Mutations in specific structural regions of immunoglobulin light chains are associated with free light chain levels in patients with AL amyloidosis

Tanya L. Poshusta, Laura A. Sikkink, Nelson Leung, Raynell J. Clark, Angela Dispenzieri, Marina Ramirez-Alvarado

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

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. Methodology/Principal Findings: We performed sequence alignments on the variable domain of 50 κ and 91 λ 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.

Original languageEnglish (US)
Article numbere5169
JournalPLoS One
Volume4
Issue number4
DOIs
StatePublished - Apr 13 2009

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immunoglobulin light chains
Immunoglobulin Light Chains
amyloidosis
Amyloidosis
amyloid
Amyloid
mutation
Light
Mutation
Proteostasis Deficiencies
tissue degeneration
somatic mutation
Sequence Alignment
Amyloid Plaques
sequence alignment
Cell death
immunoglobulins
Immunoglobulins
cell death
Proteins

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Mutations in specific structural regions of immunoglobulin light chains are associated with free light chain levels in patients with AL amyloidosis. / Poshusta, Tanya L.; Sikkink, Laura A.; Leung, Nelson; Clark, Raynell J.; Dispenzieri, Angela; Ramirez-Alvarado, Marina.

In: PLoS One, Vol. 4, No. 4, e5169, 13.04.2009.

Research output: Contribution to journalArticle

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AU - Dispenzieri, Angela

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