (1983)
found that about 5% of normal pre-B cells and 100% of XLA pre-B cells
produce incomplete mu chains (147020), i.e., C(mu) polypeptide without
associated V(H). Thus, XLA represents a block in differentiation
secondary to failure to express V(H) genes. (Cytoplasmic mu-chain
protein has served as a marker for pre-B cells. Mu-chain gene expression
precedes rearrangement and expression of light-chain genes.) Presumably
the X chromosome codes for enzyme(s) specific for translocation of V(H)
genes or a regulatory mechanism necessary for pre-B cells to
differentiate to a stage using these enzymes.

In 2 sisters heterozygous for both XLA and G6PD A-/B polymorphism,
Conley et al. (1986) found that B cells showed activity of only the A-
form of G6PD, whereas T cells and neutrophils had about equal amounts of
A- and B enzyme activity. This indicates that the basic defect in XLA is
intrinsic to the B cell.

Schwaber et al. (1988) found an unusual phenotype of B cells in a
patient with XLA, and cellular evidence for lyonization of B cells from
the mother and sister. The patient had a failure of B-cell maturation at
the stage of early B lymphocytes, associated with production of
truncated mu and delta heavy chains composed of D-J(H)-C resulting from
abortive rearrangement of variable region genes. There was also delayed
expression of L chains. Peripheral blood and B-cell lines from the
patient's mother and sister included 50% cells that expressed H chain
without L chain. B-cell lines from the mother and sister produced both
full-length mu and gamma H chains and truncated mu and delta chains
corresponding to the H chains produced by the patient's B cells.
Schwaber and Chen (1988) concluded that failure of variable region gene
rearrangement may underlie the failure of B lymphoid development in XLA.
They observed that immature B cells from a patient produced truncated mu
and delta immunoglobulin H chains. In cases of XLA there is variability
in the stage at which the arrest of development occurs; the major
phenotype is arrested at the stage of pre-B cells, while a minor
phenotype is arrested at the stage of immature B lymphocytes. The
failure of B lymphoid development is associated in both phenotypes with
a failure of Ig heavy chain variable region rearrangement. The immature
B cells of a patient with the minor phenotype of XLA produce truncated
gamma and delta heavy chains composed of a D-J-constant complex
resulting from failure to rearrange a V segment. Schwaber et al. (1988)
demonstrated that the fusion of these cells with mouse myeloma
complemented the failure of V(H) gene rearrangement. H chains produced
by such hybrid cells are composed of V(H)-D-J(H)-C. The genes encoding
each of these elements were of human parental origin, indicating that
the mouse myeloma provided a trans-acting regulatory element necessary
for V(H) rearrangement which the XLA B cells lack. Complementation
occurred in all hybrid cells examined, regardless of whether the human X
chromosome was retained.

Schwaber (1992) presented direct evidence that there is a failure of
V(D)J recombination which causes arrest in the transition from pre-B
cell to B lymphocyte. He pointed out that the arrest in B-cell
development is not absolute: rare B lymphocytes have been identified in
peripheral blood of some patients, and B-cell lines have been
established from these cells by Epstein-Barr virus transformation.
Leakiness of the mutation would not be inconsistent with the proposed
mechanism.

MOLECULAR GENETICS

- X-Linked Agammaglobulinemia

Using probes derived for the Southern analysis of DNA from 33 unrelated
families and 150 normal X chromosomes, Vetrie et al. (1993) detected
restriction pattern abnormalities in 8 families. Five of them had
deletions that were shown to be entirely intragenic to BTK, confirming
involvement of BTK in XLA. Two single-base missense mutations
(300300.0001 and 300300.0002) were identified in XLA patients. The
failure of pre-B cells in the bone marrow of XLA males to develop into
mature, circulating B cells could be the result of the product of the
mutant ATK gene failing to fulfill its role in B-cell signaling.

For further information on the molecular genetics of XLA, see 300300.

