Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the expression of T15 idiotopes (Id) on phosphorylcholine (PC)-binding monoclonal immunoglobulins and defined the structural correlates of these Id. The seven monoclonal anti-Id antibodies used as probes recognize distinct determinants that range from the antigen binding site to the CH1 domain on TEPC15. Competition between a series of PC-specific immunoglobulins and radiolabelled TEPC15 for binding to anti-Id in solid phase revealed a broad spectrum of idiotopic crossreactivity. A strong crossreactivity with TEPC15 was observed only in proteins possessing the VK22 light chain. Each of the seven discrete, overlapping T15 Id may be expressed independently of each other on PC-binding immunoglobulins, indicating a significant idiotopic heterogeneity among T15 B-cell clones. No correlation was found between the public (shared) expression of an Id and its position relative to the antigen-binding site. Variations in the primary sequences of PC-binding immunoglobulins were correlated with their effect on individual Id expression. Regions influencing the expression of three Id were localized on a computer display of the three-dimensional structure of the closely related PC-binding myeloma protein McPC603. These data show that some, but not all individual Id determinants may be influenced by amino acid substitutions in the first and third hypervariable loops.
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PMID:Serologic and molecular characterization of the T15 idiotype--II. Structural basis of independent idiotope expression on phosphorylcholine-specific monoclonal antibodies. 244 40

Protein Rou is a human IgA2 myeloma protein that carries the isoallotype marker n A2m(2). Partial amino acid sequence of its H chain (alpha) shows that the hinge region and the CH2 domain are homologous to alpha 2-chain and the CH1 and the CH3 domains homologous to alpha 1. Moreover, the CH1 domain contains the H-L disulfide bond identical to alpha 1. It is concluded that Rou H chain is a hybrid molecule caused by a recombination between alpha 1 and alpha 2 genes. The recombination event occurred between alpha 1-exon 1 and alpha 2-exon hinge and corresponds to position 222-223 of the alpha-chain.
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PMID:Protein Rou. A human IgA hybrid. 312 51

The DNA from the mouse myeloma cell, I17, which produces aberrant gamma 2b heavy chain mRNAs, was cloned and sequenced. The I17 mutant, and its parent line 10.1, share a small deletion at the splice junction of the CH1 domain which results in the absence of CH1 sequences from the mRNA. In addition, the genomic DNA of I17 has a deletion of 253 nucleotides which fuses the CH2 and CH3 exons, causes a frameshift of the next 43 amino acids and results in a truncated protein. The deleted nucleotides are flanked by two direct repeats of the CAGCA pentamer in the normal gene. One copy of the repeat and the interposed DNA is removed in the mutant. The DNA deletion is colinear with the mRNA. Both I17 and 10.1 cells have decreased accumulation of the secretory-specific gamma 2b mRNA. The amounts of membrane-specific gamma 2b mRNA are also affected in the mutants.
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PMID:An immunoglobulin heavy chain gene deletion at direct repeats: nucleotide sequence and effect on mRNA accumulation. 313 66

A series of mouse myeloma mutants, derived from a cell line of the murine MPC-11 tumor (gamma 2b, kappa), resemble human heavy-chain disease in their loss of an internal domain (exon). In these mutants, most of the gamma 2b CH1 exon was present in the nuclear RNA but was removed during splicing to form the mature cytoplasmic RNA. Amino acid sequence studies of one mutant (10.1) are consistent with the loss of the complete CH1 domain. A second mutant cell line (I17) derived from 10.1 and containing the same CH1 alteration was shown by S1 nuclease protection experiments to have an additional mRNA deletion spanning the CH2-CH3 domain boundary. This second deletion was shown to result from a genomic alteration that provided a marker for the isolation of the expressed H-chain allele. To determine the basis of the CH1 splicing defect, the 117 genome-expressed gamma 2b constant region DNA was cloned. Sequence studies showed a deletion of 99 nucleotides around the 3' end of the CH1 domain, which removed the splice site and flanking DNA, apparently causing the aberrant splicing of the RNA transcript. The sequence deleted in the mutant is flanked by short repeats of the octameric sequence CCAGCCAG in the wild-type gene. In the mutant, one copy of the repeat, in addition to the sequences between the repeats, has been lost.
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PMID:Loss of a consensus splice signal in a mutant immunoglobulin gene eliminates the CH1 domain exon from the mRNA. 609 57

