A novel mutation (Cys145-->Stop) in Bruton's tyrosine kinase is associated with newly diagnosed X-linked agammaglobulinemia in a 51-year-old male

• Published in: Molecular medicine (Cambridge, Mass.) Vol. 2; no. 5; pp. 619 - 623
• Main Authors: Kornfeld, S J, Haire, R N, Strong, S J, Tang, H, Sung, S S, Fu, S M, Litman, G W
• Format: Journal Article
• Language: English
• Published: England The Feinstein Institute for Medical Research 01.09.1996
• Subjects: Agammaglobulinemia - diagnosis; Agammaglobulinemia - genetics; Female; Genetic Linkage; Humans; Male; Middle Aged; Mutation; Pedigree; Protein-Tyrosine Kinases - genetics; X Chromosome
• ISSN: 1076-1551; 1528-3658
• DOI: 10.1007/bf03401645

X-linked agammaglobulinemia (XLA) is a severe, life-threatening disease characterized by failure of B cell differentiation and antibody production and is associated with mutations in Bruton's tyrosine kinase (Btk). The proband in this study is a 51-year-old male presenting with chronic nasal congestion, recurrent sinusitis, sporadic pneumonia, and pronounced B cell deficiency. A family history suggestive of an X-linked immunodeficiency disease was noted. cDNA was synthesized from mRNA prepared from peripheral blood mononuclear leukocytes. Btk cDNA amplified by polymerase chain reaction (PCR) was subjected to both manual and automated DNA sequencing. A DNA sequence corresponding to exons 6 and 7 of Btk was amplified from genomic DNA. Western blot analysis employed both polyclonal and monoclonal antibodies to Btk and reaction patterns were obtained both by chemiluminescence and an in vitro kinase assay. A mutation (Cys145-->Stop) was identified in Btk cDNA and was confirmed in amplified exon 6 of genomic DNA from both the proband and an affected nephew. Neither Btk nor a truncated peptide was detected in Western blot analyses of peripheral blood mononuclear cell lysates. The C145A mutation reported here is novel. This family study is extraordinary in that affected male members who did not undergo aggressive medical management either succumbed to complications in early life or survived into later life. The proband is the oldest de novo diagnosed patient with XLA reported to date.