Mutations in the Mu Heavy-Chain Gene in Patients with Agammaglobulinemia

Yel, Leman; Minegishi, Yoshiyuki; Coustan‐Smith, Elaine; Buckley, Rebecca H.; Trübel, H.; Pachman, Lauren M.; Kitchingman, Geoffrey R.; Campana, Dario; Rohrer, Jurg; Conley, Mary Ellen

doi:10.1056/nejm199611143352003

Cited by 229 publications

(130 citation statements)

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“…The remaining 15% of cases, clinically identical to XLA, are still a heterogeneous group. Some mutations have been already identified, especially in components of the pre-BCR, such as IGHM [12,15], IGLL1 [9], CD79A [10], or BLNK [11] that result in impaired pre-B cell differentiation. However, alteration in Igl expression seems to be relatively frequent.…”

Section: Discussionmentioning

confidence: 99%

“…However, alteration in Igl expression seems to be relatively frequent. For example, Yel et al [15] described three different mutations in the IGH locus. For one consanguineous family, the affected patients had a DNA deletion covering 75-100 kb that encompassed the diversity genes (DH), the JH cluster and the IGHM gene.…”

Section: Discussionmentioning

confidence: 99%

“…This receptor, expressed on pre-B cells is composed of the Igl, the YL chain (made of k-like and VpreB) and the Iga/Igb transducing complex [5]. For example, mutations affecting IGHM [12,15], CD79A [10], IGLL1 [9] or BLNK that encodes a B cell linker protein essential for Igl signal transduction [11], have been reported.…”

Section: Introductionmentioning

confidence: 99%

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A new case of autosomal recessive agammaglobulinaemia with impaired pre-B cell differentiation due to a large deletion of the IGH locus

et al. 2002

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A new case of autosomal recessive agammaglobulinaemia with impaired pre-B cell differentiation due to a large deletion of the IGH locus Abstract Males with X-linked agammaglobulinaemia (XLA) due to mutations in the Bruton tyrosine kinase gene constitute the major group of congenital hypogammaglobulinaemia with absence of peripheral B cells. In these cases, blockages between the pro-B and pre-B cell stage in the bone marrow are found. The remaining male and female cases clinically similar to XLA represent a genotypically heterogeneous group of diseases. In these patients, various autosomal recessive disorders have been identified such as mutations affecting IGHM, CD79A, IGLL1 genes involved in the composition of the pre-B cell receptor (pre-BCR) or the BLNK gene implicated in pre-BCR signal transduction. In this paper, we report on a young female patient characterised by a severe non-XLA agammaglobulinaemia that represents a new case of Igl defect. We show that the B cell blockage at the pro-B to pre-B cell transition is due to a large homologous deletion in the IGH locus encompassing the IGHM gene leading to the inability to form a functional pre-BCR. The deletion extends from the beginning of the diversity (D) region to the IGHG2 gene, with all JH segments and IGHM, IGHD, IGHG3 and IGHG1 genes missing. Conclusion: alteration in Igl expression seems to be relatively frequent and could account for most of the reported cases of autosomal recessive agammaglobulinaemia.Keywords Agammaglobulinaemia AE B cell blockage AE IGH locus AE Immunoglobulin gene deletion AE Pre-B cellAbbreviations BET: ethidium bromide AE BTK: Bruton tyrosine kinase gene AE IGH: immunoglobulin heavy chain locus AE pre-BCR: pre-B cell receptor AE XLA: X-linked agammaglobulinaemia IntroductionRecurrent infections, mostly respiratory, with pyogenic bacteria are the predominant manifestations of children suffering antibody deficiencies. In some of these patients, early B cell development in the bone marrow is arrested and hypogammaglobulinaemia results from the absence of peripheral B cells. In these cases, chronic diarrhoea could also be observed and constitutes a serious clinical problem. This occurs in X-linked agammaglobulinaemia (XLA), also known as Bruton disease, characterised by defects in the Bruton tyrosine kinase gene (BTK) [13,14] that encodes the cytoplasmic tyrosine kinase btk, involved in signal transduction. In these cases, B cell development is blocked in the bone marrow at the pre-B cell stage, resulting in the accumulation of CD34+ CD19+ pro-B cells and in the presence of variable numbers of CD34-CD19+ pre-B cells. Females with a phenotype indistinguishable from XLA have also been described and Conley et al. [2] have estimated that these immunodeficiencies represent 10% of patients with congenital hypogammaglobulinaemia. The defects behind such autosomal recessive disorders have been recently identified and shown to affect predominantly the pre-B cell receptor (pre-BCR), which is an absolute prerequisite for pro-B to pre-B cell ...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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A new case of autosomal recessive agammaglobulinaemia with impaired pre-B cell differentiation due to a large deletion of the IGH locus