Mouse myeloma mutants isolated from cell line 45.6 (gamma 2b) producing structurally altered immunoglobulin heavy (H) chains have been characterized. The mutant 10-1 synthesizes an H chain of 47 000 daltons containing a CH1 deletion; two mutants, G251 and I17, derived from 10-1 synthesize H chains of 40 000 and 35 000 daltons, respectively. The messenger ribonucleic acids (mRNAs) in these mutants have been shown to be smaller in molecular weight than mRNAs produced in 45.6 cells and lack a portion, but not all, of the CH1 domain. The H chains of G251 and I17 no longer express IgG subclass-specific determinants, are not secreted, and are structurally altered in the carboxyl-terminal portion of the molecule. In vitro the mRNAs of the mutants code for the synthesis of a polypeptide precursor characteristic of secreted proteins; the shortened proteins are apparently glycosylated intracellularly. Somatic cell hybrids between a structurally altered nonsecretor and a drug-marked wild-type myeloma cell secret only the wild-type protein. Reversion to secretion for G251 or I17 is accompanied by a change in the amino acid composition of the H chain such that gamma 2a subclass-specific determinants are expressed. Therefore, the primary structure of the H chain is an important factor in determining secretion. The gamma 2a-secreted chains from G251 and I17 fall into two classes: (1) those synthesizing proteins of approximately 47 000 daltons producing H-chain mRNAs of approximately 1.66 kilobases that are deleted for a portion, but not all, of CH1; (2) those synthesizing gamma2a proteins of approximately 55 000 daltons that are encoded in mRNAs of apparently wild-type size and that have regained CH1 sequences. The molecular explanations for the production of these alterations is discussed.
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PMID:Heavy-chain mutants derived from gamma 2b mouse myeloma: characterization of heavy-chain messenger ribonucleic acid, proteins, and secretion in delection mutants and messenger ribonucleic acid in gamma2a mutant progeny. 626 11

Two independently arising alpha heavy chain mutants have been found to synthesize heavy chains with CH1 deletions of approximately equal extent. Both were isolated from heavy chain-producing variants of the mouse myeloma W3129 and demonstrate that it is possible to arrive at the heavy chain disease phenotype by the pathway H + L leads to H leads to delta H. Analysis of genomic DNA by digestion with restriction endonucleases followed by molecular hybridization showed that one mutant (delta 37) had a deletion of approximately 0.2 kilobase and the second mutant (delta 15) had a deletion of approximately 0.5 kilobase. Mouse myeloma cells contain several alpha chain alleles but only one is expressed; the presence of the deletion in delta 37 and delta 15 made it possible to identify the restriction fragments from the expressed allele. Analysis of the fragments produced after cleavage with an isoschizomeric pair of restriction enzymes, Msp I and Hpa II, indicated that, in the W3129 cell line and its variants, the unexpressed alpha alleles contain methylated bases. The influence of methylation on gene expression remains to be elucidated.
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PMID:Two alpha heavy chain disease proteins with different genomic deletions demonstrate that nonexpressed alpha heavy chain genes contain methylated bases. 627 10

The expressed immunoglobulin heavy chain genes of five gamma 2b-gamma 2a hybrid chain-producing variants of the mouse myeloma MPC-11 (gamma 2b, kappa) have been characterized by genomic Southern blot analysis. Results show that a hybrid gamma 2b-gamma 2a gene was formed in each variant by recombination between the expressed gamma 2b gene of MPC-11 and a gamma 2a gene. The recombination sites are within regions of marked homology between gamma 2b and gamma 2a genes: at least three and probably four variants show gamma 2b-gamma 2a recombination within the heavy chain constant region 2 (CH2) domain, while the fifth has its recombination site between the penultimate nucleotide of CH1 and the eighth nucleotide of the hinge. An unexpected finding is that the hybrid heavy chain-producing variants fall into two subgroups based on their use of different gamma 2a gene forms in hybrid gene formation. This result leads to the speculation that either a tandem gamma 2a gene duplication was present in MPC-11 prior to variant generation or mitotic recombination between chromosomes occurred in the generation of one variant subgroup. The similarity of hybrid gene formation in MPC-11 variants to that apparently responsible for concerted evolution within multigene families and hybrid protein expression in various individuals is noted, and the possible relationship between hybrid gene formation and the heavy chain class switch is discussed.
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PMID:Hybrid gamma 2b-gamma 2a genes expressed in myeloma variants: evidence for homologous recombination. 631 38

