Nucleotide sequences of Immunoglobulin μ heavy chain deletion mutants

Baczynsky, W. O. T.; Sugii, Shunji; Murialdo, Helios; Pennell, Nancy; Filkin, C; Hozumi, Nobumichi; Shulman, Marc J.

doi:10.1093/nar/11.21.7471

Cited by 13 publications

(5 citation statements)

References 44 publications

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“…We have also observed this effect in the Sp6 line. After four and six recloning steps, the lines Sp602, Sp603 and Sp603.12.2 were established (Table I) and Shulman, 1980;Kohler et al, 1982;Shulnan et al, 1982;Baczynsky et al, 1983) to the ones described here we find that of 43, 21 are consistent with being premature chain termination mutants, of which eight have been shown in this paper to be due to frameshift mutations. Early chain termination leads to low levels of mRNA (Table II) and to low Ig production and secretion.…”

Section: Discussionsupporting

confidence: 72%

“…Large effects on protein structure as determined by isoelectric focusing (Adetugbo et al, 1977), size or monoclonal antibody binding (Yelton and Scharff, 1982) have been shown. Deletions and insertions within Ig genes have been correlated with gross alterations of protein structure and expression (Adetugbo et al, 1977;Kohler et al, 1982;Baczynsky et al, 1983;Hawley et al, 1982). Frameshift mutations resulting in premature termination have been described (Adetugbo et al, 1977) as well as mutants with altered subclass (Radbruch et al, 1980).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Consequences of frameshift mutations at the immunoglobulin heavy chain locus of the mouse.

Baumann¹,

Potash²,

Köhler³

1985

The EMBO Journal

176

111

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From an IgM secreting hybridoma line we have isolated 16 spontaneous mutants that produce truncated IgM polypeptides. The size of the mu‐mRNAs produced by these mutants is normal, but they express 3‐ to 100‐fold less mu‐mRNA and mutant mu‐protein than the parental cell line. Nucleotide sequence analysis of cloned mu‐genes and/or their mRNAs show frameshift mutations that generate in‐phase chain termination codons. The extent of the reduction in mu‐mRNA levels depends on the position of the nonsense codon within the gene.

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Section: Discussionsupporting

confidence: 72%

Section: Introductionmentioning

confidence: 99%

Consequences of frameshift mutations at the immunoglobulin heavy chain locus of the mouse.

Baumann¹,

Potash²,

Köhler³

1985

The EMBO Journal

176

111

View full text Add to dashboard Cite

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“…The deletions we identified in L Ϫ/Ϫ mice with the loss of C1-2 closely resemble C gene alterations in immortalized cells. 8,38,39 All have lost switch region, and in one case, part of the ␥3 switch sequence has been inserted, which has not been previously described. This suggests that production of truncated HC, perhaps initiated by prior expression of the same V H DJ H bearing full-length HC, is the consequence of faulty switch attempts and the inherent instability Figure 5A, showed that RBs are frequently generated when LC is missing.…”

Section: Discussionmentioning

confidence: 93%

Immunoglobulin aggregation leading to Russell body formation is prevented by the antibody light chain

Corcos

Osborn

Matheson

et al. 2010

Blood

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IntroductionIn the healthy organism, immunoglobulin (Ig) is present in membrane form, as part of the B-cell receptor (BCR), and in secreted form, as antibody. During B-cell development, V H DJ H rearrangement of a heavy chain (HC) precedes V L J L rearrangement of a light chain (LC). Nascent HC polypeptides are associated with the HC-binding protein (BiP, or GRP78) in the endoplasmic reticulum (ER) awaiting LC association, processing (eg, carbohydrate association), and export. [1][2][3] The key function of the BiP chaperone is to provide a scaffold to native or unfolded polypeptides, which prevents aggregation and establishes the appropriate conformation. Abnormal plasma cells called Mott cells, containing Ig aggregates, termed Russell bodies (RBs), have been found in nonsecretory myeloma, inflammatory diseases, and autoimmune disorders. 4,5 RB formation appears to indicate cellular indigestion due to a failure to eliminate misfolded or incorrectly assembled proteins. 6 An unsolved question is whether the inability to degrade or to export leads to Ig aggregation. It is possible that the production of large quantities of Ig as well as structural alterations may prevent appropriate processing.In the absence of LC, HC dissociation from chaperones and export is facilitated by deletions in the V H and/or C H 1 domain, a feature seen in pathology and also in cultured cell lines. [7][8][9] Shortened HC is produced in various lymphoid malignancies. In heavy-chain diseases (HCDs), HC is not associated with LC, lacks all or part of V H , and frequently shows deletion(s) in its C H domain(s). 7 In heavy-chain deposition disease (HCDD), a kidney disease secondary to plasma cell dyscrasia, deletions of C H 1 or of both C H 1 and C H 2 domains are found. 10,11 LCs are associated with HCs in HCDD serum antibodies but are missing from the deposits. 10,11 Expression studies showed that full-length HC cannot reach the cell surface in the absence of LC or surrogate LC, 12,13 although more recent experiments demonstrated that this is not always the case. 14-17 At the pre-B cell stage, HC pairing with surrogate LC results in surface expression and oligomerization of the pre-BCR, regarded as important for pre-BCR signaling. 18,19 HC-LC pairing permits a high level of surface IgM expression but appears to inhibit basal signaling, 20 possibly by preventing auto-aggregation.We previously found that ␥ and ␣ HCs lacking C H 1, similar to the proteins produced in HCDD, are present in the serum of LC-deficient (L Ϫ/Ϫ ) mice, which appear to be healthy. 21,22 HCs are encoded by mRNAs transcribed from somatically truncated HC genes with deletions extending from the switch region. Although membrane is required for these class-switch isotypes to be produced, no secreted HC could be detected.Here, we report that in L Ϫ/Ϫ mice, deletions in C result in the production of short HC transcripts and proteins by plasma cells; however, truncated proteins are only found in serum from older mice. In addition to this defect of secretion, a large majority ...

