Mutations in Igalpha (CD79a) result in a complete block in B-cell development.

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• Early onset hypogammaglobulinemia with absent B cells is often caused by mutations in Btk, mu heavy chain, or surrogate light chain genes.
• The genetic basis for hypogammaglobulinemia in the remaining 10-15% of patients remains largely unknown.

Purpose of the Study:

• To investigate mutations in genes encoding components of the pre-B-cell receptor (pre-BCR) complex in patients with unexplained hypogammaglobulinemia.
• To determine the role of Igalpha in B cell development by comparing an Igalpha-deficient patient with a mu heavy chain-deficient patient.

Main Methods:

• Screening of 25 patients with unexplained hypogammaglobulinemia for mutations in pre-BCR complex genes.
• Genetic analysis of a patient with a homozygous splice defect in Igalpha.
• Comparative analysis of B cell development in Igalpha-deficient and mu heavy chain-deficient patients using immunofluorescence and V-DJ sequence analysis.

Main Results:

• A homozygous splice defect in Igalpha was identified in a 2-year-old girl with agammaglobulinemia.
• Both Igalpha-deficient and mu heavy chain-deficient patients exhibited a complete block in B cell development at the pro-B to pre-B transition.
• Equivalent numbers and diversity of rearranged V-DJ sequences were observed in both patient groups, suggesting Igalpha's role is downstream of V-DJ rearrangement.

Conclusions:

• Mutations in Igalpha are a cause of agammaglobulinemia.
• Igalpha is essential for B cell development, but its critical role appears to be after its expression as part of the pre-BCR complex.
• This study expands the known genetic causes of primary immunodeficiencies.