Mutations in the mu heavy-chain gene in patients with agammaglobulinemia.
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.
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
L
L
Yel
Y
Y
Minegishi
E
E
Coustan-Smith
R H
RH
Buckley
H
H
Trübel
L M
LM
Pachman
G R
GR
Kitchingman
D
D
Campana
J
J
Rohrer
M E
ME
Conley
D000361:Agammaglobulinemia / Q000151:congenital / Q000235:genetics*; D001402:B-Lymphocytes; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007148:Immunoglobulin mu-Chains / Q000235:genetics*; D018655:Lymphocyte Count; D008297:Male; D009154:Mutation; D010375:Pedigree
D007148:Immunoglobulin mu-Chains