BTKbase: the mutation database for X-linked agammaglobulinemia

Abstract

For the Immunogenetics Special IssueX-linked agammaglobulinemia (XLA) is a hereditary immunodeficiency caused by mutations in the gene encoding Bruton tyrosine kinase (BTK). XLA patients have a decreased number of mature B cells and a lack of all immunoglobulin isotypes, resulting in susceptibility to severe bacterial infections. XLA-causing mutations are collected in a mutation database (BTKbase), which is available at http://bioinf.uta.fi/BTKbase. For each patient the following information is given (when available): the identification of the entry, a plain English description of the mutation followed by a reference, formal characterization of the mutation, and the various parameters from the patient. BTKbase is implemented with the MUTbase program suite, which provides an easy, interactive, and quality controlled submission of information to mutation databases.

The Tyrosine Kinase BMX Is an Essential Mediator of Inflammatory Arthritis in a Kinase-Independent Manner

“…This is reminiscent of the wellestablished role of the PH domain for BTK function, as underlined by mutations in the PH domain of BTK leading to a loss of function and X-linked agammaglobulinemia (59). Furthermore, our in vitro studies on the regulation of the IL-8 promoter indicate FIGURE 7.…”

Loss-of-function mutations within the IL-2 inducible kinase ITK in patients with EBV-associated lymphoproliferative diseases

“…We show that the PH domain of wt ITK directly associates with the highest specificity to phosphoinositol monophosphates in vitro, but only to a significant lesser extend with their higher order di-or tri-phosphate derivates. In contrast, the PH domain of BTK preferentially binds to phosphatidylinositol (3,4,5)triphosphate over other phosphorylated forms, including monophosphates. 44 The ITK R29H mutant exhibited dramatically reduced membrane binding in living cells, which is also consistent with a pronounced impact on its ability to induce sufficient calcium flux in human cells.…”

“…Inherited hemizygous germline BTK mutations were among the first molecularly defined primary immunodeficiency disorders and more than thousand different BTK mutations have been identified in patients with X-linked agammaglobulinemia including missense, nonsense or splice site mutations (see http://bioinf.uta.fi/BTKbase/). 5,6 In contrast, biallelic germline ITK mutations were more recently identified as the cause for severe Epstein-Barr virus -associated lymphoproliferative diseases (EBV-LPD). We identified two sisters whose T-cell immune response against EBV was severely impaired, leading to their death at the age of 7 and 10 years, respectively.…”

Phylogeny of Tec Family Kinases: Identification of a Premetazoan Origin of Btk, Bmx, Itk, Tec, Txk, and the Btk Regulator SH3BP5

“…The mammalian TFKs were cloned during 1990-1995 (Haire et al, 1994;Heyeck and Berg, 1993;Hu et al, 1995;Mano et al, 1990;Robinson et al, 1996;Siliciano et al, 1992;Tamagnone et al, 1994;Tsukada et al, 1993;Vetrie et al, 1993;Yamada et al, 1993) and immediately received wide interest, especially owing to the fact that BTK mutations cause an X-linked form of B lymphocyte deficiency (X-linked agammaglobulinemia, XLA) in man (Lindvall et al, 2005;Tsukada et al, 1993;Väliaho et al, 2006;Vetrie et al, 1993;Vihinen et al, 1995a) and X-linked immunodeficiency (XID) in mice Thomas et al, 1993). Btk is expressed in lymphoid cells but absent from T cells and plasma cells .…”

“…The BTKbase (http://bioinf.uta.fi/BTKbase) database is freely available and has served as a model for some 130 additional mutation databases, mainly for immunodeficiencies (Piirilä et al, 2006). BTKbase has constantly grown from 188 cases to the current number of 1096 patients (Lindvall et al, 2005;Väliaho et al, 2006;Vihinen et al, 1995aVihinen et al, ,b, 1996Vihinen et al, , 1997bVihinen et al, , 1998Vihinen et al, , 1999Vihinen et al, , 2001). Experimental and modeled structures for BTK domains have extensively been used to explain protein structure-function relationships and consequences of mutations (Holinski-Feder et al, 1998;Jin et al, 1995;Korpi et al, 2000;Lindvall et al, 2005;Maniar et al, 1995;Mao et al, 2001;Mattsson et al, 2000;Speletas et al, 2001;Väliaho et al, 2006;Vihinen et al, 1994bVihinen et al, ,c, 1995bVorechovsky et al, 1995Vorechovsky et al, , 1997Zhu et al, 1994).…”