Minegishi Y, Coustan-Smith E, Wang Y H, Cooper M D, Campana D, Conley M E
Department of Immunology, St. Jude Children's Research Hospital, Memphis, Tennesse 38105, USA.
J Exp Med. 1998 Jan 5;187(1):71-7. doi: 10.1084/jem.187.1.71.
B cell precursors transiently express a pre-B cell receptor complex consisting of a rearranged mu heavy chain, a surrogate light chain composed of lambda5/14.1 and VpreB, and the immunoglobulin (Ig)-associated signal transducing chains, Igalpha and Igbeta. 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 lambda5 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 lambda5/14.1. The maternal allele carried a premature stop codon in the first exon of lambda5/14.1 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 lambda5/14. 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 lambda5/14.1. These findings indicate that expression of the functional lambda5/14.1 is critical for B cell development in the human.
B细胞前体短暂表达一种前B细胞受体复合物，该复合物由重排的μ重链、由λ5/14.1和VpreB组成的替代轻链以及免疫球蛋白（Ig）相关信号转导链Igalpha和Igbeta构成。μ重链中的突变与人类和小鼠B细胞发育的完全失败相关，而小鼠λ5中的突变导致具有可检测体液反应的渗漏表型。在评估无丙种球蛋白血症且B细胞数量明显减少的患者时，我们鉴定出一名男孩，其λ5/14.1基因的两个等位基因均有突变。母本等位基因在λ5/14.1的第一个外显子中携带一个提前终止密码子，父本等位基因在外显子3的一个33碱基对序列中显示出三个碱基对替换。这三个替换对应于λ5/14.1假基因16.1中的序列，并导致一个不变脯氨酸处的氨基酸替换。当在COS细胞中表达时，携带假基因序列的等位基因导致突变型λ5/14.1的折叠和分泌缺陷。这些发现表明功能性λ5/14.1的表达对人类B细胞发育至关重要。
