Genetics

Brutons agammaglobulinemia occurs in all racial groups, with a prevalence of between 2 and 8 per 1 000 000. As is true with all X-linked disorders that are lethal without medical intervention, the disorder is maintained in the population by the occurrence of new mutations. This has two important consequences. First, approximately half of the patients with the clinical and laboratory characteristics of XLA have no family history of the disorder because they are the first manifestation in their family of a new mutation. Second, the mutations in Btk that cause XLA are independently derived and highly variable.

The gene for Btk consists of 19 exons spread over 37 kb at Xq22. Human Btk has over 95% homology to murine Btk and 58% homology to a drosophila kinase, Dsrc28C. Over 100 different mutations in Btk have been identified. Although deletions that are detectable by Southern blot analysis do occur, they constitute less than 10% of the mutations in this gene. About one-third of the mutations result in amino acid substitutions, the majority of which are in the kinase domain; however, amino acid substitutions in the PH domain and the SH2 domain have also been seen. The remaining mutations are almost equally divided between single base pair substi

Figure 1 Structure of the 659 amino acid cytoplasmic tyrosine kinase, Btk. The amino-terminal pleckstrin homology domain (PH) is followed by a proline rich region (Pro), and SH2 and SH3 domains and the catalytic domain. The mutations causing amino acid substitutions in patients with XLA and the codons affected by those mutations are shown. Some codons have been altered by two different mutations; xid mice have an amino acid substitution in codon 28 in the PH domain.

Figure 1 Structure of the 659 amino acid cytoplasmic tyrosine kinase, Btk. The amino-terminal pleckstrin homology domain (PH) is followed by a proline rich region (Pro), and SH2 and SH3 domains and the catalytic domain. The mutations causing amino acid substitutions in patients with XLA and the codons affected by those mutations are shown. Some codons have been altered by two different mutations; xid mice have an amino acid substitution in codon 28 in the PH domain.

tutions that cause premature stop codons, small insertions or deletions that result in frameshift mutations and splice defects. These mutations are spread almost evenly throughout the Btk gene. Studies done on EBV-transformed cell lines or myeloid cells from patients with XLA indicate that this last group of mutations (stop codons, frameshifts and splice defects) usually result in poor accumulation of the Btk mRNA in the cytoplasm. Thus, these mutations are functionally equivalent.

Attempts to correlate the severity of the clinical manifestations of XLA with specific mutations in Btk suggest that the site or type of mutation may influence the phenotype. Amino acid substitutions in the SH2 domain or noncritical regions of the catalytic domain are sometimes seen in patients with milder disease. However, additional factors, including other genes, past infections and therapy, may also influence the phenotype of patients with XLA.

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