- X-Linked Hypogammaglobulinemia

Kornfeld et al. (1995) described the case of a 16-year-old boy who had
recurrent upper respiratory tract infections at 13 months of age and was
diagnosed as having transient hypogammaglobulinemia of infancy on the
basis of low immunoglobulin levels, normal diphtheria and tetanus
antibody responses, normal anterior and posterior cervical nodes, normal
tonsillar tissue, and normal numbers of B cells in the blood. IgA levels
returned to normal at 15 months of age and remained within normal limits
over the next 12 months, and IgG and IgM levels remained relatively
unchanged. At age 10, he began receiving intravenous gammaglobulin,
which resulted in cessation of infections. The clinical picture was
thought to be that of common variable immunodeficiency disease. However,
gene studies revealed the deletion of exon 16 of the BTK gene resulting
from a splice junction defect. The patient represents an example of the
extreme variation that can occur in the XLA phenotype.

ANIMAL MODEL

For information on animal models of XLA, including the X-linked
immunodeficiency (xid) mouse mutation, see 300300.

*FIELD* SA
Erlendsson et al. (1985); Garvie and Kendall (1961); Gitlin and Craig
(1963); Janeway et al. (1953); Perryman et al. (1983); Saulsbury et
al. (1979); Schwaber et al. (1988); Thompson et al. (1980)
*FIELD* RF
1. Allen, R. C.; Nachtman, R. G.; Rosenblatt, H. M.; Belmont, J. W.
: Application of carrier testing to genetic counseling for X-linked
agammaglobulinemia. Am. J. Hum. Genet. 54: 25-35, 1994.

2. Ament, M. E.; Ochs, H. D.; Davis, S. D.: Structure and function
of the gastrointestinal tract in primary immunodeficiency syndromes:
a study of 39 patients. Medicine 52: 227-248, 1973.

3. Bruton, O. C.: Agammaglobulinemia. Pediatrics 9: 722-727, 1952.

4. Buckle, V. J.; Edwards, J. H.; Evans, E. P.; Jonasson, J. A.; Lyon,
M. F.; Peters, J.; Searle, A. G.: Comparative maps of human and mouse
X chromosomes. (Abstract) Cytogenet. Cell Genet. 40: 594-595, 1985.

5. Cohen, D. I.; Hedrick, S. M.; Nielsen, E. A.; D'Eustachio, P.;
Ruddle, F.; Steinberg, A. D.; Paul, W. E.; Davis, M. M.: Isolation
of a cDNA clone corresponding to an X-linked gene family (XLR) closely
linked to the murine immunodeficiency disorder xid. Nature 314:
372-374, 1985.

6. Conley, M. E.; Brown, P.; Pickard, A. R.; Buckley, R. H.; Miller,
D. S.; Raskind, W. H.; Singer, J. W.; Fialkow, P. J.: Expression
of the gene defect in X-linked agammaglobulinemia. New Eng. J. Med. 315:
564-567, 1986.

7. Edwards, N. L.; Magilavy, D. B.; Cassidy, J. T.; Fox, I. H.: Lymphocyte
ecto-5-prime-nucleotidase deficiency in agammaglobulinemia. Science 201:
628-630, 1978.

8. Erlendsson, K.; Swartz, T.; Dwyer, J. M.: Successful reversal
of echovirus encephalitis in X-linked hypogammaglobulinemia by intraventricular
administration of immunoglobulin. New Eng. J. Med. 312: 351-353,
1985.

9. Fearon, E. R.; Winkelstein, J. A.; Civin, C. I.; Pardoll, D. M.;
Vogelstein, B.: Carrier detection in X-linked agammaglobulinemia
by analysis of X-chromosome inactivation. New Eng. J. Med. 316:
427-431, 1987.

10. Ferrari, S.; Lougaris, V.; Caraffi, S.; Zuntini, R.; Yang, J.;
Soresina, A.; Meini, A.; Cazzola, G.; Rossi, C.; Reth, M.; Plebani,
A.: Mutations of the Ig-beta gene cause agammaglobulinemia in man. J.
Exp. Med. 204: 2047-2051, 2007.

11. Garvie, J. M.; Kendall, A. C.: Congenital agammaglobulinaemia:
report of two further cases. Brit. Med. J. 1: 548-550, 1961.

