Role of the Location of Mutations in Light Chain Amyloidosis
Amyloid light chain (AL) amyloidosis is characterized by the abnormal proliferation of monoclonal plasma B cells, which secrete monoclonal immunoglobulin light chains. B cell development involves the rearrangement of immunoglobulin (Ig) gene segments, conferring on each mature B cell a unique combination of one heavy and one light chain variable region gene (VH and VL) that subsequently may undergo somatic hypermutation in the germinal centers of lymph nodes. VH and VL genes associated with AL amyloidosis display evidence of hypermutation, adding further support that AL clones derive from post-germinal center B cells.
The secreted monoclonal AL light chains misfold and deposit as amyloid fibrils in vital organs leading to organ failure and death. There are two VL gene subtypes, λ and κ. There is a preponderance of L versus κ in light chain genes associated with AL (λ:κ= 3:1) compared with normal individuals (λ: κ =1:2). According to research done by several groups, the most commonly used germline donor sequences in AL patients are λ6a, λ3r, λ2 and λ1. Our analyses have shown that the location of the mutation, not the number of mutations, is the most important characteristic for AL amyloidosis proteins.