Mutations in the mu heavy-chain gene in patients with agammaglobulinemia.

Journal Article (Journal Article)

BACKGROUND: Most patients with congenital hypogammaglobulinemia and absent B cells are males with X-linked agammaglobulinemia, which is caused by mutations in the gene for Bruton's tyrosine kinase (Btk); however, there are females with a similar disorder who do not have mutations in this gene. We studied two families with autosomal recessive defects in B-cell development and patients with presumed X-linked agammaglobulinemia who did not have mutations in Btk. METHODS: A series of candidate genes that encode proteins involved in B-cell signal-transduction pathways were analyzed by linkage studies and mutation screening. RESULTS: Four different mutations were identified in the mu heavy-chain gene on chromosome 14. In one family, there was a homozygous 75-to-100-kb deletion that included D-region genes, J-region genes, and the mu constant-region gene. In a second family, there was a homozygous base-pair substitution in the alternative splice site of the mu heavy-chain gene. This mutation would inhibit production of the membrane form of the mu chain and produce an amino acid substitution in the secreted form. In addition, a patient previously thought to have X-linked agammaglobulinemia was found to have an amino acid substitution on one chromosome at an invariant cysteine that is required for the intrachain disulfide bond and, on the other chromosome, a large deletion that included the immunoglobulin locus. CONCLUSIONS: Defects in the mu heavy-chain gene are a cause of agammaglobulinemia in humans. This implies that an intact membrane-bound mu chain is essential for B-cell development.

Full Text

Duke Authors

Cited Authors

  • Yel, L; Minegishi, Y; Coustan-Smith, E; Buckley, RH; Trübel, H; Pachman, LM; Kitchingman, GR; Campana, D; Rohrer, J; Conley, ME

Published Date

  • November 14, 1996

Published In

Volume / Issue

  • 335 / 20

Start / End Page

  • 1486 - 1493

PubMed ID

  • 8890099

International Standard Serial Number (ISSN)

  • 0028-4793

Digital Object Identifier (DOI)

  • 10.1056/NEJM199611143352003


  • eng

Conference Location

  • United States