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

Poshusta TL, Sikkink LA, Leung N, Clark RJ, Dispenzieri A, Ramirez-Alvarado M - PLoS ONE (2009)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.

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 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.

Show MeSH

Related in: MedlinePlus

Structural models showing the common locations of non-conservative mutations in ALVλ proteins in our study.Protein models were based on the crystal structure for Vλ VI germline (2CDO.pdb). The β-strands in the structure are shown as red ribbons; mutation regions discussed in the captions are shown in green.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2664898&req=5

pone-0005169-g004: Structural models showing the common locations of non-conservative mutations in ALVλ proteins in our study.Protein models were based on the crystal structure for Vλ VI germline (2CDO.pdb). The β-strands in the structure are shown as red ribbons; mutation regions discussed in the captions are shown in green.

Mentions: Because Vλ VI sequences are virtually always found in amyloid producing clones, the ratio of non-conservative mutations over total number of patients for Vλ VI versus VλI, II and III was analyzed (Figure 2C). The overall pattern for the Vλ I, II, and III proteins follows the same trends as the total Vλ group of sequences in Figure 2B. The Multiple Myeloma sequences follow the trend of the normal Vκ for the most part (Figure 3 and Figure S11). The Vλ VI proteins accumulate non-conservative mutations in loop C–C′ (part of CDR2) with 83% of patients with mutations in this region and presenting an absence of non-conservative mutations in loop A–B and loop D–E (structural representation of differences in Vλ is shown in Figure 4). High numbers of non-conservative mutations are found in β-strands A and G in all Vλ proteins; β-strand G has more non-conservative mutations in Vλ VI sequences. All of the control sequences show comparable levels of non-conservative mutations among each other.


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

Poshusta TL, Sikkink LA, Leung N, Clark RJ, Dispenzieri A, Ramirez-Alvarado M - PLoS ONE (2009)

Structural models showing the common locations of non-conservative mutations in ALVλ proteins in our study.Protein models were based on the crystal structure for Vλ VI germline (2CDO.pdb). The β-strands in the structure are shown as red ribbons; mutation regions discussed in the captions are shown in green.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2664898&req=5

pone-0005169-g004: Structural models showing the common locations of non-conservative mutations in ALVλ proteins in our study.Protein models were based on the crystal structure for Vλ VI germline (2CDO.pdb). The β-strands in the structure are shown as red ribbons; mutation regions discussed in the captions are shown in green.
Mentions: Because Vλ VI sequences are virtually always found in amyloid producing clones, the ratio of non-conservative mutations over total number of patients for Vλ VI versus VλI, II and III was analyzed (Figure 2C). The overall pattern for the Vλ I, II, and III proteins follows the same trends as the total Vλ group of sequences in Figure 2B. The Multiple Myeloma sequences follow the trend of the normal Vκ for the most part (Figure 3 and Figure S11). The Vλ VI proteins accumulate non-conservative mutations in loop C–C′ (part of CDR2) with 83% of patients with mutations in this region and presenting an absence of non-conservative mutations in loop A–B and loop D–E (structural representation of differences in Vλ is shown in Figure 4). High numbers of non-conservative mutations are found in β-strands A and G in all Vλ proteins; β-strand G has more non-conservative mutations in Vλ VI sequences. All of the control sequences show comparable levels of non-conservative mutations among each other.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, College of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America.

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 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.

Show MeSH
Related in: MedlinePlus