Exon skipping without splice site mutation accounting for abnormal immunoglobulin chains in nonsecretory human myeloma

Abstract

The proliferating plasma cells of patient COM with nonsecretory myeloma synthesized truncated 42 kDa gamma 1 chains made of a complete constant region but devoid of variable domain. In the absence of light chain expression, the shortened gamma chains were retained intracellularly and were subsequently degraded within 12 h. COM neoplastic plasma cells contained short gamma 1 heavy chain transcripts in which the leader peptide exon was directly joined to the CH1 exon using the regular splice sites. However, study of the productive gamma gene showed that the skipped variable exon was bounded by normal splicing signals and that the adjacent intron organization was not altered. Since this unusual splicing pattern was maintained when COM gamma gene was transfected in murine plasmocytoma cells, exon skipping possibly relates to the modified structure of COM variable region. The latter showed a 2-base pair deletion introducing a translation frameshift in the VH region and a DNA insertion at the VH-DJH junction consisting in a perfect duplication of the first 54 nucleotides of the recombined DJH segment. The lack of light chain production by COM cells was explained by alterations of the variable region of the rearranged kappa gene leading to abnormally spliced transcripts.

Non-secretory multiple myeloma: from biology to clinical management

“…In individual case reports, it has been shown that true non-secretors have lost the polyadenylation site that is necessary for extracellular Ig secretion 24. Other reports have shown that loss of the V domain of the heavy chain also prevents secretion and stimulates intracellular degradation 25. Interestingly, in the same patient, the MM cells had also entirely lost light-chain production due to kappa-chain mutations 25.…”

“…Other reports have shown that loss of the V domain of the heavy chain also prevents secretion and stimulates intracellular degradation 25. Interestingly, in the same patient, the MM cells had also entirely lost light-chain production due to kappa-chain mutations 25. A case report in 2004 also detailed a frameshift mutation in a patient with kappa-restricted MM.…”

A molecular basis for nonsecretory myeloma

“…[3][4][5][6]15 Notably, our studies provide the first evidence that an aberrant product of a mutated C L gene also can be associated with this disorder. The primary sequence alterations that resulted from the frameshift mutation included loss of the cysteine residues normally present at positions 194 and 214 that are involved in formation of intrachain and interchain disulfide bonds, respectively.…”

“…However, there is only limited information regarding the molecular factors that might account for this phenomenon. [3][4][5][6][7] We now report our finding that the plasma cells of an individual with NSM indeed synthesized aberrant monoclonal light chains that resulted from a somatic mutation in the gene encoding the constant (C L ) region of the molecule. Our studies provide the first conclusive evidence that an abnormality in this portion of the light chain may be implicated in the pathogenesis of this disorder.…”

Relationship between elevated immunoglobulin free light chain and the presence of IgH translocations in multiple myeloma

“…(29) While excess of heavy or light chain can occur depending on the affected component, this appears to affect the heavy chain less commonly. (30) While there are likely to be several reasons for this observation, including inability of the endoplasmic reticulum to secrete the heavy chain that is unbound to a light chain leading to an unfolded protein response and intracellular degradation of the heavy chain through a proteasome mediated pathway as well as toxicity of non-secreted full size heavy chain. (29, 31, 32) Light chains unbound to a heavy chain seem less susceptible to such degradation mechanisms and are more likely to be secreted alone in the absence of an accompanying heavy chain.…”