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5/14.1 Gene Result in B Cell Deficiency and Agammaglobulinemia
Departments of Pediatrics and Microbiology, Howard Hughes Medical Institute, Birmingham, Alabama 35294; and Department of Pediatrics, University of Tennessee, Memphis, Tennessee 38105
B cell precursors transiently express a pre–B cell receptor complex consisting of a rearranged mu heavy chain, a surrogate light chain composed of
5/14.1 and VpreB, and the immunoglobulin (Ig)-associated signal transducing chains, Ig
and Igβ. Mutations in the mu heavy chain are associated with a complete failure of B cell development in both humans and mice, whereas mutations in murine 5 result in a leaky phenotype with detectable humoral responses. In evaluating patients with agammaglobulinemia and markedly reduced numbers of B cells, we identified a boy with mutations on both alleles of the gene for 5/14.1. The maternal allele carried a premature stop codon in the first exon of 5/14.1 and the paternal allele demonstrated three basepair substitutions in a 33-basepair sequence in exon 3. The three substitutions correspond to the sequence in the 5/14.1 pseudogene 16.1 and result in an amino acid substitution at an invariant proline. When expressed in COS cells, the allele carrying the pseudogene sequence resulted in defective folding and secretion of mutant 5/14.1. These findings indicate that expression of the functional 5/14.1 is critical for B cell development in the human.
We appreciate the willingness of the patients and their families to participate in research studies. We also thank J.C. Treadaway and D.K. Mathias for technical assistance, and Drs. J. Rohrer, T. Inukai, and A. Kitanaka for helpful discussions.
1 Abbreviations used in this paper: Btk, Bruton's tyrosine kinase; RT-PCR, reverse transcriptase PCR; SSCP, single strand conformation polymorphism; TdT, terminal deoxyhucleotidyl transferase.
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