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Previous Volume 335:1486-1493 November 14, 1996 Number 20 Next

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ABSTRACT

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.

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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