12. Geha, R. S.; Rosen, F. S.; Merler, E.: Identification and characterization
of subpopulations of lymphocytes in human peripheral blood after fractionation
on discontinuous gradients of albumin: the cellular defect in X-linked
agammaglobulinemia. J. Clin. Invest. 52: 1726-1734, 1973.

13. Gitlin, D.; Craig, J. M.: The thymus and other lymphoid tissues
in congenital agammaglobulinemia. I. Thymic alymphoplasia and lymphocytic
hypoplasia and their relation to infection. Pediatrics 32: 517-530,
1963.

14. Guioli, S.; Arveiler, B.; Bardoni, B.; Notarangelo, L. D.; Panina,
P.; Duse, M.; Ugazio, A.; Oberle, I.; de Saint Basile, G.; Mandel,
J. L.; Camerino, G.: Close linkage of probe p212 (DXS178) to X-linked
agammaglobulinemia. Hum. Genet. 84: 19-21, 1989.

15. Hendriks, R. W.; Mensink, E. J. B. M.; Kraakman, M. E. M.; Thompson,
A.; Schuurman, R. K. B.: Evidence for male X chromosomal mosaicism
in X-linked agammaglobulinemia. Hum. Genet. 83: 267-270, 1989.

16. Hitzig, W. H.; Willi, H.: Hereditary lymphoplasmocytic dysgenesis
('alymphocytose mit agammaglobulinamia'). Schweiz. Med. Wschr. 91:
1625-1633, 1961.

17. Janeway, C. A.; Apt, L.; Gitlin, D.: Agammaglobulinemia. Trans.
Assoc. Am. Phys. 66: 200-202, 1953.

18. Janeway, C. A.; Gitlin, D.; Craig, J. M.; Grice, D. C.: 'Collagen
disease' in patients with congenital agammaglobulinemia. Trans. Assoc.
Am. Phys. 69: 93-97, 1956.

19. Journet, O.; Durandy, A.; Doussau, M.; Le Deist, F.; Couvreur,
J.; Griscelli, C.; Fischer, A.; de Saint-Basile, G.: Carrier detection
and prenatal diagnosis of X-linked agammaglobulinemia. Am. J. Med.
Genet. 43: 885-887, 1992.

20. Kerstens, P. J. S. M.; Endtz, H. P.; Meis, J. F. G. M.; Oyen,
W. J. G.; Koopman, R. J. I.; van den Broek, P. J.; van der Meer, J.
W. M.: Erysipelas-like skin lesions associated with Campylobacter
jejuni septicemia in patients with hypogammaglobulinemia. Europ.
J. Clin. Microbiol. Infect. Dis. 11: 842-847, 1992.

21. Kornfeld, S. J.; Kratz, J.; Haire, R. N.; Litman, G. W.; Good,
R. A.: X-linked agammaglobulinemia presenting as transient hypogammaglobulinemia
of infancy. J. Allergy Clin. Immun. 95: 915-917, 1995.

22. Kwan, S.-P.; Kunkel, L.; Bruns, G.; Wedgwood, R. J.; Latt, S.;
Rosen, F. S.: Mapping of the X-linked agammaglobulinemia locus by
use of restriction fragment-length polymorphism. J. Clin. Invest. 77:
649-652, 1986.

23. Kwan, S.-P.; Terwilliger, J.; Parmley, R.; Raghu, G.; Sandkuyl,
L. A.; Ott, J.; Ochs, H.; Wedgwood, R.; Rosen, F.: Identification
of a closely linked DNA marker, DXS178, to further refine the X-linked
agammaglobulinemia locus. Genomics 6: 238-242, 1990.

24. Landreth, K. S.; Engelhard, D.; Anasetti, C.; Kapoor, N.; Kincade,
P. W.; Good, R. A.: Pre-B cells in agammaglobulinemia: evidence for
disease heterogeneity among affected boys. J. Clin. Immun. 5: 84-89,
1985.

25. Lau, Y. L.; Levinsky, R. J.; Malcolm, S.; Goodship, J.; Winter,
R.; Pembrey, M.: Genetic prediction in X-linked agammaglobulinaemia. Am.
J. Med. Genet. 31: 437-448, 1988.