et al. 2002

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“…The G4A single base transition at codon 433 within exon 4 found in P15 is a previously known mutation described by Yel et al 10 and Granados et al 11 It affects the À1 position of the alternative splice site required for the production of the membrane-bound isoform of the protein and, in addition, it causes a glycine to serine substitution in the secreted isoform. It has been assumed that the mutation impairs the alternative splicing required to encode the membrane isoform of the mHC, but its actual effect on RNA splicing has not yet been demonstrated experimentally.…”

Section: Patient Selectionmentioning

confidence: 94%

“…9 Four point mutations, a 2-bp deletion and few large deletions of the human mHC gene (IGHM) have been identified previously by genetic analysis in patients with autosomal-recessive forms of agammaglobulinemia. 10,11 Another member of the pre-BCR complex -the l5 genewas also knocked out in the mouse, resulting in a leaky phenotype with a specific block at the pre-B-cell stage of differentiation; however, 4-months-old mice retain 20% of peripheral B cells and show a normal capability to mount an antibody response to both T-dependent and T-independent antigens. 12 In humans, a single case of compound heterozygote mutations in the l5/14.1 gene was associated with classical autosomal-recessive agammaglobulinemia, 13 emphasizing the fact that mutations in the same gene often affect B-cell development and functionality to different extents in humans and mice.…”

Section: Introductionmentioning

confidence: 99%

Molecular analysis of the pre-BCR complex in a large cohort of patients affected by autosomal-recessive agammaglobulinemia

et al. 2007

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Autosomal-recessive agammaglobulinemia is a rare and heterogeneous disorder, characterized by early-onset infections, profound hypogammaglobulinemia of all immunoglobulin isotypes and absence of circulating B lymphocytes. To investigate the molecular basis of the disease, 23 patients with early-onset disease and no mutations in Bruton tyrosine kinase, the gene responsible for X-linked agammaglobulinemia, were selected and analyzed by direct sequencing of candidate genes. Two novel mutations in the m heavy chain (mHC) gene (IGHM) were identified in three patients belonging to two unrelated families. A fourth patient carries a previously described G4A nucleotide substitution at the À1 position of an alternative splice site in IGHM; here, we demonstrate that this mutation is indeed responsible for aberrant splicing. Comparison of bone marrow cytofluorimetric profiles in two patients carrying different mutations in the IGHM gene suggests a genotype-phenotype correlation with the stage at which B-cell development is blocked. Several new single nucleotide polymorphisms (SNPs) both in the mHC and in the l5-like/VpreB-coding genes were identified. Two unrelated patients carry compound heterozygous variations in the VpreB1 gene that may be involved in disease ethiology.

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Primary Immunodeficiency Diseases

Puck¹

1997

JAMA

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Primary immunodeficiencies are rare, but important for 3 reasons. First, a high index of suspicion and prompt diagnosis can lead to lifesaving treatment or significant improvement in quality of life. Second, appreciation of the genetic nature of a host defense defect makes possible family counseling and carrier and prenatal diagnosis. Finally, the large and growing list of human genetic defects in immune pathways provides an important tool for understanding human immunoregulation. Many inherited immunodeficiency diseases have had their genetic cause proven with the discovery of their disease genes within the past 5 years. These diseases provide a framework into which additional diseases and disease gene discoveries can be added as the rapid progress in molecular immunology and genetics continues.

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Mutations in the Mu Heavy-Chain Gene in Patients with Agammaglobulinemia

Abstract: 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.

Cited by 229 publications

References 40 publications

A new case of autosomal recessive agammaglobulinaemia with impaired pre-B cell differentiation due to a large deletion of the IGH locus

A new case of autosomal recessive agammaglobulinaemia with impaired pre-B cell differentiation due to a large deletion of the IGH locus

Molecular analysis of the pre-BCR complex in a large cohort of patients affected by autosomal-recessive agammaglobulinemia

Primary Immunodeficiency Diseases

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