Alternative titles; symbols
HGNC Approved Gene Symbol: IGLC1
Cytogenetic location: 22q11.22 Genomic coordinates (GRCh38): 22:22,895,375-22,895,694 (from NCBI)
The constant region of the lambda light chain of immunoglobulins are of 4 subtypes, as defined by amino acid substitutions in 3 monoclonal myeloma L chains (OZ, KERN, Mcg). Subtype 1 is OZ plus KERN, Mcg-. Subtype 2 is OZ-KERN plus Mcg+. Subtype 3 is OZ-KERN plus Mcg-. Subtype 4 is OZ-KERN-Mcg-. Although no idiotypic variation of lambda light chains has been found (comparable to Inv and Gm variants of kappa light chains and gamma heavy chains), the existence of at least 1 locus for lambda light chains can be inferred from the amino acid sequence of immunoglobulins. The same type of evidence indicates the existence of mu, delta, and epsilon heavy chain loci which determine the structure of heavy chains in IgM, IgD and IgE, respectively. Each immunoglobulin molecule is composed of 2 heavy chains and 2 light chains. Since there are 5 types of heavy chains and 2 types of light chains, a minimum of 10 classes of immunoglobulins result. Actually, since there are at least four subtypes of gamma heavy chains, there are at least 32 types of immunoglobulins. Six subgroups of lambda L chains are recognized and designated V-lambda I-VI. They are presumably determined by separate but closely linked loci. For assignment of gamma globulin-specific chromosomes, Kucherlapati et al. (1979) created hybridomas between a variant mouse myeloma cell line that produces no immunoglobulin and lymphocytes from patients with chronic lymphocytic leukemia. (Hybrids between mouse myeloma cells and spleen cells from immunized mice had been used for 'rescuing' immunoglobulin producing mouse cells and producing monoclonal antibodies.) They concluded that chromosome 6 and-or 11 is involved in expression of human heavy and-or lambda chain production. The antibody genes provide a unique opportunity for studying the molecular basis of eukaryotic differentiation. Rearrangement of gene segments is correlated with the expression of antibody molecules. The light chains are encoded by 3 gene segments, V(L), J(L) and C(L), which are separated in the genomes of cells undifferentiated with regard to antibody gene expression. During differentiation of the antibody-producing or B cell, the V(L) and V(J) gene segments are rearranged and joined together while the intervening DNA between the J(L) and C(L) segments remains unmodified. This portion of the transcript is removed by RNA splicing to produce light chain mRNA with contiguous V(L), J(L) and C(L) coding segments. See review in Davis et al. (1980).
Klein (1981) found that B cell-derived tumors (mouse myeloma and human Burkitt lymphoma (113970) and B-cell acute lymphoblastic leukemia) have anomalous patterns of immunoglobulin synthesis which correlate with the type of chromosomal aberration. Similar observations were made by Lenoir (1981) who had collected the largest number of variant Burkitt lymphoma translocations. Of 10 tested, all agreed with the hypothesis as to light chain expression: all the 8;22 translocation cells produced lambda as the only light chain; all the 2;8 translocation cells produced only kappa; and 8;14 translocation cells produced either kappa or lambda, with an approximate ratio of 2:1. Erikson et al. (1981) confirmed assignment of the lambda gene cluster to chromosome 22 by the study of derivative clones from somatic cell hybrids between mouse myeloma cells and human B cells.
Hieter et al. (1981) found that the lambda light chain locus of man contains 6 lambda-like genes arranged tandemly on a 50-kb segment of chromosomal DNA. The sequences of 3 of the 6 correspond to 3 known nonallelic lambda chain isotypes: Mcg, Ke(-)Oz(-), and Ke(-)Oz(+). These are situated at the 5-prime end of the cluster of 6. In addition to the 6, three as yet unlinked lambda-like sequences were cloned. The authors suggested that the lambda genes may form an unexpectedly large family within the human genome. At the protein level, at least a fourth nonallelic form of the human lambda constant region has been identified (Solomon, 1977): Kern(+)Oz(-). The amino acids at positions 112, 114, 152, 163, 190, and 216 are, respectively, for Ke(-)Oz(-): ala-ser-ser-thr-arg; for Ke(+)Oz(-): ala-ser-gly-thr-arg; for Ke(-)Oz(+): ala-ser-ser-thr-lys; for Mcg: asn-thr-gly-lys-arg. The 6 genes surround a highly polymorphic and evidently unstable region that was repeatedly deleted when cloned in E. coli. Hereditary restriction fragment length polymorphism was demonstrated in the lambda gene locus. The complete characterization of the lambda locus with regard, for example, to the J regions and the mechanism for achieving diversity remains to be done.
Using a genomic probe and in situ hybridization, Leder (1982) and his colleagues tentatively assigned the lambda gene cluster to 22q11. Using nucleic acid probes prepared from the cloned gene in Southern blots of DNA from somatic cell hybrids, McBride et al. (1982) assigned the kappa constant gene to chromosome 2 and the lambda constant gene to chromosome 22. The human chromosomes carried by each hybrid cell line were identified by isozyme markers.
