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Proc Natl Acad Sci U S A. Sep 13, 1994; 91(19): 9062–9066.

Genomic organization and structure of Bruton agammaglobulinemia tyrosine kinase: localization of mutations associated with varied clinical presentations and course in X chromosome-linked agammaglobulinemia.


X chromosome-linked agammaglobulinemia is a life-threatening disease that involves a failure in normal development of B lymphocytes and is associated with missense mutations in BTK, a gene encoding a cytoplasmic tyrosine kinase (Bruton agammaglobulinemia tyrosine kinase, EC, a member of the Tec family of protein-tyrosine kinases. The genomic organization has been determined by using conventional restriction fragment mapping, extended DNA sequencing, and PCR fragment-sizing approaches. The DNA sequences of the 18 coding exons composing BTK and their flanking-region sequences are reported; an additional exon(s) encodes a 5' untranslated segment. Single-base-pair substitutions and 4-nt deletions resulted in amino acid replacement, premature termination, frameshift, and exon deletion in a group of X chromosome-linked agammaglobulinemia patients exhibiting different clinical presentations and courses. The nature of the mutations is interpreted in terms of the genomic organization of the BTK gene and the disease course in individual patients. Several examples are found in which the same mutation occurs in unrelated patients, and one of these mutations occurs at the same codon that is substituted in the murine form of BTK, resulting in X chromosome-linked immunodeficiency disease. Considerable variation in presentation and disease course in X chromosome-linked agammaglobulinemia appears associated with the nature and position of different missense mutations.

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  • BRUTON OC. Agammaglobulinemia. Pediatrics. 1952 Jun;9(6):722–728. [PubMed]
  • Campana D, Farrant J, Inamdar N, Webster AD, Janossy G. Phenotypic features and proliferative activity of B cell progenitors in X-linked agammaglobulinemia. J Immunol. 1990 Sep 15;145(6):1675–1680. [PubMed]
  • Conley ME. Molecular approaches to analysis of X-linked immunodeficiencies. Annu Rev Immunol. 1992;10:215–238. [PubMed]
  • Kwan SP, Kunkel L, Bruns G, Wedgwood RJ, Latt S, Rosen FS. Mapping of the X-linked agammaglobulinemia locus by use of restriction fragment-length polymorphism. J Clin Invest. 1986 Feb;77(2):649–652. [PMC free article] [PubMed]
  • Mensink EJ, Thompson A, Schot JD, van de Greef WM, Sandkuyl LA, Schuurman RK. Mapping of a gene for X-linked agammaglobulinemia and evidence for genetic heterogeneity. Hum Genet. 1986 Aug;73(4):327–332. [PubMed]
  • Malcolm S, de Saint Basile G, Arveiler B, Lau YL, Szabo P, Fischer A, Griscelli C, Debre M, Mandel JL, Callard RE, et al. Close linkage of random DNA fragments from Xq 21.3-22 to X-linked agammaglobulinaemia (XLA). Hum Genet. 1987 Oct;77(2):172–174. [PubMed]
  • Guioli S, Arveiler B, Bardoni B, Notarangelo LD, Panina P, Duse M, Ugazio A, Oberlé I, de Saint Basile G, Mandel JL, et al. Close linkage of probe p212 (DXS178) to X-linked agammaglobulinemia. Hum Genet. 1989 Dec;84(1):19–21. [PubMed]
  • Kwan SP, Terwilliger J, Parmley R, Raghu G, Sandkuyl LA, 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. 1990 Feb;6(2):238–242. [PubMed]
  • Vetrie D, Vorechovský I, Sideras P, Holland J, Davies A, Flinter F, Hammarström L, Kinnon C, Levinsky R, Bobrow M, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature. 1993 Jan 21;361(6409):226–233. [PubMed]
  • Tsukada S, Saffran DC, Rawlings DJ, Parolini O, Allen RC, Klisak I, Sparkes RS, Kubagawa H, Mohandas T, Quan S, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell. 1993 Jan 29;72(2):279–290. [PubMed]
  • Thomas JD, Sideras P, Smith CI, Vorechovský I, Chapman V, Paul WE. Colocalization of X-linked agammaglobulinemia and X-linked immunodeficiency genes. Science. 1993 Jul 16;261(5119):355–358. [PubMed]
  • Rawlings DJ, Saffran DC, Tsukada S, Largaespada DA, Grimaldi JC, Cohen L, Mohr RN, Bazan JF, Howard M, Copeland NG, et al. Mutation of unique region of Bruton's tyrosine kinase in immunodeficient XID mice. Science. 1993 Jul 16;261(5119):358–361. [PubMed]
  • Smith CI, Baskin B, Humire-Greiff P, Zhou JN, Olsson PG, Maniar HS, Kjellén P, Lambris JD, Christensson B, Hammarström L, et al. Expression of Bruton's agammaglobulinemia tyrosine kinase gene, BTK, is selectively down-regulated in T lymphocytes and plasma cells. J Immunol. 1994 Jan 15;152(2):557–565. [PubMed]
  • de Weers M, Mensink RG, Kraakman ME, Schuurman RK, Hendriks RW. 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 Mol Genet. 1994 Jan;3(1):161–166. [PubMed]
  • Bradley LA, Sweatman AK, Lovering RC, Jones AM, Morgan G, Levinsky RJ, Kinnon C. Mutation detection in the X-linked agammaglobulinemia gene, BTK, using single strand conformation polymorphism analysis. Hum Mol Genet. 1994 Jan;3(1):79–83. [PubMed]
  • Sanger F, Nicklen S, Coulson AR. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. [PMC free article] [PubMed]
  • Rouer E, Van Huynh T, Lavareda de Souza S, Lang MC, Fischer S, Benarous R. Structure of the human lck gene: differences in genomic organisation within src-related genes affect only N-terminal exons. Gene. 1989 Dec 7;84(1):105–113. [PubMed]
  • Haire RN, Ohta Y, Lewis JE, Fu SM, Kroisel P, Litman GW. TXK, a novel human tyrosine kinase expressed in T cells shares sequence identity with Tec family kinases and maps to 4p12. Hum Mol Genet. 1994 Jun;3(6):897–901. [PubMed]
  • Scher I. The CBA/N mouse strain: an experimental model illustrating the influence of the X-chromosome on immunity. Adv Immunol. 1982;33:1–71. [PubMed]
  • Eck MJ, Shoelson SE, Harrison SC. Recognition of a high-affinity phosphotyrosyl peptide by the Src homology-2 domain of p56lck. Nature. 1993 Mar 4;362(6415):87–91. [PubMed]
  • Waksman G, Kominos D, Robertson SC, Pant N, Baltimore D, Birge RB, Cowburn D, Hanafusa H, Mayer BJ, Overduin M, et al. Crystal structure of the phosphotyrosine recognition domain SH2 of v-src complexed with tyrosine-phosphorylated peptides. Nature. 1992 Aug 20;358(6388):646–653. [PubMed]
  • Haire RN, Buell RD, Litman RT, Ohta Y, Fu SM, Honjo T, Matsuda F, de la Morena M, Carro J, Good RA, et al. Diversification, not use, of the immunoglobulin VH gene repertoire is restricted in DiGeorge syndrome. J Exp Med. 1993 Sep 1;178(3):825–834. [PMC free article] [PubMed]
  • Monaco AP, Bertelson CJ, Liechti-Gallati S, Moser H, Kunkel LM. An explanation for the phenotypic differences between patients bearing partial deletions of the DMD locus. Genomics. 1988 Jan;2(1):90–95. [PubMed]

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