Alternative titles; symbols
HGNC Approved Gene Symbol: IGLL1
Cytogenetic location: 22q11.23 Genomic coordinates (GRCh38): 22:23,573,125-23,580,290 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q11.23 | Agammaglobulinemia 2 | 613500 | Autosomal recessive | 3 |
The VPREB (605141) and IGLL1 (lambda-5) genes encode the iota and omega polypeptide chains, respectively (Pillai and Baltimore, 1988), which associate with the immunoglobulin (Ig) mu chain to form a molecular complex that is expressed on the surface of pre-B cells. This complex presumably regulates Ig gene rearrangements in the early steps of B-cell differentiation.
In the mouse, the VpreB and lambda-5 genes are simultaneously expressed in pre-B cells, are only 4.6 kb apart, and belong to the same transcription unit. A primary transcript is synthesized from which the pre-B and lambda-5 mRNAs are derived by alternative splicing. In the human, however, Mattei et al. (1991) concluded that the 2 genes, designated VPREB1 and IGLL1, are separate.
Schiff et al. (1989) isolated clones from a human fetal liver cDNA library that were only 85% homologous to the functional C-lambda genes (IGLC; 147220) and showed that they represent additional nonallelic members of a C-lambda-like family. Using pulsed field gel electrophoresis, the genes were shown to be present on a 200-kb DNA fragment, distinct from the C-lambda cluster. A splicing event accounted for differences between the 2 cDNAs.
By in situ hybridization, Mattei et al. (1991) demonstrated that the pre-B-specific lambda-like cluster is located in the 22q11.2-q12.3 region, distal to the IgC lambda locus.
Pseudogene
Linnebank et al. (2002) stated that a gene on 22q11.2 thought to represent a pseudogene of the argininosuccinate lyase gene (ASL; 608310) on 7cen-q11.2 may in fact be a gene coding for immunoglobulin-lambda-like mRNA.
B-cell precursors transiently express a pre-B cell receptor complex consisting of a rearranged mu heavy chain, a surrogate light chain composed of lambda-5/14.1 and VpreB, and the immunoglobulin-associated signal transducing chains, Ig-alpha and Ig-beta (Minegishi et al., 1998).
In a boy with agammaglobulinemia and markedly reduced numbers of B cells (AGM2; 613500), Minegishi et al. (1998) identified mutations on both alleles of the gene encoding lambda-5/14.1 (146770.0001; 146770.0002). The maternal allele carried a premature stop codon in the first exon of the gene and the paternal allele demonstrated 3-bp substitutions in a 33-bp sequence in exon 3. The 3 substitutions corresponded to the sequence in the lambda-5/14.1 pseudogene 16.1 and resulted in an amino acid substitution at an invariant proline. When expressed in COS cells, the allele carrying the pseudogene sequence resulted in defective folding and secretion of mutant lambda-5/14.1. These findings indicated that expression of the functional lambda-5/14.1 is critical for B-cell development in the human.
Moens et al. (2014) used a sequencing capture assay together with Illumina sequencing and CNV analysis to identify the disease-causing mutation across 179 known primary immunodeficiency genes in 33 patients with primary immunodeficiency. Eighteen of the patients already had at least one known causal mutation, and the authors resolved the mutation status for 12 of 16 individuals. Two sisters (EGS539 and EGS540) who were deficient in B cells were found to be homozygous for a deletion (c.258delG; 146770.0003) in the IGLL1 gene. Their parents were heterozygous for the mutation.
In a boy with agammaglobulinemia and markedly reduced numbers of B cells (AGM2; 613500), Minegishi et al. (1998) identified compound heterozygosity for 2 mutations in the IGLL1 gene: on 1 allele, a C-to-T transition at codon 22 of exon 1, resulting in a gln22-to-ter (Q22X) substitution; on the other allele, 3 basepair substitutions, T-to-C at nucleotide 393 (codon 131), T-to-C at nucleotide 420 (codon 140), and C-to-T at nucleotide 425 (codon 142). The first 2 substitutions did not change the coding sequence; however, the third resulted in replacement of the wildtype proline with leucine (P142L; 146770.0002). The proline at this site, which occurs in the loop linking the second and third strands of 1 of the 2 beta pleated sheets that compose the immunoglobulin domain, is conserved not only in lambda constant region domains in all species evaluated, but also in most immunoglobulin domains. The 3 substitutions corresponded to the sequence in a lambda-5 pseudogene. When expressed in COS cells, the allele carrying the pseudogene sequence resulted in defective folding and secretion of mutant lambda-5/14.1.
For discussion of the pro142-to-leu (P142L) mutation in the IGLL1 gene that was found in compound heterozygous state in a patient with agammaglobulinemia and markedly reduced numbers of B cells (AGM2; 613500) by Minegishi et al. (1998), see 146770.0001.
In 2 sisters (EGS539 and EGS540) with reduced B lymphocytes and increased susceptibility to bacterial infections (AGM2; 613500), Moens et al. (2014) found homozygosity for a single nucleotide deletion (c.258delG) resulting in a frameshift at codon 86 (Gly86fs). They confirmed the mutation by Sanger sequencing and identified it in heterozygosity in the unaffected parents.
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Linnebank, M., Tschiedel, E., Haberle, J., Linnebank, A., Willenbring, H., Kleijer, W. J., Koch, H. G. Argininosuccinate lyase (ASL) deficiency: mutation analysis in 27 patients and a completed structure of the human ASL gene. Hum. Genet. 111: 350-359, 2002. [PubMed: 12384776] [Full Text: https://doi.org/10.1007/s00439-002-0793-4]
Mattei, M.-G., Fumoux, F., Roeckel, N., Fougereau, M., Schiff, C. The human pre-B-specific lambda-like cluster is located in the 22q11.2-22q12.3 region, distal to the IgC-lambda locus. Genomics 9: 544-546, 1991. [PubMed: 1903358] [Full Text: https://doi.org/10.1016/0888-7543(91)90422-b]
Minegishi, Y., Coustan-Smith, E., Wang, Y.-H., Cooper, M. D., Campana, D., Conley, M. E. Mutations in the human lambda-5/14.1 gene result in B cell deficiency and agammaglobulinemia. J. Exp. Med. 187: 71-77, 1998. [PubMed: 9419212] [Full Text: https://doi.org/10.1084/jem.187.1.71]
Moens, L. N., Falk-Sorqvist, E., Asplund, A. C., Bernatowska, E., Smith, C. I. E., Nilsson, M. Diagnostics of primary immunodeficiency diseases: a sequencing capture approach. PLoS One 9: e114901, 2014. Note: Electronic Article. [PubMed: 25502423] [Full Text: https://doi.org/10.1371/journal.pone.0114901]
Pillai, S., Baltimore, D. The omega and iota surrogate immunoglobulin light chains. Curr. Top. Microbiol. Immun. 137: 136-139, 1988. [PubMed: 3138073] [Full Text: https://doi.org/10.1007/978-3-642-50059-6_20]
Sakaguchi, N., Melchers, F. Lambda 5, a new light-chain-related locus selectively expressed in pre-B lymphocytes. Nature 324: 579-582, 1986. [PubMed: 3024017] [Full Text: https://doi.org/10.1038/324579a0]
Schiff, C., Milili, M., Fougereau, M. Isolation of early immunoglobulin lambda-like gene transcripts in human fetal liver. Europ. J. Immun. 19: 1873-1878, 1989. [PubMed: 2511029] [Full Text: https://doi.org/10.1002/eji.1830191018]