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

被引:168
作者
Yel, L
Minegishi, Y
CoustanSmith, E
Buckley, RH
Trubel, H
Pachman, LM
Kitchingman, GR
Campana, D
Rohrer, J
Conley, ME
机构
[1] ST JUDE CHILDRENS RES HOSP, DEPT IMMUNOL, MEMPHIS, TN 38105 USA
[2] ST JUDE CHILDRENS RES HOSP, DEPT HEMATOL ONCOL, MEMPHIS, TN 38105 USA
[3] ST JUDE CHILDRENS RES HOSP, DEPT VIROL, MEMPHIS, TN 38105 USA
[4] DUKE UNIV, SCH MED, DEPT PEDIAT, DURHAM, NC USA
[5] UNIV MAINZ, DEPT PEDIAT, D-6500 MAINZ, GERMANY
[6] NORTHWESTERN UNIV, SCH MED, DEPT PEDIAT, CHICAGO, IL 60611 USA
[7] UNIV TENNESSEE, DEPT PEDIAT, MEMPHIS, TN USA
关键词
D O I
10.1056/NEJM199611143352003
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
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 additions, 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. (C) 1996, Massachusetts Medical Society.
引用
收藏
页码:1486 / 1493
页数:8
相关论文
共 44 条
  • [21] GENOMIC ORGANIZATION OF THE BTK GENE AND EXON SCANNING FOR MUTATIONS IN PATIENTS WITH X-LINKED AGAMMAGLOBULINEMIA
    HAGEMANN, TL
    CHEN, YX
    ROSEN, FS
    KWAN, SP
    [J]. HUMAN MOLECULAR GENETICS, 1994, 3 (10) : 1743 - 1749
  • [22] HYPO-IMMUNOGLOBULINEMIA WITH NORMAL T CELL-FUNCTION IN FEMALE SIBLINGS
    HOFFMAN, T
    WINCHESTER, R
    SCHULKIND, M
    FRIAS, JL
    AYOUB, EM
    GOOD, RA
    [J]. CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY, 1977, 7 (03): : 364 - 371
  • [23] ORGANIZATION OF HUMAN-IMMUNOGLOBULIN HEAVY-CHAIN DIVERSITY GENE LOCI
    ICHIHARA, Y
    MATSUOKA, H
    KUROSAWA, Y
    [J]. EMBO JOURNAL, 1988, 7 (13) : 4141 - 4150
  • [24] IDENTIFICATION OF BTK MUTATIONS IN 20 UNRELATED PATIENTS WITH X-LINKED AGAMMAGLOBULINEMIA (XLA)
    JIN, H
    WEBSTER, ADB
    VIHINEN, M
    SIDERAS, P
    VORECHOVSKY, I
    HAMMARSTROM, L
    BERNATOWSKAMATUSZKIEWICZ, E
    SMITH, CIE
    BOBROW, M
    VETRIE, D
    [J]. HUMAN MOLECULAR GENETICS, 1995, 4 (04) : 693 - 700
  • [25] TYROSINE PHOSPHORYLATION AND ACTIVATION OF BRUTON TYROSINE KINASE UPON FC-EPSILON-RI CROSS-LINKING
    KAWAKAMI, Y
    YAO, LB
    MIURA, T
    TSUKADA, S
    WITTE, ON
    KAWAKAMI, T
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1994, 14 (08) : 5108 - 5113
  • [26] A B-CELL-DEFICIENT MOUSE BY TARGETED DISRUPTION OF THE MEMBRANE EXON OF THE IMMUNOGLOBULIN MU-CHAIN GENE
    KITAMURA, D
    ROES, J
    KUHN, R
    RAJEWSKY, K
    [J]. NATURE, 1991, 350 (6317) : 423 - 426
  • [27] KU G, 1994, IMMUNOGENETICS, V40, P300, DOI 10.1007/BF00189976
  • [28] MCKINNEY RE, 1987, REV INFECT DIS, V9, P334
  • [29] MELCHERS F, 1994, ANNU REV IMMUNOL, V12, P209, DOI 10.1146/annurev.iy.12.040194.001233
  • [30] MULTIPLE DNA FRAGMENT POLYMORPHISMS ASSOCIATED WITH IMMUNOGLOBULIN MU-CHAIN SWITCH-LIKE REGIONS IN MAN
    MIGONE, N
    FEDER, J
    CANN, H
    VANWEST, B
    HWANG, J
    TAKAHASHI, N
    HONJO, T
    PIAZZA, A
    CAVALLISFORZA, LL
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1983, 80 (02): : 467 - 471