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“…The following mouse mAbs were used in this study : (a) MH-59-10 (mouse UK isotype), SA-DA4-4 ('YtK), LP-13B2-3 ('y2,K), and LP-13A3-6 (y26K) are specific for human F . chains (25,26) ; (b) BH-EB2-1 (AK), NC-BB2-6 (y,K), and GH-EA5-1 (y2,K) are specific for human y chains (25,27) ; (c) CH-EB6-8 (y,K) is an anti-human a chain antibody (27); (d) 57 .1 (it,K) and 35 .3 ('Y,K) have anti-DNP specificity (25); (e) CIa (AK) is specific for a chicken la determinant (28); (f) IA10 (y2 ,K, a kind gift of Dr. V. Nussenzweig, New York University School of Medicine, New York) is specific for decay-accelerating factor (DAF; reference 29) ; and (g) Leu-16 ( ,ytK) is an anti-CD20 mAb (Becton Dickinson & Co., Mountain View, CA) . All mAbs with specificity for human Ig determinants were purified from ascites fluid by affinity chromatography on Sepharose 4B columns coupled with the appropriate human Ig.…”

Section: Methodsmentioning

confidence: 99%

“…The purity of each fragment was confirmed by SDS-PAGE analysis under both reducing and nonreducing conditions and by ELISA using anti-it and anti-n mAbs . For studies using IgM domain deletion mutants, culture supernatants were obtained from the mouse hybridoma clones secreting IgM with well-characterized H chain (C H) domain deletions: clone 43 (CHI deletion, HIoLIo), clone 427 (CHI-2 deletion, H2L2), and their parental clone Sp6.18 (intact IgM), and clone 128 (CHI-2 deletion, HL), clone 208 (CHI-3 deletion, HL), and 482 (CH4 deletion, H2L2) (33)(34)(35) (generous gifts from Dr. M. J. Shulman, University of Toronto, and Dr. G. Mr KShler, Max Planck Institute for Immunology, Freiburg). The concentration of IgM, estimated by ELISA using rat anti-mouse K mAb forcoating plates and alkaline phosphatase-labeled goat anti-mouse K antibody as a developing reagent was adjusted to 0.05 mg/ml.…”

Section: Methodsmentioning

confidence: 99%

Biochemical nature of an Fc mu receptor on human B-lineage cells.

Ohno

Kubagawa

Sanders

et al. 1990

The Journal of Experimental Medicine

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SummaryAn IgM-binding protein of -60 kD has been identified on activated B cells, but not on resting and activated T cells, monocytes, or granulocytes. Here, we characterize this IgM-binding protein as a receptor for the Fc portion (CH3 and/or CH4 domains) of IgM molecules (FcAR) . The Fct.R can be expressed as a cell surface activation antigen throughout the pre-B and B cell stages in differentiation . Receptor expression is not directly linked with IgM production, as both u-pre-B cells and isotype-switched B cells may express the FcjiR. The receptor molecules produced by both pre-B and B cells are identical in size and are characterized as an acidic sialoglycoprotein with 0-linked, but no Winked, oligosaccharide. The FcIAR is anchored to the surface of B-lineage cells via a glycosyl phosphatidylinositol linkage. The Fcp,R is thus the third member of a family of Fc receptors expressed on B-lineage cells, and its preferential expression on activated B cells suggests a potential role in the response to antigens .

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Nucleotide sequences of Immunoglobulin μ heavy chain deletion mutants

Cited by 13 publications

References 44 publications

Consequences of frameshift mutations at the immunoglobulin heavy chain locus of the mouse.

Consequences of frameshift mutations at the immunoglobulin heavy chain locus of the mouse.

Immunoglobulin aggregation leading to Russell body formation is prevented by the antibody light chain

Biochemical nature of an Fc mu receptor on human B-lineage cells.

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