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

Baumann, Britta; Potash, Mary Jane; Köhler, Georges

doi:10.1002/j.1460-2075.1985.tb03636.x

Cited by 176 publications

(119 citation statements)

References 32 publications

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“…In both prokaryotes and eukaryotes nonsense mutations in a gene can reduce the abundance of the mRNA transcribed from that gene (Morse and Yanofsky 1969;Losson and Lacroute 1979;Maquat et al 1981;Pelsy and Lacroute 1984;Baumann et al 1985;Nilsson et al 1987;Daar and Maquat 1988;Urlaub et al 1989;Cheng et al 1990;Gozalbo and Hohmann 1990;Barker and Beamon 1991;Gaspar et al 1991;Leeds et al 1991;Baserga and Benz 1992;Lim et al 1992;Cheng and Maquat 1993). Results of this study and others indicate that in S. cerevisiae this nonsense-mediated effect can be attributed to cytoplasmic events that are concurrent with mRNA translation.…”

Section: Nonsense Mutations Accelerate Cytoplasmic Mrna Decay In Yeastmentioning

confidence: 60%

mRNA destabilization triggered by premature translational termination depends on at least three cis-acting sequence elements and one trans-acting factor.

Peltz¹,

Brown²,

Jacobson³

1993

Genes Dev.

285

349

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Nonsense mutations in a gene can accelerate the decay rate of the mRNA transcribed from that gene, a phenomenon we describe as nonsense-mediated mRNA decay. Using amber (UAG) mutants of the yeast PGK1 gene as a model system, we find that nonsense-mediated mRNA decay is position dependent, that is, nonsense mutations within the initial two-thirds of the PGKl-coding region accelerate the decay rate of the PGK1 transcript ~<12-fold, whereas nonsense mutations within the carboxy-terminal third of the coding region have no effect on mRNA decay. Moreover, we find that this position effect reflects (1) a requirement for sequences 3' to the nonsense mutation that may be necessary for translational reinitiation or pausing, and (2) the presence of an additional sequence that, when translated, inactivates the nonsense-mediated mRNA decay pathway. This stabilizing element is positioned within the coding region such that it constitutes the boundary between nonsense mutations that do or do not affect mRNA decay. Rapid decay of PGK1 nonsense-containing transcripts is also dependent on the status of the UPF1 gene. Regardless of the position of an amber codon in the PGK1 gene, deletion of the UPF1 gene restores wild-type decay rates to nonsense-containing PGK1 transcripts.

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Section: Nonsense Mutations Accelerate Cytoplasmic Mrna Decay In Yeastmentioning

confidence: 60%

mRNA destabilization triggered by premature translational termination depends on at least three cis-acting sequence elements and one trans-acting factor.

Peltz¹,

Brown²,

Jacobson³

1993

Genes Dev.

285

349

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“…Kappa surface staining was performed with fluorosceinconjugated rat anti-mouse ,u heavy-chain antibody (b7.6 [6]) and rabbit anti-mouse K light-chain antibody (Cappel Laboratories) as previously described (26). Stained cells were analyzed by using a fluorescent microscope (Nikon).…”

Section: Methodsmentioning

confidence: 99%

Corrective recombination of mouse immunoglobulin kappa alleles in Abelson murine leukemia virus-transformed pre-B cells.

Feddersen¹,

Ness²

1990

Mol. Cell. Biol.

