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J. Exp. Med.,
Volume 187, Number 1, January 5, 1998 71-77
5/14.1 Gene Result in B Cell
Deficiency and Agammaglobulinemia
By
From the * Departments of Immunology and Hematology/Oncology, St. Jude Children's Research
Hospital, Memphis, Tennesse 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 Departments of Pediatrics and Microbiology, Howard Hughes
Medical Institute, Birmingham, Alabama 35294; and § Department of Pediatrics, University of
Tennessee, Memphis, Tennessee 38105
5/14.1 and VpreB, and the immunoglobulin (Ig)-associated signal transducing chains, Ig
and Ig
. 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.
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