26. Lederman, H. M.; Winkelstein, J. A.: X-linked agammaglobulinemia:
an analysis of 96 patients. Medicine 64: 145-156, 1985.

27. Levitt, D.; Ochs, H.; Wedgwood, R. J.: Epstein-Barr virus-induced
lymphoblastoid cell lines derived from the peripheral blood of patients
with X-linked agammaglobulinemia can secrete IgM. J. Clin. Immun. 4:
143-150, 1984.

28. Lopez Granados, E.; Porpiglia, A. S.; Hogan, M. B.; Matamoros,
N.; Krasovec, S.; Pignata, C.; Smith, C. I. E.; Hammarstrom, L.; Bjorkander,
J.; Belohradsky, B. H.; Casariego, G. F.; Garcia Rodriguez, M. C.;
Conley, M. E.: Clinical and molecular analysis of patients with defects
in mu heavy chain gene. J. Clin. Invest. 110: 1029-1035, 2002.

29. Malcolm, S.; de Saint Basile, G.; Arveiler, B.; Lau, Y. L.; Szabo,
P.; Fischer, A.; Griscelli, C.; Debre, M.; Mandel, J. L.; Callard,
R. E.; Robertson, M. E.; Goodship, J. A.; Pembrey, M. E.; Levinsky,
R. J.: Close linkage of random DNA fragments from Xq21.3-22 to X-linked
agammaglobulinaemia (XLA). Hum. Genet. 77: 172-174, 1987.

30. Malcolm, S.; Goodship, J.; Read, A. P.; Donnai, D.; Levinsky,
R. J.: Linkage of Bruton's agammaglobulinemia (IMD1) to probes in
Xq21.3-22: evidence for a second gene coding for X linked agammaglobulinemia.
(Abstract) Cytogenet. Cell Genet. 51: 1038, 1989.

31. McKinney, R. E., Jr.; Katz, S. L.; Wilfert, C. M.: Chronic enteroviral
meningoencephalitis in agammaglobulinemic patients. Rev. Infect.
Dis. 9: 334-356, 1987.

32. Mease, P. J.; Ochs, H. D.; Wedgwood, R. J.: Successful treatment
of echovirus meningoencephalitis and myositis-fasciitis with intravenous
immune globulin therapy in a patient with X-linked agammaglobulinemia. New
Eng. J. Med. 304: 1278-1281, 1981.

33. Melamed, I.; Bujanover, Y.; Igra, Y. S.; Schwartz, D.; Zakuth,
V.; Spirer, Z.: Campylobacter enteritis in normal and immunodeficient
children. Am. J. Dis. Child. 137: 752-753, 1983.

34. Mensink, E. J. B. M.; Schot, J. D. L.; Tippett, P.; Ott, J.; Schuurman,
R. K. B.: X-linked agammaglobulinemia and the red blood cell determinants
Xg and 12E7 are not closely linked. Hum. Genet. 68: 303-309, 1984.

35. Mensink, E. J. B. M.; Thompson, A.; Schot, J. D. L.; Kraakman,
M. E. M.; Sandkuyl, L. A.; Schuurman, R. K. B.: Genetic heterogeneity
in X-linked agammaglobulinemia complicates carrier detection and prenatal
diagnosis. Clin. Genet. 31: 91-96, 1987.

36. Mensink, E. J. B. M.; Thompson, A.; Schot, J. D. L.; van de Greef,
W. M. M.; Sandkuyl, L. A.; Schuurman, R. K. B.: Mapping of a gene
for X-linked agammaglobulinemia and evidence for genetic heterogeneity. Hum.
Genet. 73: 327-332, 1986.

37. Ochs, H. D.; Smith, C. I. E.: X-linked agammaglobulinemia: a
clinical and molecular analysis. Medicine 75: 287-299, 1996.

38. Ott, J.; Mensink, E. J. B. M.; Thompson, A.; Schot, J. D. L.;
Schuurman, R. K. B.: Heterogeneity in the map distance between X-linked
agammaglobulinemia and a map of nine RFLP loci. Hum. Genet. 74:
280-283, 1986.

