MUTATIONS IN THE MU HEAVY-CHAIN GENE IN PATIENTS WITH AGAMMAGLOBULINEMIA

Background Most patients with congenital hypogammaglobulinemia and abs ent B cells are males with X-linked agammaglobulinemia, which is cause d 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 agammaglobu linemia who did not have mutations in Btk. Methods A series of candida te genes that encode proteins involved in B-cell signal-transduction p athways were analyzed by linkage studies and mutation screening. Resul ts 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 cons tant-region gene. In a second family, there was a homozygous base-pair substitution in the alternative splice site of the mu heavy-chain gen e. This mutation would inhibit production of the membrane form of the mu chain and produce an amino acid substitution in the secreted form. In additions, a patient previously thought to have X-linked agammaglob ulinemia was found to have an amino acid substitution on one chromosom e at an invariant cysteine that is required for the intrachain disulfi de bond and, on the other chromosome, a large deletion that included t he immunoglobulin locus. Conclusions Defects in the mu heavy-chain gen e are a cause of agammaglobulinemia in humans. This implies that an in tact membrane-bound mu chain is essential for B-cell development. (C) 1996, Massachusetts Medical Society.