Predominance of sterile immunoglobulin transcripts in a female phenotypically resembling Bruton's agammaglobulinemia

Abstract

The transcription pattern of the heavy chain immunoglobulin gene locus was analyzed in a 6-month-old female with agammaglobulinemia characterized by the absence of mature B cells in peripheral blood, arrested B cell development in the bone marrow and lack of germinal center development. DNA sequencing provided no evidence of mutations within the coding region of the Bruton's tyrosine kinase gene. Polymerase chain reaction-generated cDNA libraries from blood and bone marrow were screened initially using JH and CH oligodeoxynucleotide probes and VH family-specific probes. Only 10% of the transcripts constituted mature VDJC mu recombinations. Ninety percent of the cDNA were sterile immunoglobulin transcripts comprised of: DJC mu (DH-JHC mu), JC mu (JH-C mu), EC mu (enhancer spliced to C mu), SC mu and IC mu [corresponding to switch (S) and intron (I) regions spliced to C mu]. In the mature immunoglobulin transcripts, VH use indicated germline expression with little evidence of somatic mutation. All cDNA were of the C mu type. Different D segments, D-D joining events and unknown D-like elements were noted in the DJC mu and VDJC mu transcripts. This pattern of immunoglobulin rearrangements, along with the phenotypic cell surface antigen characteristics (CD19-), suggest that an earlier arrest in B cell development than is characteristic of Bruton's X-linked agammaglobulinemia has occurred in this patient.

Agammaglobulinemia and absent B lineage cells in a patient lacking the p85α subunit of PI3K

“…The patient, who has been previously reported (de la Morena et al, 1995), was from a consanguineous family of Chinese/Peruvian descent. She was evaluated for immunodeficiency at 3.5 mo of age because of neutropenia (absolute neutrophil count of 0), interstitial pneumonia, and gastroenteritis.…”

Mutations in the Mu Heavy-Chain Gene in Patients with Agammaglobulinemia

“…[12][13][14][15][16] In addition, approximately 5 to 10 percent of patients with early-onset hypogammaglobulinemia and absent B cells are girls. [17][18][19][20] Together, these findings suggest that there may be autosomal recessive disorders that are phenotypically identical to X-linked agammaglobulinemia. To investigate this possibility, we studied two consanguineous families in which both boys and girls had panhypogammaglobulinemia and markedly reduced numbers of B cells (Fig.…”

A human non-XLA immunodeficiency disease characterized by blockage of B cell development at an early proB cell stage.

“…Conley and Sweinberg have reported in two girls a recessive disorder that is phenotypically identical to XLA but which is of possible autosomal origin (27). Recently in a similar case, defect in the Btk gene was also ruled out (28). In this patient, presence of CD10 ϩ cells but absence of CD19 ϩ cells and a 10-fold decrease of mature V-D-J-C transcripts suggested a blockage at an earlier stage of B cell development.…”

“…Therefore, the origin of the disease may result rather from an homozygous defect of an autosomal gene. Although similar non-XLA primary immune deficiencies have been reported (27,28,41), the precise stage of differentiation that was affected by the genetic defect was not characterized.…”