Correspondence

Atypical X-Linked Agammaglobulinemia

N Engl J Med 1994; 331:949-951October 6, 1994

Article

To the Editor:

The Brief Report by Saffran et al.1 and the companion editorial by Buckley2 (May 26 issue) concern the effects of mutations in the gene for Bruton's tyrosine kinase (Btk)3,4 on the phenotypic expression of X-linked agammaglobulinemia. We take exception to Dr. Buckley's conclusion that less severe (atypical) X-linked agammaglobulinemia may be associated with changes in non-kinase regions of Btk.

Recently, we evaluated eight patients in whom six different mutations in the Btk gene have been identified5. In one of our patients, Btk transcripts lacked the exon encoding most of the kinase domain, had a frame shift, and terminated prematurely. This patient presented with an atypical, very mild form of clinical disease, had a good response to immunization with diphtheria and tetanus-toxoid vaccines, and had quite normal IgG levels. A substitution in this same exon, seen in three male members of another family, was also associated with atypical disease in which normal production of IgG was sustained and there were adequate responses to immunization with tetanus-toxoid and diphtheria vaccines past two years of age. A third mutation involved a frame shift and premature termination within the same exon and was associated with the typical course of X-linked agammaglobulinemia, including multiple severe, life-threatening infections from an early age.

In the light of these findings, we believe that it is premature to predict the clinical course of a patient with X-linked agammaglobulinemia on the basis of the position or extent of a mutation in the Btk gene. Although the patient described by Saffran et al. had an extensive workup, their hypothesis that “atypical X-linked agammaglobulinemia is due to more subtle mutations in the gene responsible for typical X-linked agammaglobulinemia”1 is not supported by our findings. We predict that the view Buckley has put forth will not hold up as the number of genotyped cases increases. We believe that X-linked agammaglobulinemia encompasses a broad spectrum of clinical disease that is related at least in part to the individual mutation responsible. It is premature to link the atypical or typical expression of X-linked agammaglobulinemia to the portion of the Btk gene that is affected by the mutation. Compensatory processes encoded at separate loci by as yet unknown mechanisms may contribute importantly to phenotypic variation, as is reflected by the severity of disease, the immunologic abnormalities involved, and the age at the onset of clinical disease.

Stephen J. Kornfeld, M.D.
Robert A. Good, M.D., Ph.D., D.Sc.
Gary W. Litman, Ph.D.
All Children's Hospital, St. Petersburg, FL 33701-4899

5 References

1. 1

   Saffran DC, Parolini O, Fitch-Hilgenberg ME, et al. A point mutation in the SH2 domain of Bruton's tyrosine kinase in atypical X-linked agammaglobulinemia. N Engl J Med 1994;330:1488-1491
   Full Text | Web of Science | Medline

2. 2

   Buckley RH. Assessing inheritance of agammaglobulinemia. N Engl J Med 1994;330:1526-1528
   Full Text | Web of Science | Medline

3. 3

   Vetrie D, Vorechovsky I, Sideras P, et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 1993;361:226-233
   CrossRef | Web of Science | Medline

4. 4

   Tsukada S, Saffran DC, Rawlings DJ, et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 1993;72:279-290
   CrossRef | Web of Science | Medline

5. 5

   Ohta Y, Haire RN, Litman RT, et al. Genomic organization and structure of the Bruton's tyrosine kinase: localization of mutations associated with varied clinical presentations and course in X-linked agammaglobulinemia. Proc Natl Acad Sci U S A (in press).
   

Author/Editor Response

The authors reply:

To the Editor: The letter of Kornfeld et al. raises two separate questions: Do some patients with mild hypogammaglobulinemia have defects in the same gene as patients with typical X-linked agammaglobulinemia? Can you predict the clinical phenotype of X-linked agammaglobulinemia on the basis of the site of the Btk mutation? Our paper answers the first question by demonstrating that a mutation in Btk can cause an atypical or mild form of X-linked agammaglobulinemia. The results described by Kornfeld et al. support this conclusion. We did not address the second question; however, emerging data indicate that the genotype-phenotype correlations in X-linked agammaglobulinemia are likely to be complex.

Within a single family, such as our patient's family, some members may have mild X-linked agammaglobulinemia whereas others have more typical disease, indicating that factors other than the site of mutation influence the phenotype. These factors may include past infections, the age of the patient, and the treatment received, as well as modifying or compensatory genetic factors. As suggested by Kornfeld et al., mutations in non-kinase domains of Btk have been associated with typical X-linked agammaglobulinemia and mutations in the kinase domain have been associated with mild disease1. However, we would argue that both the site and the type of Btk mutation make important contributions to the phenotype.