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Previous characterization of mouse immunoglobulin K gene rearrangement products cloned from murine plasmacytomas has indicated that two recombination events can take place on a single K allele (R. M. Feddersen and B. G. Van Ness, Proc. Natl. Acad. Sci. USA 82:4792-4797, 1985; M. A. Shapiro and M. Weigert, J. Immunol. 139:3834-3839, 1987). To determine whether multiple recombinations on a single K allele can contribute to the formation of productive V-J genes through corrective recombinations, we have examined several Abelson murine leukemia virus-transformed pre-B-cell clones which rearrange the K locus during cell culture. Clonal cell lines which had rearranged one K allele nonproductively while maintaining the other allele in the germ line configuration were grown, and secondary subclones, which subsequently expressed K protein, were isolated and examined for further K rearrangement. A full spectrum of rearrangement patterns was observed in this sequential cloning, including productive and nonproductive recombinations of the germ line allele and secondary recombinations of the nonproductive allele. The results show that corrective V-J recombinations, with displacement of the nonproductive K gene, occur with a significant frequency (6 of 17 K-producing subclones). Both deletion and maintenance of the primary (nonfunctional) V-J join, as a reciprocal product, were observed.The expression of immunoglobulin by B cells is dependent on gene segment rearrangements which are unique to lymphoid development (41). Highly conserved, site-specific sequences flanking variable (V) and joining (J) gene segments of the kappa (K) light-chain locus direct the complex enzymology required for DNA cutting and ligation (2). In addition to the functional products generated from rearrangement of the K locus, many defective products have been observed (3,7,10,12,14,15,19,27,30,32,36,40,43,44). In fact, from both plasmacytomas and normal B cells it has been estimated that more than one-third of all K rearrangement events are aberrant (11). Collectively, these aberrant rearrangements have suggested that clonal selection may actually mask an otherwise inefficient rearrangement process.In addition to functional and nonfunctional K transcription units, Southern blot hybridization analyses, coupled with cloning and sequencing, have identified reciprocal products of VK-JK recombination (13, 21-23, 37, 39, 42). These byproducts of V-J joining events are characterized by the back-to-back fusion of the recombination signal sequences (the conserved heptamers and nonamers) that border the germ line gene segments. The characterization of reciprocal products supports the intrastrand DNA inversion mechanism of V-J recombination. We and others (12, 38) previously characterized additional products of K locus recombination in mouse plasmacytomas. These novel elements were shown to contain a VK-JK rearrangement followed by the reciprocal element of another VK-JK rearrangement. We designated these double recombination products (DRPs). Significantly, it a...

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“…3, top). This finding is interesting since it is generally believed that the expression of nonproductively rearranged Ig genes is substantially downregulated by posttranscriptional mechanisms (24,25). To investigate if both alleles undergo isotype-switching, we performed primer extensions of the PCR amplified ␣ and ␥ transcripts with oligonucleotides specific for the CDR3 regions of the productive and non-productive allele.…”

Section: Detection Of Clonally Related Isotype-switched Cll H-chain Tmentioning

confidence: 99%

IgM-producing chronic lymphocytic leukemia cells undergo immunoglobulin isotype-switching without acquiring somatic mutations.

Efremov¹,

Ivanovski²,

Batista³

et al. 1996

J. Clin. Invest.

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The malignant B cells in chronic lymphocytic leukemia (CLL) typically express low-density membrane IgM or IgM/ IgD. In vitro experiments have shown that the CLL cells can be induced to differentiate into cells that secrete immunoglobulin (Ig) and can occasionally undergo heavy (H) chain class switching. We now show that the CLL cells also undergo isotype-switching in vivo, since ␥ and/or ␣ H chain transcripts with identical FW3/CDR3/FW4 regions as the CLL transcripts were detected in all of the 13 investigated patients with IgM ϩ CLL. In most cases switching had occurred to ␣ 1 and ␥ 3, but CLL transcripts corresponding to the other ␥ chain isotypes were also detected. In one case both the productively and nonproductively rearranged allele were found to undergo H chain class switching. CLL ␥ transcripts were also present in surface IgG ϩ sorted B cells, demonstrating that a small subset of the CLL cells express membrane IgG. In addition, transcripts encoding secretory ␥ 2 and ␥ 3 H chains were detected in two cases, which suggests that some serum IgG could be produced by the leukemic clone. Analysis of sorted PBL showed that isotypeswitching occurs in CLL cells that express the CD5 antigen.

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

Cited by 176 publications

References 32 publications

mRNA destabilization triggered by premature translational termination depends on at least three cis-acting sequence elements and one trans-acting factor.

mRNA destabilization triggered by premature translational termination depends on at least three cis-acting sequence elements and one trans-acting factor.

Corrective recombination of mouse immunoglobulin kappa alleles in Abelson murine leukemia virus-transformed pre-B cells.

IgM-producing chronic lymphocytic leukemia cells undergo immunoglobulin isotype-switching without acquiring somatic mutations.

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