Genes required for B cell development

Abstract

Mutations in a variety of genes can cause congenital agammaglobulinemia and a failure of B cell development. The currently known genes encode components of the pre-B cell receptor or proteins that are activated by cross-linking of the pre-B cell receptor. Defects in these genes result in a block in B cell differentiation at the pro-B to pre-B cell transition. A patient with a translocation involving a previously unknown gene, LRRC8, demonstrated a block at exactly the same point in B cell differentiation (see the related article beginning on page 1707). It will be interesting to determine whether the protein encoded by this gene interacts with the pre-B cell receptor signal transduction pathway or is involved in a new pathway.

Figure 1

Early stages of B cell differentiation can be identified by the status of the Ig genes and by the cell surface markers CD34, CD19, and surface Ig (sIg). In stem cells and common lymphoid precursors, the Ig genes are in germ-line configuration. These cells express CD34 but not CD19 or sIg. In pro–B cells, cells committed to the B cell lineage, the first step in μ heavy chain gene rearrangement, D-to-J rearrangement, is occurring. All of the components of the pre–B cell receptor except μ heavy chain (the surrogate light chain proteins λ5 and VpreB, and the proteins that constitute the pre–B cell receptor signal transduction module, Igα and Igβ) can be found in the cytoplasm of these cells. Pro–B cells are positive for CD34 and CD19, but they are negative for sIg. Once an effective, in-frame VDJ heavy chain rearrangement has occurred, and the resulting μ heavy chaine light chain genes are in germ-line configuration. These cells express cytoplasmic μ heavy chain and cell surface CD19, but they are negative for CD34 and sIg. After successful rearrangement of a light chain gene, the conventional B-cell receptor can be expressed on the cell surface, and the cell becomes an immature B cell that is positive for CD19 and sIg and negative for CD34.

Figure 2

(a) Wild-type LRRC8 is an 810–amino acid protein with four transmembrane domains. Both the amino-terminal and carboxy-terminal ends of this protein are extracellular. The carboxy-terminal end contains nine leucine-rich repeats. (b) The mutant LRRC8, produced as a consequence of a translocation that transected the gene between exon 1 and exon 2, lacks the last two-and-a-half leucine-rich repeats and contains 35 amino acids derived from the intron 1 sequence.