39. Pearl, E. R.; Vogler, L. B.; Okos, A. J.; Crist, W. M.; Lawton,
A. R., III; Cooper, M. D.: B-lymphocyte precursors in human bone
marrow: an analysis of normal individuals and patients with antibody-deficient
states. J. Immun. 120: 1169-1175, 1978.

40. Perryman, L. E.; McGuire, T. C.; Banks, K. L.: Infantile X-linked
agammaglobulinemia: agammaglobulinemia in horses. Am. J. Path. 111:
125-127, 1983.

41. Race, R.; Sanger, R.: Blood Groups in Man. Oxford: Blackwell
(pub.) (6th ed.): 1975. P. 601.

42. Rawlings, D. J.; Witte, O. N.: Bruton's tyrosine kinase is a
key regulator in B-cell development. Immun. Rev. 138: 105-119, 1994.

43. Rosen, F. S.; Cooper, M. D.; Wedgwood, R. J. P.: The primary
immunodeficiencies. New Eng. J. Med. 311: 235-242 and 300-310, 1984.

44. Rudge, P.; Webster, A. D.; Revesz, T.; Warner, T.; Espanol, T.;
Cunningham-Rundles, C.; Hyman, N.: Encephalomyelitis in primary hypogammaglobulinaemia. Brain 119:
1-15, 1996.

45. Sakamoto, M.; Kanegane, H.; Fujii, H.; Tsukada, S.; Miyawaki,
T.; Shinomiya, N.: Maternal germinal mosaicism of X-linked agammaglobulinemia. Am.
J. Med. Genet. 99: 234-237, 2001.

46. Saulsbury, F. T.; Bernstein, M. T.; Winkelstein, J. A.: Pneumocystis
carinii pneumonia as the presenting infection in congenital hypogammaglobulinemia. J.
Pediat. 95: 559-561, 1979.

47. Schuurman, R. K. B.; Mensink, E. J. B. M.; Sandkuyl, L. A.; Post,
E. D. M.; van Velzen-Blad, H.: Early diagnosis in X-linked agammaglobulinaemia. Europ.
J. Pediat. 147: 93-95, 1988.

48. Schwaber, J.: Evidence for failure of V(D)J recombination in
bone marrow pre-B cells from X-linked agammaglobulinemia. J. Clin.
Invest. 89: 2053-2059, 1992.

49. Schwaber, J.; Chen, R. H.: Premature termination of variable
gene rearrangement in B lymphocytes from X-linked agammaglobulinemia. J.
Clin. Invest. 81: 2004-2009, 1988.

50. Schwaber, J.; Koenig, N.; Girard, J.: Correction of the molecular
defect in B lymphocytes from X-linked agammaglobulinemia by cell fusion. J.
Clin. Invest. 82: 1471-1476, 1988.

51. Schwaber, J.; Molgaard, H.; Orkin, S. H.; Gould, H. J.; Rosen,
F. S.: Early pre-B cells from normal and X-linked agammaglobulinaemia
produce C(mu) without an attached V(H) region. Nature 304: 355-358,
1983.

52. Schwaber, J.; Payne, J.; Chen, R.: B lymphocytes from X-linked
agammaglobulinemia: delayed expression of light chain and demonstration
of lyonization in carriers. J. Clin. Invest. 81: 514-522, 1988.

53. Seligmann, M.; Fudenberg, H. H.; Good, R. A.: A proposed classification
of primary immunologic deficiencies. (Editorial) Am. J. Med. 45:
817-825, 1968.

54. Smith, C. I. E.; Witte, O. N.: X-linked agammaglobulinemia: a
disease of Btk tyrosine kinase.In: Ochs, H. D.; Smith, C. I. E.; Puck,
J. M. (eds.): Primary Immunodeficiency Diseases: A Molecular and
Genetic Approach. New York: Oxford University Press 1999. Pp.
263-284.

55. Thompson, L. F.; Boss, G. R.; Spiegelberg, H. L.; Bianchino, A.;
Seegmiller, J. E.: Ecto-5'-nucleotidase activity in lymphoblastoid
cell lines derived from heterozygotes for congenital X-linked agammaglobulinemia. J.
Immun. 125: 190-193, 1980.