Wabl and Steinberg (1982) proposed a theory to explain allelic exclusion (only 1 of 2 alleles is functional in any one lymphocyte) and L chain isotypic exclusion (in a given lymphocyte, either kappa or lambda light chain but not both can combine with heavy chain to form a complete Ig molecule). Whereas in Burkitt lymphoma of the t(8;22) type the lambda light chain genes are translocated to chromosome 8, they remain on chromosome 22 (i.e., on the Philadelphia chromosome) in chronic myelogenous leukemia (CML; 608232) (Selden et al., 1983). The rearrangements in Burkitt lymphomas have permitted definition of the normal orientation in the immunoglobulin genes on chromosomes 2p, 14q, and 22q. The 5-prime to 3-prime order is cen--V--J--C--ter for the kappa genes on 2p; ter--V--J--C--cen for the heavy chain genes on 14q; and cen--V--C--ter for the lambda genes on 22q.
According to Croce (1984), the relative frequencies of the 3 forms of Burkitt lymphoma are 75%, 8;14; 16%, 8;22; and 9%, 8;2. One hundred percent of cases show one or another of these 3 types of translocation. The breakpoint in 22q in Burkitt lymphoma is cytogenetically indistinguishable from the breakpoint in CML. Molecular genetic studies indicate that the Burkitt breakpoint is centromeric to the C-lambda locus and the CML breakpoint is distal to C-lambda. Through studies of an 8;22-carrying Burkitt lymphoma cell line by somatic cell genetic and in situ hybridization techniques, Emanuel et al. (1984) concluded that the lambda variable region genes are on the centromeric side of the lambda constant region genes (which lie distal). Six nonallelic immunoglobulin lambda constant region genes have been characterized on a 40-kb stretch of DNA. The nucleotide sequences of the 3 upstream genes of this cluster (Cl1, Cl2, and Cl3) were determined and shown to encode, respectively, Kern(-)Oz(-), and Kern(-)Oz(+) constant regions of the lambda chains.
Dariavach et al. (1987) reported the sequence of the 3 downstream genes of this cluster and showed that 2 of them (Cl4 and Cl5) are pseudogenes. They also showed that Cl6 encodes a Kern(+)Oz(-) chain. By determining the DNA sequence of the complete human C lambda complex, Vasicek and Leder (1990) found a previously undescribed seventh C lambda region that may encode the Ke(+)Oz(-) lambda protein. They demonstrated that the 7 constant regions are organized in a tandem array and that each is preceded by a single J lambda region. Lambda 1, lambda 2, lambda 3, and lambda 7 are apparently active genes, while lambda 4, lambda 5, and lambda 6 are pseudogenes. There are no other J lambda or C lambda regions within a 60-kb region surrounding the C lambda complex; however, there are at least 4 other lambda-like genes and lambda pseudogenes in the human genome. They found a 1,377-bp open reading frame located on the opposite strand in the region containing lambda 7. They had no evidence that it was part of a functional gene, however.
Frippiat et al. (1995) completed a map of the human lambda locus on 22q11.2. They mapped 52 V-lambda genes from 10 V-lambda families and 7 J-lambda and C-lambda genes on an 1140-kb contig constructed from 8 YACs in 129 cosmid clones. Variable genes were contained within 800 kb and the 10 families were arranged in 3 clusters, in contrast to the dispersed organization of the different variable family genes of the heavy-chain and kappa light chain. The VpreB gene (VPREB1; 605141), encoding part of the surrogate light chain, the GGT2 gene (137181), and the BCR4 pseudogene (see 151410) were also mapped within the lambda locus.
Using FISH, Kosak et al. (2002) demonstrated that the IgH (see 147100) and Ig-kappa (IgK; 147200) loci, but not the smaller Ig-lambda locus, which has only 3 V gene segments, have an inverse nuclear distribution in mouse hemopoietic progenitors and pro-T lymphocytes compared with pro-B lymphocytes. In pro-T cells, in which these large multisegmented loci are inactive, they are preferentially positioned at the nuclear periphery, whereas in pro-B cells, which actively express Ig loci, they have a central configuration and undergo large-scale IL7R (146661)-dependent compaction. Kosak et al. (2002) proposed that a peripheral positioning of these loci inhibits their transcription and rearrangement by being sequestered away from the transcription and recombination apparatus and/or by the assembly of a refractory structure. In addition, the large-scale central compaction may function to facilitate long-range V(D)J rearrangement.
