Background Most patients with congenital hypogammaglobulinemiaand absent B cells are males with X-linked agammaglobulinemia,which is caused by mutations in the gene for Bruton's tyrosinekinase (Btk); however, there are females with a similar disorderwho do not have mutations in this gene. We studied two familieswith autosomal recessive defects in B-cell development and patientswith presumed X-linked agammaglobulinemia who did not have mutationsin Btk.
Methods A series of candidate genes that encode proteins involvedin B-cell signal-transduction pathways were analyzed by linkagestudies and mutation screening.
Results Four different mutations were identified in the mu heavy-chaingene on chromosome 14. In one family, there was a homozygous75-to-100-kb deletion that included D-region genes, J-regiongenes, and the mu constant-region gene. In a second family,there was a homozygous base-pair substitution in the alternativesplice site of the mu heavy-chain gene. This mutation wouldinhibit production of the membrane form of the mu chain andproduce an amino acid substitution in the secreted form. Inaddition, a patient previously thought to have X-linked agammaglobulinemiawas found to have an amino acid substitution on one chromosomeat an invariant cysteine that is required for the intrachaindisulfide bond and, on the other chromosome, a large deletionthat included the immunoglobulin locus.
Conclusions Defects in the mu heavy-chain gene are a cause ofagammaglobulinemia in humans. This implies that an intact membrane-boundmu chain is essential for B-cell development.
Source Information
From the Departments of Immunology (L.Y., Y.M., J.R., M.E.C.), Hematology/Oncology (E.C.-S., D.C.), and Virology (G.R.K.), St. Jude Children's Research Hospital, Memphis, Tenn.; the Department of Pediatrics, Duke University School of Medicine, Durham, N.C. (R.H.B.); the Department of Pediatrics, University of Mainz, Mainz, Germany (H.T.); the Department of Pediatrics, Northwestern University Medical School, Chicago (L.M.P.); and the Department of Pediatrics, University of Tennessee, Memphis (L.Y., D.C., M.E.C.).
Address reprint requests to Dr. Conley at St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105.
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