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

Abstract

X chromosome-linked agammaglobulinemia is a life-threatening disease that involves a failure in normal development ofB lymphocytes and is associated with missense mutations in BTK, a gene encoding a cytoplasmic tyrosine kinase (Bruton agammaglobulinemia tyrosine kinase, EC 2.7.1.112), 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.

Interactions between Protein Kinase C and Pleckstrin Homology Domains

“…Therefore, these conserved residues seem to be major determinants for PKC binding, and most PH domains presumably have PKC-interacting capacity. Mutations of Arg-28 in Btk are reported to be pathogenic for xid mice (substitution of Cys for Arg-28 (26,27) and for some X-linked agammaglobulinemia patients (substitution of His for Arg-28 in two unrelated cases (45,46)). Therefore, defects in binding to either PKC or PIP 2 might be the mechanism for these immunodeficiencies.…”

Characterisation and chromosome mapping of the human non receptor tyrosine kinase gene, brk

“…AT consensus for the 5' and 3' ends of introns (Mount, 1982) (Table 1). As BRK shows the highest degree of sequence similarity to the SRC family of non-receptor PTKs the genomic structure of brk was ®rst compared to that of the src family and then, in addition, to the known genomic structures of two other non-receptor PTK families, csk/matk (Brauninger et al, 1993;Avraham et al, 1995) and btk/txk (Hagemann et al, 1994;Ohta et al, 1994Ohta et al, , 1996, which have similar protein structures. brk has 2 exon boundaries that are conserved with src family members.…”

Bruton tyrosine kinase gene mutations in Argentina

“…One of them was a CCTG deletion at codon 401 leading to premature stop. The other was a TTTG (or GTTT) in patient 22 at -12 to -9 (or -13 to -10) at the 3' end of intron 15 probably resulting in a failure to correctly process exon 16, as well as a subsequent exon 17 frameshift and premature stop (Ohta et al, 1994). In patient 3 at position +11 at the 5' end of intron 2 we found a C to T change, although it should be analyzed at cDNA level to know if it might cause aberrant splicing, this mutation is absent among the 50 normal samples and no reported in the literature as a polymorphism.…”