Immunoglobulin heavy chain gene rearrangements in X‐linked agammaglobulinemia

Abstract

X-linked agammaglobulinemia (XLA) appears to involve a defect in human B lymphocyte differentiation which is manifested at the pre-B cell stage. The defect segregates as an X-linked recessive trait but is not a single genetic entity. IgM-producing B cell clones were established by Epstein-Barr virus transformation of peripheral blood mononuclear cells of patients with the XLA defect linked to the DXS3 and DXS17 chromosomal loci. Individual XLA B cell clones were demonstrated to have rearrangements of the J_H regions of both immunoglobulin V_H region loci. The rearranged J_H regions of the B cell clone ALA 19 were molecularly cloned and their nucleotide sequence was determined. Both J_H-associated rearrangements (designated 191 and 192) resulted from the juxtaposition of variable (V_H), diversity (D) and joining (J_H) segments (V_HDJ_H rearrangements). The 191 rearrangement employed a V_H segment belonging to V_H subgroup III and a J_H4 segment. The 192 rearrangement employed a V_HII and a J_H6 segment. The D191 and D192 segments encompassed 21 and 28 nucleotides, respectively, and showed little homology to each other or to previously reported human D sequences. Surprisingly, both V_HDJ_H complexes had open reading frames. However, in accord with principles of allelic exclusion, only the 191 allele was detectably expressed in the total RNA of the cell. A possible mechanism for the lack of expression of the 192 allele is discussed. We conclude that the DXS3-DXS17-linked XLA defect does not preclude V_H to DJ_H rearrangements or the expression of V_Hcontaining heavy chain molecules.