A novel type D retrovirus was isolated by cocultivation of explants of fibromatous tissue from a rhesus monkey (Macaca mulatta) with immunodeficiency and retroperitoneal fibromatosis. This type D virus, isolated from a macaque with simian acquired immunodeficiency syndrome (SAIDS-D/Washington), is exogenous and is partially related to the Mason-Pfizer and the langur monkey type D viruses. The SAiDS-D virus can be distinguished from all other primate retroviruses by antigenicity and molecular hybridization. Nucleic acid hybridization studies reveal that the origin of the SAIDS-D isolate may reside in Old World monkey (subfamily Colobinae) cellular DNA.
X-linked agammaglobulinemia (XLA) is a hereditary defect of B-cell differentiation in man caused by deficiency of Bruton tyrosine kinase (BTK). A three-dimensional model for the BTK kinase domain, based on the core structure of cAMP-dependent protein kinase, was used to interpret the structural basis for disease in eight independent point mutations in patients with XLA. As Arg-525 of BTK has been thought to functionally substitute for a critical lysine residue in proteinserine kinases, the mutation Arg-525 -* Gln was studied and found to abrogate the tyrosine kinase activity of BTK. All of the eight mutations Glu, Arg-520 -+ Glu, Arg-525 --Gln, Arg-562 -+ Pro, Ala-582 --Val, Glu-589 --Gly, Gly-594 --Glu, and Gly-613-* Asp) were located on one face ofthe BTK kinase domain, indicating structural clustering of functionally important residues. X-linked agammaglobulinemia (XLA) is a human immunodeficiency disease characterized by a lymphocyte differentiation block that results in a deficiency of B cells and immunoglobulins, leading to increased susceptibility to infections (1). Recently, the gene mutated in XLA was shown to encode a cytoplasmic protein-tyrosine kinase (PTK) designated Bruton XLA tyrosine kinase (BTK; formerly ATK or BPK) (2, 3). XLA is thus the first Mendelian disease in which a cytoplasmic PTK was found to be mutated. BTK has a single kinase domain (also designated Src homology 1 [SH1] domain) and SH2 and SH3 domains, but lacks both an N-terminal consensus myristoylation sequence and a C-terminal regulatory region. Together with murine Tec and Itk/Tsk it forms a new family ofcytoplasmic PTKs (4-7). The two point mutations reported to cause XLA have both been found in the kinase domain (2), whereas the murine X-linked immunodeficiency defect represents the first missense mutation (8, 9) in the recently identified pleckstrin homology region located in the N terminus of BTK (10-13).The catalytic core of the large protein kinase family contains 9 invariant and 15 highly conserved residues involved in ATP binding and catalysis (14)(15)(16) (23).The x-ray structures, including the independently solved ternary complex (24), provide a comprehensive description of the enzyme, which has been used in modeling of myosin light chain kinase (25), cell division cycle 2 (CDC2) protein kinase (26), and epidermal growth factor receptor PTK (27). The crystal structures of the human cyclin-dependent kinase 2 (CDK2) (28) and mitogen-activated protein (MAP) kinase ERK2 (extracellular signal-related kinase 2) (29) have the same overall fold as cAPK, suggesting that the kinase homology models are valid.In addition to the previously known point mutations in XLA (Lys-430 -* Glu and Arg-525 --Gln) (2), six new missense mutations were found in this disease: Arg-520 -)Glu, Arg-562 -* Pro, Ala-582 -* Val, Gly, Gly-594 --Glu, and Gly-613 --Asp. The functional implications of these mutants were investigated in structural terms by modeling the BTK structure to provide the first three-dimensional model of a cytoplasmic PTK...
X-linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations in the gene coding for Bruton's agammaglobulinemia tyrosine kinase (BTK). A database (BTKbase) of BTK mutations has been compiled and the recent update lists 463 mutation entries from 406 unrelated families showing 303 unique molecular events. In addition to mutations, the database also lists variants or polymorphisms. Each patient is given a unique patient identity number (PIN). Information is included regarding the phenotype including symptoms. Mutations in all the five domains of BTK have been noticed to cause the disease, the most common event being missense mutations. The mutations appear almost uniformly throughout the molecule and frequently affect CpG sites that code for arginine residues. The putative structural implications of all the missense mutations are given in the database. The improved version of the registry having a number of new features is available at http://www. helsinki.fi/science/signal/btkbase.html
X‐linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations in the gene coding for Bruton agammaglobulinemia tyrosine kinase (BTK). A database (BTKbase) of BTK mutations lists 544 mutation entries from 471 unrelated families showing 341 unique molecular events. In addition to mutations, a number of variants or polymorphisms have been found. Mutations in all the five domains of BTK cause the disease, the single most common event being missense mutations. Most mutations lead to truncation of the enzyme. The mutations appear almost uniformly throughout the molecule. About one‐third of point mutations affect CpG sites, which usually code for arginine residues. The putative structural implications of all the missense mutations are provided in the database. BTKbase is available at http://www.uta.fi/imt/bioinfo. Hum Mutat 13:280–285, 1999. © 1999 Wiley‐Liss, Inc.
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