56. Thorsteinsson, L.; Ogmundsdottir, H. M.; Sigfusson, A.; Arnason,
A.; Eyjolfsson, G.; Jensson, O.: The first Icelandic family with
X-linked agammaglobulinaemia: studies of genetic markers and immune
function. Scand. J. Immun. 32: 273-280, 1990.

57. van der Meer, J. W. M.; Mouton, R. P.; Daha, M. R.; Schuurman,
R. K. B.: Campylobacter jejuni bacteraemia as a cause of recurrent
fever in a patient with hypogammaglobulinaemia. J. Infect. 12: 235-239,
1986.

58. van der Meer, J. W. M.; Weening, R. S.; Schellekens, P. T. A.;
van Munster, I. P.; Nagengast, F. M.: Colorectal cancer in patients
with X-linked agammaglobulinaemia. Lancet 341: 1439-1440, 1993.

59. Vetrie, D.; Vorechovsky, I.; Sideras, P.; Holland, J.; Davies,
A.; Flinter, F.; Hammarstrom, L.; Kinnon, C.; Levinsky, R.; Bobrow,
M.; Smith, C. I. E.; Bentley, D. R.: The gene involved in X-linked
agammaglobulinaemia is a member of the src family of protein-tyrosine
kinases. Nature 361: 226-233, 1993. Note: Erratum: Nature 364: 362
only, 1993.

60. Wood, P. M. D.; Mayne, A.; Joyce, H.; Smith, C. I. E.; Granoff,
D. M.; Kumararatne, D. S.: A mutation in Bruton's tyrosine kinase
as a cause of selective anti-polysaccharide antibody deficiency. J.
Pediat. 139: 148-151, 2001.

*FIELD* CS
INHERITANCE:
X-linked recessive

HEAD AND NECK:
[Ears];
Otitis media;
Hearing loss;
[Eyes];
Conjunctivitis

RESPIRATORY:
[Nasopharynx];
Sinusitis;
Rudimentary adenoids;
Rudimentary tonsils;
[Lung];
Pneumonia;
Hypoxemia and cor pulmonale

ABDOMEN:
[Liver];
Enteroviral hepatitis;
[Gastrointestinal];
Diarrhea

GENITOURINARY:
[Internal genitalia, male];
Epididymitis;
Prostatitis;
[Kidney];
Urinary tract infections

SKELETAL:
[Limbs];
Septic arthritis

SKIN, NAILS, HAIR:
[Skin];
Pyoderma

MUSCLE, SOFT TISSUE:
Enteroviral dermatomyositis syndrome

NEUROLOGIC:
[Central nervous system];
Meningitis;
Encephalitis;
Delayed speech acquisition

IMMUNOLOGY:
Frequent bacterial infections;
Severe enteroviral infections;
Small lymph nodes;
Absent B-lymphocytes in all organs;
Absent plasma cells in all organs

NEOPLASIA:
Increased incidence of rectosigmoid cancer

LABORATORY ABNORMALITIES:
Absent or severely reduced levels of serum immunoglobulins

MISCELLANEOUS:
Susceptibility to infections start in the first year of life

MOLECULAR BASIS:
Caused by mutation in the Bruton agammaglobulinemia tyrosine kinase
gene (BTK, 300300.0001)

*FIELD* CN
Ada Hamosh - reviewed: 8/28/2000
Assil Saleh - revised: 8/25/2000

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

*FIELD* ED
joanna: 10/22/2013
joanna: 7/2/2013
joanna: 1/18/2010
joanna: 3/14/2005
joanna: 8/28/2000
kayiaros: 8/25/2000

*FIELD* CN
Cassandra L. Kniffin - updated: 7/29/2010

*FIELD* CD
Matthew B. Gross: 12/18/2008

*FIELD* ED
terry: 10/03/2012
carol: 1/31/2011
carol: 8/3/2010
ckniffin: 7/29/2010
terry: 5/12/2010
carol: 8/28/2009
mgross: 12/19/2008
mgross: 12/18/2008