Roix et al. (2003) examined the question of why translocations between chromosomes tend to recur at specific breakpoints in the genome. They provided evidence that higher-order spatial genome organization is a contributing factor in the formation of recurrent translocations. They showed that MYC (190080), BCL (168461), and immunoglobulin loci, which are recurrently translocated in various B-cell lymphomas, are preferentially positioned in close spatial proximity relative to each other in normal B cells. Roix et al. (2003) first assessed the global nuclear organization of translocation-prone genes by localizing them using fluorescence in situ hybridization. The preferred positioning they found was statistically distinct from a uniform random distribution. They then measured the physical distance between MYC and its various translocation partners in karyotypically normal cells and compared their physical proximity with the clinically observed frequencies of translocation. They found that MYC was separated from its 2 most frequent translocation partners, IgH and IgL, by 40.7% and 41.0% of the nuclear diameter, respectively, whereas its separation from its rare translocation partner, IgK, was 47.1%. This last value was similar to that observed for a negative control locus, TGFBR2 (190182), which had never been reported to translocate with MYC; its mean separation was 49.4% of the nuclear diameter.
Liu et al. (2005) analyzed the putative promoter regions (PPRs) of 333 Ig genes to determine their CpG island content. CpG islands are regions of about 200 bp rich in CpG dinucleotides that are typically associated with housekeeping genes. Liu et al. (2005) noted that IGK light chain genes are located on the plus and minus strands of chromosome 2, IGH heavy chain genes are located on the minus strand only of chromosome 14, and IGL light chain genes are located on the plus strand only of chromosome 22. They found that none of the joining region genes have CpG islands in their PPRs. While IGKC (147200) and 6 of 11 IGHC constant region genes have CpG islands, none of the 7 IGLC constant region genes have CpG islands. Among Ig variable region genes, the frequency of CpG islands is somewhat greater for the heavy chain genes on chromosome 14 than for the light chain genes on chromosomes 2 and 22. Compared with non-Ig genes on chromosome 22, a CpG-rich chromosome, Ig genes are significantly less likely to have CpG islands and significantly more likely to have less-dense CpG islands. Liu et al. (2005) concluded that the occurrence of CpG islands in the PPRs of human and mouse Ig genes is nonrandom and nonneutral.
Using FISH and activated nonhomologous end joining-deficient mouse splenic B cells, Wang et al. (2009) observed an accumulation of V(D)J recombination-associated breaks at the Igl locus, as well as class switch recombination-associated Igh breaks, often in the same cell. The Igl and Igh breaks frequently joined to form translocations, a phenomenon associated with specific Igh-Igl colocalization. Igh and Myc also colocalized in these cells, and the introduction of frequent Myc double-strand breaks robustly promoted Igh-Myc translocations.
Pseudogenes
Hollis et al. (1982) postulated the existence of 'processed genes': gene-like sequences that, as opposed to their normal counterparts, bear some evidence of RNA-type processing, e.g., coincident homology to the site of transcriptional initiation, clean loss of intervening sequences, or coincident homology to the site of poly(A) tail. Hollis et al. (1982) described a pseudogene of the human lambda immunoglobulin chain that fulfills these expectations. Lambda-psi-1, as they termed it, is thought not to be on chromosome 22 and the J and C regions, rather than being discontinuous, are cleanly joined in accordance with the rules of RNA splicing. Furthermore, the homology of the pseudogene to the normal gene ends abruptly in a long sequence of adenylic acid residues that resembles a poly(A) tail. The association of gene movement and precise splicing suggested to them that an RNA intermediate may have been involved in the formation of the novel gene as well as in its conveyance to a new location. Pseudogenes of the alpha-globin genes in the mouse show the same phenomenon.
Croce, C. M. Personal Communication. Philadelphia, Pa. 4/6/1984.
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Leder, P. Personal Communication. Boston, Mass. 1/16/1982.
Lenoir, G. Personal Communication. Lyon, France 1981.
Liu, G. B., Yan, H., Jiang, Y. F., Chen, R., Pettigrew, J. D., Zhao, K.-N. The properties of CpG islands in the putative promoter regions of human immunoglobulin (Ig) genes. Gene 358: 127-138, 2005. [PubMed: 16112518] [Full Text: https://doi.org/10.1016/j.gene.2005.06.002]
McBride, O. W., Hieter, P. A., Hollis, G. F., Swan, D., Otey, M. C., Leder, P. Chromosomal location of human kappa and lambda immunoglobulin light chain constant region genes. J. Exp. Med. 155: 1480-1490, 1982. [PubMed: 6802926] [Full Text: https://doi.org/10.1084/jem.155.5.1480]
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Selden, J. R., Emanuel, B. S., Wang, E., Cannizzaro, L., Palumbo, A., Erikson, J., Nowell, P. C., Rovera, G., Croce, C. M. Amplified C-lambda and c-abl genes are on the same marker chromosome in K562 leukemia cells. Proc. Nat. Acad. Sci. 80: 7289-7292, 1983. [PubMed: 6580644] [Full Text: https://doi.org/10.1073/pnas.80.23.7289]
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Wang, J. H., Gostissa, M., Yan, C. T., Goff, P., Hickernell, T., Hansen, E., Difilippantonio, S., Wesemann, D. R., Zarrin, A. A., Rajewsky, K., Nussenzweig, A., Alt, F. W. Mechanisms promoting translocations in editing and switching peripheral B cells. Nature 460: 231-236, 2009. [PubMed: 19587764] [Full Text: https://doi.org/10.1038/nature08159]