Mutations in specific structural regions of immunoglobulin light chains are associated with free light chain levels in patients with AL amyloidosis.
BACKGROUND
The amyloidoses are protein misfolding diseases characterized by the deposition of amyloid that leads to cell death and tissue degeneration. In immunoglobulin light chain amyloidosis (AL), each patient has a unique monoclonal immunoglobulin light chain (LC) that forms amyloid deposits. Somatic mutations in AL LCs make these proteins less thermodynamically stable than their non-amyloidogenic counterparts, leading to misfolding and ultimately the formation of amyloid fibrils. We hypothesize that location rather than number of non-conservative mutations determines the amyloidogenicity of light chains.


RESULTS
We performed sequence alignments on the variable domain of 50 kappa and 91 lambda AL light chains and calculated the number of non-conservative mutations over total number of patients for each secondary structure element in order to identify regions that accumulate non-conservative mutations. Among patients with AL, the levels of circulating immunoglobulin free light chain varies greatly, but even patients with very low levels can have very advanced amyloid deposition.


CONCLUSIONS
Our results show that in specific secondary structure elements, there are significant differences in the number of non-conservative mutations between normal and AL sequences. AL sequences from patients with different levels of secreted light chain have distinct differences in the location of non-conservative mutations, suggesting that for patients with very low levels of light chains and advanced amyloid deposition, the location of non-conservative mutations rather than the amount of free light chain in circulation may determine the amyloidogenic propensity of light chains.
Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.
Tanya L
TL
Poshusta
Laura A
LA
Sikkink
Nelson
N
Leung
Raynell J
RJ
Clark
Angela
A
Dispenzieri
Marina
M
Ramirez-Alvarado
D000595:Amino Acid Sequence; D000686:Amyloidosis / Q000235:genetics* / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007147:Immunoglobulin Light Chains / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009101:Multiple Myeloma / Q000235:genetics / Q000276:immunology; D009154:Mutation; D017433:Protein Structure, Secondary; D016415:Sequence Alignment
D007147:Immunoglobulin Light Chains