AL-Base: a visual platform analysis tool for the study of amyloidogenic immunoglobulin light chain sequences

Abstract

AL-Base, a curated database of human immunoglobulin (Ig) light chain (LC) sequences derived from patients with AL amyloidosis and controls, is described, along with a collection of analytical and graphic tools designed to facilitate their analysis. AL-Base is designed to compile and analyse amyloidogenic Ig LC sequences and to compare their predicted protein sequence and structure to non-amyloidogenic LC sequences. Currently, the database contains over 3000 de-identified LC nucleotide and amino acid sequences, of which 433 encode monoclonal proteins that were reported to form fibrillar deposits in AL patients. Each sequence is categorised according to germline gene usage, clinical status and sample source. Currently, tools are available to search for sequences by various criteria, to analyse the biochemical properties of the predicted amino acids at each position and to display the results in a graphical fashion. The likelihood that each sequence has evolved through somatic hypermutation can be predicted using an automated binomial or multinomial distribution model. AL-Base is available to the scientific community for research purposes.

Clarifying immunoglobulin gene usage in systemic and localized immunoglobulin light-chain amyloidosis by mass spectrometry

“…Figure 3 provides a comparison between our results and those that have been published in the literature, [6][7][8][9] and those that can be found in AL Base. 21 Of the 29 to 33 functional IGV l genes and the 31 to 36 functional IGV k genes in the human genomic repertoire, consistent with previous publications, LV6-57 is the most common IGVL gene identified among patients with ALs. 8,22 Approximately half of the light-chain variable gene repertoire in AL S is comprised of LV6-57, LV3-01, and LV2-14 genes and the KV1 family (particularly KV1-33).…”

“…Not only are these genes the most commonly observed in AL S , but they and their gene families are also conspicuously more common in AL S than in the normal B-repertoire. 21,23,24 In contrast, the distribution of IGVL genes and families for patients with AL L was very similar to that seen in the normal B-cell repertoire, with LV6 found less commonly and the KV3 family (and the KV3-20 gene in particular) more commonly. 8 The potential mechanisms underlying the differences between IGVL gene usage in AL S, AL L , nonamyloidogenic plasma cell dyscrasias, and normal controls are not clear.…”

“…Data for the prior ALs series are pooled from references 6-9,18 and data for both the other plasma cell dyscrasias and normal B cells are derived from AL Base. 21 specimens. We show for the first time that IGVL gene and family repertoire is different between AL S and AL L .…”

Mutational and genetic determinants of λ6 light chain amyloidogenesis

“…Gly25 has been mistaken for a somatic mutation [11,17]; however, available data suggest that it is actually an allotypic variant of the IGLV6-57 locus. The alleles C/G determining the variation Arg/Gly are identified in the dbSNP database by the reference single-nucleotide polymorphism (SNP) ID number rs2073447 (http:// www.ncbi.nlm.nih.gov/projects/SNP/).…”

“…The use of V L gene segments also appears to be an important factor in the potential of light chains to aggregate as amyloid fibrils, as evidenced by the bias of kappa and lambda V L gene segments expressed in AL amyloidosis [7][8][9][10]. A small set of V L gene segments [IGLV6-57 (6a), IGLV1-44 (1c), IGLV2-14 (2a2), IGLV3-1 (3r) and IGKV1-33 (018)], which comprise approximately 7% of all V L functional segments, accounts for approximately 70% of the entire set of AL light chains reported in the AL-BASE [11]. Among these segments, gene segment IGLV6-57, the only member of the k6 subgroup, is the most strongly associated with AL [12].…”