MIM 307200
*RECORD*
*FIELD* NO
307200
*FIELD* TI
#307200 ISOLATED GROWTH HORMONE DEFICIENCY, TYPE III; IGHD3
;;IGHD III;;
GROWTH HORMONE DEFICIENCY WITH HYPOGAMMAGLOBULINEMIA;;
read moreHYPOGAMMAGLOBULINEMIA AND ISOLATED GROWTH HORMONE DEFICIENCY, X-LINKED;;
AGAMMAGLOBULINEMIA AND ISOLATED GROWTH HORMONE DEFICIENCY, X-LINKED;;
FLEISHER SYNDROME
*FIELD* TX
A number sign (#) is used with this entry because of evidence that this
compound phenotype is due to mutation in the BTK gene (300300), the same
gene that is mutated in X-linked agammaglobulinemia.

See entry 262400 for a summary of the different types of IGHD.

CLINICAL FEATURES

Fleisher et al. (1980) described a kindred in which 2 brothers and 2
sons of their oldest sister had hypogammaglobulinemia deficiency.
Recurrent sinopulmonary infections were a prominent feature in 2
patients. Short stature, retarded bone age, and delayed onset of puberty
were other features. The immunodeficiency was characterized by absent
specific antibody production in vivo and impaired immunoglobulin
production in vitro. In 3 of the 4 affected persons, there was marked
deficiency of all immunoglobulin isotypes; in 1, IgM and IgA levels were
normal although B cells were diminished in number. Three of the 4
patients lacked circulating B lymphocytes, even though tonsils were
present in these patients. All 4 had deficient growth hormone responses
to insulin and arginine or levodopa. Coexistence of growth hormone
deficiency and immunodeficiency is found in 2 mouse mutants: the
Snell-Bagg mouse and the Ames dwarf mouse. The patient who did have
circulating B lymphocytes had been treated with growth hormone.

Monafo et al. (1991) described this syndrome in a 13-year-old boy. An
earlier born agammaglobulinemic brother, who died at 6 years of age, was
below the third percentile for height. Conley et al. (1989, 1991)
studied 2 unrelated families with this disorder. G-banded karyotypes and
flow cytometric analysis of metaphase chromosomes gave no indication of
deletion. Studies of X inactivation showed that the mothers of the
affected boys from both families exhibited selective use of a single X
chromosome as the active X chromosome in B cells but not in T cells.
This pattern is the same as that seen in obligate carriers of typical
XLA (300300). Linkage analysis demonstrated the most likely location of
the gene (or genes) to be the midportion of Xq between DXS3 and DXS94.
This segment includes the gene for XLA. The findings were considered
consistent with this combination of XLA and growth hormone deficiency
being a contiguous gene syndrome due to deletion or its being an allelic
variant of the gene for typical XLA.

Sitz et al. (1990) described a family in which 3 males in 2 generations
had the combination of X-linked hypogammaglobulinemia and isolated
growth hormone deficiency. The first case in the family was a boy who
died at the age of 7 years of staphylococcal septicemia and had a height
of 118 cm (25th percentile) at autopsy and his only brother who also had
hypogammaglobulinemia which was treated with immune globulin. Height
growth velocity did not decrease until age 10 years. Growth hormone
deficiency was documented by a levodopa insulin stimulation test at the
age of 15 years. At age 17 his height was more than 2 standard
deviations below the mean and he was in Tanner stage II of sexual
development. The only son of a sister of these 2 boys was found to have
hypogammaglobulinemia and a partial growth hormone deficiency.

MOLECULAR GENETICS

Duriez et al. (1994) presented evidence suggesting that the syndrome
combining X-linked agammaglobulinemia and isolated growth hormone
deficiency is caused by mutation in the BTK gene. The BTK gene was
analyzed in a sporadic case by RT-PCR analysis of BTK transcripts,
sequencing of cDNA and genomic DNA, and in vitro splicing assays. They
found an intronic point mutation, 1882+5G-A (300300.0004), leading to
skipping of an exon located in the tyrosine kinase domain. The exon
skipping event resulted in a frameshift leading to a premature stop
codon 14 amino acids downstream and in the loss of the last 61 residues
of the carboxy-terminal end of the protein.