We were surprised to find that a high percentage of our patients with mild disease lacked the Btk transcript in cell lines transformed by Epstein-Barr virus or neutrophils. To identify the mutations in these patients, we screened genomic DNA by single-strand conformation polymorphism using polymerase-chain-reaction primers that flanked each of the 19 exons of Btk2. The patients lacking the transcript were found to have premature stop codons as the result of either substitutions in a single base pair or small insertions or deletions associated with frame shifts. It is well recognized that premature stop codons in some genes, for example β-globin, are associated with a failure to accumulate transcript in the cytoplasm3. As was true with Kornfeld's patients, some but not all of our patients with premature stop codons had mild disease4. We interpret this finding as indicating that in the absence of Btk, other kinases may partially compensate. This leads to the further observation that some mutant Btk proteins may be more deleterious to B-cell proliferation or survival than a complete absence of Btk.

As gene therapy and other sophisticated treatments for X-linked agammaglobulinemia are contemplated, it becomes increasingly important to understand how all the factors that contribute to the phenotype for this deficiency interact.

Ornella Parolini, Ph.D.
Jurg Rohrer, Ph.D.
Mary Ellen Conley, M.D.
St. Jude Children's Research Hospital, Memphis, TN 38101

4 References

1. 1

   Bradley LA, Sweatman AK, Lovering RC, et al. Mutation detection in the X-linked agammaglobulinemia gene, BTK, using single strand conformation polymorphism analysis. Hum Mol Genet 1994;3:79-83
   CrossRef | Web of Science | Medline

2. 2

   Rohrer J, Parolini O, Belmont JW, Conley ME. The genomic structure of human Btk, the defective gene in X-linked agammaglobulinemia. Immunogenetics (in press).
   

3. 3

   Baserga SJ, Benz EJ Jr. β-globin nonsense mutation: deficient accumulation of mRNA occurs despite normal cytoplasmic stability. Proc Natl Acad Sci U S A 1992;89:2935-2939
   CrossRef | Web of Science | Medline

4. 4

   Conley ME, Rohrer J, Fitch-Hilgenberg ME, Parolini O. Variable clinical consequences of premature stop codons in Btk, the defective gene in X-linked agammaglobulinemia (XLA). Pediatr Res 1994;35:10A-10A abstract.
   Web of Science

Author/Editor Response

The observations of Dr. Kornfeld and colleagues in their eight patients with X-linked agammaglobulinemia are interesting and in keeping with a recent report by de Weers et al.1 They described a boy with typical X-linked agammaglobulinemia who had a point mutation in the Btk gene resulting in an amino acid substitution in the N-terminal domain at the same location as in X-linked immunodeficient (Xid) mice. However, Dr. Kornfeld and coworkers are not accurate when they say that I concluded that “less severe (atypical) X-linked agammaglobulinemia may be associated with changes in non-kinase regions of Btk.” The sentence to which they refer is not a conclusion but a speculation and reads, “It is entirely possible that some of the other less severe antibody-deficiency syndromes could be caused by mutations in the non-kinase portions of the Btk gene.”

This speculation was based on the observations by both Rawlings et al.2 in Xid mice, which have a much less severe B-cell defect than do patients with typical X-linked agammaglobulinemia, and Saffran et al. in a patient with atypical X-linked agammaglobulinemia; thus, it did not originate with me. However, it remains a valid speculation, since Bradley et al.3 have also described a patient with atypical X-linked agammaglobulinemia who had a mutation in the non-kinase portion of the Btk gene. As more of these mutations are identified, we will learn whether the speculation has merit. I concur with Kornfeld's last statement that many other influences may determine the ultimate phenotypic outcome in any given patient. It appears from their findings that there may be milder forms of the disease, even in patients with mutations in the kinase domain.

Rebecca H. Buckley, M.D.
Duke University Medical Center, Durham, NC 27710

3 References

1. 1

   de Weers M, Mensink RG, Kraakman ME, Schuurman RK, Hendriks RW. Mutation analysis of the Bruton's tyrosine kinase gene in X-linked agammaglobulinemia: identification of a mutation which affects the same codon as is altered in immunodeficient xid mice. Hum Mol Genet 1994;3:161-166
   CrossRef | Web of Science | Medline

2. 2

   Rawlings DJ, Saffran DC, Tsukada S, et al. Mutation of unique region of Bruton's tyrosine kinase in immunodeficient XID mice. Science 1993;261:358-361
   CrossRef | Web of Science | Medline

3. 3

   Bradley LA, Sweatman AK, Lovering RC, et al. Mutation detection in the X-linked agammaglobulinemia gene, BTK, using single strand conformation polymorphism analysis. Hum Mol Genet 1994;3:79-83
   CrossRef | Web of Science | Medline

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