The complete amino acid sequence of the 432-residue heavy (alpha) chain of mouse myeloma MOPC 511 has been determined. The variable region of the alpha chain of IgA 511, a phosphocholine-binding protein, is highly homologous to that of the other phosphocholine-binding immunoglobulins. Comparison of the 511 alpha chain constant region with that of other mouse and human heavy chains shows that sequence divain. The CH3 domain disulfide bridge of the 511 alpha chain, for example, consists of only 28 amino acid residues compared to 60 residues for other chains and domains. Sequence divergences are alsos apparent at the CH2/CH3 domain boundary, an area where a number of frameshift mutations have occurred. One mutant, mouse IgA 47A, lacks the entire CH3 domain. Comparison of the 511 alppha chain with the 47A alpha chain reveals two noncconservative amino acid changes at the COOH terminus of the 47A chain, Ser-Gln for VAl-Thr in the 511 chain. These changes and the deletion of the CH3 domain can be explained by a single genetic event--namely, a frameshift mutation followed by premature chain termination. The remainder of the 47A constant region, including the hinge region, is identical to the 511 alpha chain, except for two conservative changes in the CH1 domain: serine-126 and theonine-197 in the 511 alpha chain are both replaced by alanine in the 47A chain.
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PMID:Complete amino acid sequence of a mouse immunoglobulin alpha chain (MOPC 511). 677 28

We report here the primary structure of an immunoglobulin heavy chain synthesized by ICR 16, a variant of the MPC 11 mouse myeloma cell line. The ICR 16 heavy chain is a gamma 2b-gamma 2a hybrid, consisting of the CH1 domain of gamma 2b and the hinge, CH2 and CH3 domains of gamma 2a subclasses. The genetic mechanism by which ICR 16 occurred may be recombination, based on homologies in both coding and intervening sequences in gamma 2b and gamma 2a constant region genes. Although the Fc fragment of ICR 16 is completely gamma 2a-like and has been shown to bind to gamma 2a Fc receptors on mouse macrophages, the intact H2L2 molecules is unable to do so. Such an observation underscores the crucial role that conformation may play in the ability of immunoglobulins to carry out biologic functions.
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PMID:Effects of immunoglobulin structure on Fc receptor binding: a mouse myeloma variant immunoglobulin with a gamma 2b-gamma 2a hybrid heavy chain having a complete gamma 2a Fc region fails to bind to gamma 2a Fc receptors on mouse macrophages. 680 75

This paper describes an IgA related protein Vla which occurred in the serum and urine of a patient with multiple myeloma. The protein was isolated from urine; it had a molecular mass of 70,000 daltons. It was shown to be a two chain IgA half molecule, consisting of a deleted alpha heavy chain, with a molecular mass of 42,000 daltons, which was disulphide linked to a normal kappa type light chain. Fabc fragments were produced from an unrelated myeloma IgA. These had the same biochemical properties as protein V1a, except for the absence of the disulphide linkage between the deleted heavy chains and the light chains. Protein Vla and the Fabc fragments could both be cleaved by IgA1 protease from Streptococcus sanguis, which indicates the presence of the alpha 1 hinge region. An inventory of its antigenic determinants and their similarity to those of previously characterized F(abc)2 fragments, indicates that protein Vla, like the Fabc fragments, contains the CH1 and CH2 domains, but lacks most of the CH3 domain. The fact that cleavage by IgA1 protease from S. sanguis yields a Fab fragment but fails to yield a CH2 domain demonstrates that cleavage by the enzyme is not only restricted to the Pro227-Thr228 bond in the IgA1 hinge region.
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PMID:IgA1 half molecules in human multiple myeloma and the in vitro production of similar fragments from intact IgA1 molecules. 683 48


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