*FIELD* RF
1. Conley, M. E.; Burks, A. W.; Herrod, H. G.; Puck, J. M.: Molecular
analysis of X-linked agammaglobulinemia with growth hormone deficiency. J.
Pediat. 119: 392-397, 1991.

2. Conley, M. E.; Burks, A. W.; Stewart, C. C.; Puck, J. M.: The
relationship between typical X-linked agammaglobulinemia (XLA) and
XLA with isolated growth hormone deficiency. (Abstract) Am. J. Hum.
Genet. 45 (suppl.): A181 only, 1989.

3. Duriez, B.; Duquesnoy, P.; Dastot, F.; Bougneres, P.; Amselem,
S.; Goossens, M.: An exon-skipping mutation in the btk gene of a
patient with X-linked agammaglobulinemia and isolated growth hormone
deficiency. FEBS Lett. 346: 165-170, 1994.

4. Fleisher, T. A.; White, R. M.; Broder, S.; Nissley, S. P.; Blaese,
R. M.; Mulvihill, J. J.; Olive, G.; Waldmann, T. A.: X-linked hypogammaglobulinemia
and isolated growth hormone deficiency. New Eng. J. Med. 302: 1429-1434,
1980.

5. Monafo, V.; Maghnie, M.; Terracciano, L.; Valtorta, A.; Massa,
M.; Severi, F.: X-linked agammaglobulinemia and isolated growth hormone
deficiency. Acta Paediat. Scand. 80: 563-566, 1991.

6. Sitz, K. V.; Burks, A. W.; Williams, L. W.; Kemp, S. F.; Steele,
R. W.: Confirmation of X-linked hypogammaglobulinemia with isolated
growth hormone deficiency as a disease entity. J. Pediat. 116: 292-294,
1990.

*FIELD* CS
INHERITANCE:
X-linked recessive

GROWTH:
[Height];
Short stature

HEAD AND NECK:
[Head];
Sinusitis;
[Ears];
Chronic otitis media;
Hearing loss;
[Eyes];
Conjunctivitis

RESPIRATORY:
[Lung];
Pneumonia

ABDOMEN:
[Liver];
Enteroviral hepatitis;
[Gastrointestinal];
Diarrhea

GENITOURINARY:
[Internal genitalia, male];
Epididymitis;
Prostatitis;
[Kidneys];
Urinary tract infections

SKELETAL:
[Limbs];
Septic arthritis;
Retarded bone age

SKIN, NAILS, HAIR:
[Skin];
Pyoderma

MUSCLE, SOFT TISSUE:
Enteroviral dermatomyositis syndrome

NEUROLOGIC:
[Central nervous system];
Meningitis;
Encephalitis

ENDOCRINE FEATURES:
Growth hormone deficiency;
Delayed onset of puberty;
Deficient growth hormone response to insulin, arginine, or levodopa

IMMUNOLOGY:
Frequent bacterial infections;
Severe enteroviral infections;
Absent B lymphocytes in all organs;
Absent antibody production;
Present but small tonsils;
Normal number of T cells

LABORATORY ABNORMALITIES:
Panhypogammaglobulinemia

MISCELLANEOUS:
Susceptibility to infections starts in the first week of life

MOLECULAR BASIS:
Caused by mutation in the Bruton tyrosine kinase gene (BTK, 300300.0004)

*FIELD* CN
Ada Hamosh - reviewed: 1/4/2001
Assil Saleh - revised: 8/25/2000

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

*FIELD* ED
joanna: 07/23/2013
joanna: 7/2/2013
joanna: 7/19/2012
joanna: 1/5/2001
joanna: 1/4/2001
kayiaros: 8/25/2000

*FIELD* CN
Victor A. McKusick - updated: 9/25/2001

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

*FIELD* ED
alopez: 06/02/2009
alopez: 6/2/2009
carol: 9/27/2001
terry: 9/25/2001
carol: 11/9/1999
carol: 7/9/1995
terry: 8/24/1994
mimadm: 2/27/1994
supermim: 3/17/1992
carol: 11/4/1991
carol: 7/23/1991